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International Lung Cancer Congress

Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick

By Peter P. Yu, MD, FASCO, as told to Jo Cavallo

tereotactic body radiation therapy (SBRT) is safe and effective in early-stage non–small cell lung cancer (NSCLC), as it confers local control in 90% or more patients with T1 disease, according to Roy Decker, MD, PhD, Associate Professor in the Department of Therapeutic Radiology at Yale Cancer Center, New Haven, Connecticut. Dr. Decker described the use of SBRT in high-risk early-stage NSCLC patients at the 15th Annual International Lung Cancer Congress in Huntington Beach, California. “In high-risk patients, SBRT appears to offer approximately equivalent control and survival when compared to surgical resection, in retrospective series,” he said. “I can say that SBRT is approximately as good as surgery.”

Transformative Study Dr. Decker said that a multidisciplinary approach is always ideal. “Our guidelines state that all patients hav-

ing SBRT who are at high risk should be evaluated by an experienced thoracic surgeon for minimally invasive surgery,” he said. “I never call a patient ‘inoperable’ without that consultation.” However, results with stereotactic body radioRoy Decker, MD, PhD therapy are essentially equivalent to surgery, and may be preferred over surgery for some patients. The technique has been used in practice for 2 decades, and based on mature prospective trial data, the appropriate and inappropriate candidates for SBRT can now be identified, he said. Several important studies have informed current SBRT practice in the United States. A number of years ago, phase II studies suggested that the failure pattern

am honored and privileged to lead ASCO during its 51st year, a year that promises to bring both challenges and opportunities to our members and our patients. As the theme for my Presidential term, I’ve chosen Illumination and Innovation: Transforming Data Into Learning, because we are positioned to reap the benefits of the accelerating transformation of data into knowledge. Now, we have to take the next step by applying that knowledge and learning how to move our healthcare delivery and research systems forward. Although we have generated more effective therapies in the treatment of cancer through the knowledge we have gained in clinical trials, we have not always focused as much attention on how to apply that knowledge to individual continued on page 102

continued on page 9

Issues in Oncology

Oncology Practice: What Are the Factors Driving Change?

Dr. Yu is President of the American Society of Clinical Oncology for 2014–2015 and Director of Cancer Research at Palo Alto Medical Foundation in California.

MORE IN THIS ISSUE

By Caroline McNeil

My Priorities for the Year Ahead

such biomarker, the mutated KRAS gene in colorectal cancer. They identified three events that might have influenced physicians to stop prescribing cetuximab (Erbitux) and panitumumab (Vectibix) for patients whose tumors have a mutation, once conclusive data emerged showing that the targeted drugs were not effective in these patients. The events were public reporting of the data, publication These results suggest the attentiveness of new guidelines, and a U.S. Food and Drug Adof the oncologic community to clinical ministration (FDA) label change. The study showed presentations at national meetings and that all three—especially ASCO guidance…. It is also evidence the FDA action—were followed by significant changthat oncologists change their practice es in practice. promptly in the face of highly publicized The authors, led by Efrat Dotan, MD, Asdata, even years after a drug’s approval. sistant Professor at Fox —Efrat Dotan, MD

linical practice changes in response to new medical evidence, but not always immediately or all at once. So what else determines whether and how quickly practice changes in response to evidence, for instance, that a widely used drug is effective only in patients with a certain biomarker? In a new study,1 researchers looked at the case of one

Oncology Meetings Coverage Pan Pacific Lymphoma Conference ��3, 4, 41 International Lung Cancer Congress ��6 New Orleans Cancer Meeting �� 12, 19 ASPHO Annual Meeting �� 37, 38 Debates and Didactics in Hem/Onc �� 62 Hugo F. Fernandez, MD, on AML ��20 Alok A. Khorana, MD, on CRC ��30 Direct From ASCO �� 46–49 Jacek Jassem, MD, PhD, on NSCLC ��57 In Memoriam: Jesse L. Steinfeld, MD and Emanuel Farber, MD, PhD �� 106

continued on page 86

September Is Ovarian and Prostate Cancers Awareness Month

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Pan Pacific Lymphoma Conference Hematology

International Group Updates Recommendations on Managing Lymphoma By Susan London

n international multidisciplinary group of experts has updated their recommendations for staging and treatment response assessment in patients with Hodgkin and non-Hodgkin lymphomas. Bruce D. Cheson, MD, Professor of Medicine, Deputy Chief of Hematology-Oncology, and Head of Hematology at the Georgetown University Hospital’s Lombardi Cancer Center in Washington, DC, presented some highlights at the Pan Pacific Lymphoma Conference; the recommendations were published in their entirety in August.1

Clearer, Simpler, More Practical Guidance The recommendations, last revised in 2007,2 are now called the Lugano Classification as they arose out of a workshop held in Lugano, Switzerland. “This will be a substantial change in how clinicians practice,” Dr. Cheson predicted in an interview. The update entailed “taking the initiative to reject some of the ways we did things in the past to try and make these new staging and response criteria more contemporary and to reflect how we actually manage patients today.” “These recommendations will hopefully be adopted as widely as those in the past and will serve the patients better, particularly with the elimination of some unnecessary procedures; will serve the clinical research community better because these are hopefully clearer than past recommendations, and the regulatory agencies because they will now have standardized, internationally accepted staging as well as response criteria; and will better serve the pharmaceutical industry, which has always had some questions about how to interpret one thing or another,” he commented. “We have modified both staging and response criteria to make them more relevant to how we currently practice hematology-oncology,” Dr. Cheson noted (see Table 1 for highlights). “We have done our best to eliminate various procedures and tests that are not necessary and may be onerous to the patient, where possible. We have clarified how you interpret response to make it easier to understand and use, and to compare study vs study. And we have better defined how to use and how to interpret positron-emission tomography (PET) scans, when to use

We have modified both staging and response criteria to make them more relevant to how we currently practice hematology-oncology. —Bruce D. Cheson, MD

them, when not to use them.” Dr. Cheson said that he expected the National Comprehensive Cancer Network (NCCN) will incorporate the new recommendations into their guidelines, which some insurers use when making coverage decisions. “The last version [in 2007] was adopted by the NCCN guidelines, so I am fairly certain that this version will be as well,” he said.

Staging Recommendations In the area of staging, “we have updated the staging criteria for lymphoma, incorporating for the first time PET for those histologies of lymphoma that are fluorodeoxyglucose (FDG)-avid,” Dr. Cheson explained. Although hematologists often obtained these scans before treatment in the past, they were not formally used in staging. The updated recommendations have eliminated the need for routine chest xrays as all patients now undergo computed tomography. Additionally, “we eliminated the need for the dreaded bone marrow biopsy in patients with Hodgkin lymphoma and most patients with diffuse large B-cell lymphoma because the PET scan will be a better predictor of bone marrow involvement than a simple random bone marrow biopsy. The bone marrow biopsy is a vestige of the past—patients came in and we did things reflexively, we staged them with a bone marrow biopsy,” but PET now provides the same information much less invasively. Staging terminology has been streamlined by eliminating use of the terms A and B for non-Hodgkin lymphoma and use of X to denote bulky disease, and by recommending a switch from the 1, 2, 3, and 4 numerical staging system (the Ann Arbor classification) to a simple dichotomous one of limited disease and advanced disease, reflecting how hematologists have typically grouped patients for treatment in real-world practice.

Response Assessment Recommendations For assessing treatment response, the recommendations endorse use of the 5-point Deauville scale that has been internationally validated as a means of standardization. “The scale has been coming into use slowly but has not been widely recognized because people have

not been informed about it,” Dr. Cheson commented. “Now it’s going to be the way for the foreseeable future to interpret PET scans so that how one person interprets the scan will be more likely the way another person does. There used to be considerable interobserver or interinterpreter variability.” The recommendations also outline new definitions of complete response, partial response, and progressive disease. In particular, “a patient can get a complete response in the presence of a mass as long as the mass is no longer avid, and progressive disease can now be determined on the basis of a single node,” he noted. Finally, “we also made recommendations on management of patients posttreatment, how best to follow patients, continued on page 4

Table 1: Highlights of the Updated Recommendations Staging • 18F-FDG PET-CT is formally incorporated into standard staging for FDG-avid lymphomas. PET-CT is the standard for FDG-avid lymphomas, whereas CT is indicated for nonavid histologies. • A modification of the Ann Arbor descriptive terminology is recommended for use for the anatomic distribution of disease extent. The A and B suffixes for symptoms will be included only for HL. • The designation X for bulky disease is no longer necessary; instead, the largest tumor diameter should be reported. • If PET-CT is performed, bone marrow biopsy is no longer indicated for routine staging of HL and most DLBCLs. Bone marrow biopsy is needed only for diffuse large B-cell lymphoma if PET is negative and if identifying discordant histology is important for patient management. • Regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky) or advanced (stage III or IV) disease; stage II bulky disease is considered as limited or advanced based on histology and prognostic factors. Response Assessment • PET-CT is to be used to assess response in FDG-avid histologies using the 5-point scale; CT is preferred for low or variable FDG avidity. • A complete metabolic response is considered a complete remission even with a persistent mass. • Partial response requires a decrease by > 50% in the sum of the product of the perpendicular diameters of up to six representative nodes or extranodal lesions. • Progressive disease on CT criteria requires only an increase in the perpendicular diameters of a single node by ≥ 50%. • Surveillance scans after remission are discouraged, particularly for DLBCL and HL; repeat scans may be considered in cases of equivocal findings after treatment. Judicious use of follow-up scans can be considered in indolent lymphomas with residual intra-abdominal or retroperitoneal disease. CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; FDG = fluorodeoxyglucose; HL = Hodgkin lymphoma; PET = positron-emission tomography.

The ASCO Post | SEPTEMBER 1, 2014

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Pan Pacific Lymphoma Conference Hematology

Jury Still Out on Interim PET for Response-Adapted Therapy in Hodgkin Lymphoma By Susan London

nterim positron-emission tomography (PET) scans provide good prognostic information in patients with Hodgkin lymphoma, but more research is needed to determine whether patients benefit when the findings are used to alter treatment, according to Oliver Press, MD, PhD, Professor at the University of Washington School of Medicine and Chair of Lymphoma Research at the Fred Hutchinson Cancer Research Center, both in Seattle. Interim PET—performed during induction therapy, after one to four cycles of treatment—remains a hotbutton issue, he told attendees of the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii. “There are some very strong but diametrically opposed views that people in this room have about this topic,” he said.

Use for Prognostication Studies have validated the prognostic value of interim PET in this setting. For example, a pooled analysis found that the PET result after two cycles of chemotherapy was highly predictive of progression-free survival in patients with advanced disease.1 “Using this very powerful prognostic tool, other prognostic factors really weren’t very relevant, including the international prognostic score … after adjusting for the PET scan results,” Dr. Press noted. A retrospective study comparing visual inspection of PET scans with the 5-point Deauville scale with a change in maximal standardized uptake value cutoff of 70% suggests that the latter may yield better discrimination.2 “This is probably the way the field is moving,” he said. “But the consensus is that we are not quite ready yet to move away from the visual scale, that we really need larger studies and prospective studies. And most importantly, this requires really tight standardization in how the scans are done.”

Updated Recommendations continued from page 3

where imaging fits in, where it doesn’t fit in, and those sorts of issues,” Dr. Cheson said. n Disclosure: Dr. Cheson has served in a

Response-Adapted Therapy in Early-Stage Disease At least eight trials are studying the use of interim PET for responseadapted therapy in early-stage Hodgkin lymphoma, according to Dr. Press. In one trial, patients were randomized after two cycles of chemotherapy to standard therapy or to PET response-adapted therapy.3 The respective 1-year rates of progressionfree survival were 100% and 94% among patients with favorable disease and 97.3% and 94.7% among patients with unfavorable disease. The data safety monitoring com-

ings.4 Among PET-negative patients, the 3-year rate of progression-free survival was 94.5% with radiation therapy and 90.8% without it—a nonsignificant difference in intentto-treat analysis. However, these investigators concluded that “excellent outcomes” were possible without radiation therapy. “These were obviously two trials with similar results and opposite conclusions about interim PET and its role, and the role of radiation therapy. So the jury is out, I would say, on early-stage disease and interim PET,” Dr. Press commented.

The prognostic value of interim PET imaging is not very controversial—it’s a great tool for determining which patients are going to do well with their treatment and which aren’t. But whether outcomes are improved by changing treatment based on the interim PET scan results remains controversial. —Oliver Press, MD, PhD

mittee concluded that response-adapted therapy was unlikely to meet noninferiority criteria and halted the trial. It also concluded that PET did not meet the goal of identifying patients who did not need radiation therapy. “This was a very controversial study and very controversial decision by the data safety monitoring board. It led to a lot of debate,” Dr. Press noted. “A lot of people feel that they made this decision too soon, that progression-free survival is not the right endpoint, that overall survival is most important. And a lot of people felt the trial should stay open.” A second trial in which patients underwent PET after three cycles of chemotherapy had similar findconsultant or advisory role for Gilead, Celgene, Genentech, Pharmacyclics, AstraZeneca, and Spectrum. He has received honoraria from Gilead, Celgene, Genentech, and Pharmacyclics, and other remuneration from Gilead, Celgene, Genentech, and Pharmacyclics. For full

Use in Advanced-Stage Disease Many trials are also evaluating the use of interim PET to guide therapy in advanced-stage Hodgkin lymphoma. In the Southwest Oncology Group (SWOG) S0816 trial, patients have a PET scan after two cycles of chemotherapy; those with negative results are given standard therapy and those with positive results are given escalated therapy.5 Recently updated findings, with median follow-up of about 28 months, show that 2-year progression-free survival is 62% in PET-positive patients and 82% in PET-negative patients. “Everybody would probably agree that the results look promising for disclosure of all study authors, visit JCO.org.

References 1. Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging and response assessment of

the PET-positive patients,” Dr. Press commented, “but people might argue about whether the 82% progressionfree survival is good enough in the PET-negative patients.” Although results thus far suggest a benefit of switching to escalated therapy in the PET-positive group, “we really do need truly randomized studies to definitely prove the value of this response-adapted approach, and we need longer follow-up on this trial,” he said. A similar trial undertaken in Europe also found that PET-positive patients switched to escalated therapy had a 1-year failure-free survival rate of 76.5%, and PET-negative patients who continued on standard therapy had a rate of 96.2%.6

Putting It All Together “The prognostic value of interim PET imaging is not very controversial—it’s a great tool for determining which patients are going to do well with their treatment and which aren’t. But whether changing your treatment based on what the interim PET scan shows improves outcomes remains at least somewhat controversial,” Dr. Press concluded. At present, the National Comprehensive Cancer Network endorses PET response-adapted therapy in Hodgkin lymphoma.7 “So they have embraced the preliminary results very firmly,” he said. “I agree that it seems promising, but this does seem to be just a little bit out ahead of the data. Many people want the truly randomized studies, where half the patients get standard treatment, half the patients get a response-adapted treatment, and then you compare the outcomes and make the final decisions.” An international consensus group has developed a more reserved statement.8 The forthcoming statement finds a lack of conclusive evidence warranting a change in treatment based solely continued on page 5

Hodgkin and non-Hodgkin lymphoma— the Lugano Classification. J Clin Oncol. August 11, 2014 (early release online). 2. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-586, 2007.

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Pan Pacific Lymphoma Conference Interim PET Imaging continued from page 4

on the results of interim PET. “My tendency would be to agree with this consensus group,” Dr. Press concluded. n Disclosure: Dr. Press reported no potential conflicts of interest.

References 1. Gallamini A, Hutchings M, Rigacci L, et al: Early interim 2-[18F]fluoro2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: A report from a joint Italian-Danish study. J

Clin Oncol 25:3746-3752, 2007. 2. Rossi C, Kanoun S, Berriolo-Riedinger A, et al: Interim 18F-FDG PET SUVmax reduction is superior to visual analysis in predicting outcome early in Hodgkin lymphoma patients. J Nucl Med 55:569-573, 2014. 3. Raemaekers JM, André MP, Federico M, et al: Omitting radiotherapy in early positron emission tomographynegative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 32:1188-1194, 2014.

4. Radford J, Barrington S, Counsell N, et al: Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD: Results of the UK NCRI RAPID trial. 2012 ASH Annual Meeting. Abstract 547. Presented December 10, 2012. 5. Press OW, LeBlanc M, Rimsza LM, et al: A phase II trial of response-adapted therapy of stage III-IV Hodgkin lymphoma using early interim FDG-PET imaging: US Intergroup S0816. Hematol Oncol 31(suppl 1):Abstract 124, 2013. 6. Gallamini A, Tarella C, Patti C, et al: Multicentre clinical study with early treat-

ment intensification in high-risk Hodgkin Lymphoma (HL) patients with a positive FDG-PET scan after two ABVD courses: GITIL HD0607 study. Ann Oncol 22(suppl 4):O167, 2011. 7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Hodgkin Lymphoma, version 2.2014. Available at www.nccn.org/professionals/ physician_gls/pdf/hodgkins.pdf. Accessed August 12, 2014. 8. Barrington SF, Mikhaeel NG, Kostkoglu L, et al: Conclusion on interim PET/ CT from consensus conference (Lugano, Menton). J Clin Oncol. 2014. In press.

Journal Spotlight

Study Estimates Risk of Premature Menopause After Treatment for Hodgkin Lymphoma

revious research has suggested that women with Hodgkin lymphoma who receive certain types of chemotherapy or radiotherapy are at increased risk of future infertility, but there was insufficient information to provide patients with detailed advice. In a study published in the Journal of the National Cancer Institute, Swerdlow et al estimated the risk of premature menopause in women being treated for Hodgkin lymphoma.1 The findings are based on the experience of more than 2,000 young women in England and Wales over a period of more than 40 years. The new study, led by scientists at The Institute of Cancer Research, London, provides precise estimates of risk for women depending on which treatment types and doses they received and at what age, allowing doctors to give them detailed advice about their risks of future infertility.

Study Details The research team followed 2,127 women who had been treated for Hodgkin lymphoma in England and Wales at ages younger than 36 years from 1960 to 2004. All patients had received treatment with chest radiotherapy, sometimes alongside other treatments. Follow-up took place from 2008 through 2012. Some 605 of the women in the

study underwent nonsurgical menopause before the age of 40. This was a large enough number for the researchers to estimate accurate risks of menopause at different ages, depending on the mixture and doses of treatments they received and the age they received them.

Increases in Premature Menopause The researchers produced a risk table which could help improve the advice that clinicians are able to give to women who have undergone treatment for the disease. Several of the treatments caused a sharp increase in premature menopause risk. For example, a woman who had received six or more cycles of a standard chemotherapy regimen without pelvic radiotherapy in her late 20s had an approximately 18% chance of undergoing meno-

We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy. —Anthony Swerdlow, DSc

pause by the age of 30, or 58% by age 40. Overall, there was a 20-fold increased risk of premature menopause after ovarian radiotherapy and also after some specific chemotherapy regimens. Risk of menopause by age 40 was 81% after receiving ovarian radiotherapy of at least 5 Gy, and up to 75% after chemotherapy, depending on the type. There was no statistically increased risk associated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). “Hodgkin lymphoma often affects younger women, and although fortunately most survive the disease, treat-

Premature Menopause After Treatment for Hodgkin Lymphoma ■■ Women who received six or more cycles of a standard chemotherapy regimen without pelvic radiotherapy in their late 20s had an approximately 18% chance of undergoing menopause by the age of 30, or 58% by age 40. ■■ There was a 20-fold increased risk of premature menopause after ovarian radiotherapy and some chemotherapy regimens. ■■ The findings will allow doctors to provide patients with detailed advice about their risks of future infertility based on their treatment history.

ments including certain types of chemotherapy and pelvic radiotherapy can lead to premature menopause,” said study leader Anthony Swerdlow, DSc, of The Institute of Cancer Research, London. “We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy. By looking in a much larger group of women than previous studies of this type, we were able to produce ageand treatment-specific risk estimates that we hope will be of practical use to individual women. I’m extremely grateful to the patients and doctors who made it possible for us to produce this information.” n

Disclosure: The research was supported by Breakthrough Breast Cancer and the European Commission. For full disclosures for the study authors, visit jnci.oxfordjournals.org

Reference 1. Swerdlow AJ, Cooke R, Bates A, et al: Risk of premature menopause after treatment for Hodgkin’s lymphoma. J Natl Cancer Inst. August 2014 (early release online).

The ASCO Post | SEPTEMBER 1, 2014

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International Lung Cancer Congress Thoracic Oncology

Targeting KRAS Mutations in Lung Cancer: No Longer Impossible By Caroline Helwick

he KRAS mutation has long been considered “undruggable,” but new approaches in drug development may change this. The end result could be effective new treatment options for KRAS-mutated non–small cell lung cancer (NSCLC), according to David R. Gandara, MD, who described the emerging findings at the 15th Annual International Lung Cancer Congress in Huntington Beach, California. “The KRAS mutation story has evolved from what we thought we knew, to the controversies about what we don’t know,” said Dr. Gandara, Professor of Medicine and Director of the Thoracic Oncology Program at the University of California, Davis, Comprehensive Cancer Center in Sacramento.

Key Concepts Dr. Gandara described several key concepts regarding KRAS mutations: • KRAS mutations occur in approximately 25% of NSCLC tumors, compared to 39% of colorectal tumors. They are more likely to be transversions (78%) than transitions (22%), in contrast to colorectal cancer, where transitions are more common. This difference may explain the discordant response to treatment between the two tumor types. • There are many different KRAS mutation subtypes, some but not all of which are associated with cigarette smoking. • KRAS mutations in smokers may track together with other mutations, such as those in TP53 or Lkb1, which are tumor-suppressor genes. • KRAS mutations—at least de novo mutations—are typically mutually exclusive of epidermal growth factor receptor (EGFR)-activating mutations and ALK translocations, though this is sometimes not the case, especially with ALK-positive tumors that have been exposed to an ALK inhibitor. • There is an association between KRAS mutations and lack of response to EGFR tyrosine kinase inhibitors and chemotherapy, though the universality of this concept is now being questioned. • A number of drug classes have targets downstream of KRAS, but no currently available drug inhibits KRAS directly.

Direct Targeting A landmark paper published last year suggested it is possible to directly target a KRAS mutational subtype.1 “For the first time, we have data to

suggest that we can target the KRAS G12C mutation with a small molecule,” he said. According to the study’s investigators, these compounds rely on mutant cysteine for binding, without affecting the wild-type KRAS protein. In other words, they are selective for a specific KRAS mutation subtype. Cell growth inhibition and apoptosis were observed with KRAS targeting only in cell lines with the G12C mutation. “The data suggest that these smallmolecule inhibitors of KRAS are not only possible, but are quite effective in preclinical studies,” Dr. Gandara said. “They are directed toward the common G12C lung cancer mutation, which appears to be far more common in smokers than in nonsmokers, and they were developed to target only the mutated

KRAS in Non–Small Cell Lung Cancer ■■ The KRAS mutation occurs in approximately 25% of non–small lung cancer tumors, and often coexists with TP53 and LKB1 mutations. ■■ Once thought “undruggable,” the KRAS mutation can be targeted by a G12Cmutation–specific novel small-molecular inhibitor in early-phase development. ■■ MEK inhibitors plus docetaxel may be an effective means of targeting KRASmutated tumors through downstream signaling pathways.

of either TP53 or LKB1 markedly impaired the response of KRAS-mutant cancers to docetaxel monotherapy. The addition of selumetinib provided substantial benefit for mice with lung cancer caused by KRAS and KRAS-plusTP53 mutations, though mice with co-mutations in KRAS and LKB1 were resistant to the combination. “There was a big difference in the wa-

The KRAS mutation story has evolved from what we thought we knew, to the controversies about what we don’t know. —David R. Gandara, MD

KRAS. In that regard they are very different from what we have had before.”

Targeting Downstream Meanwhile, work continues on drugs that target downstream pathways and that indirectly affect KRAS. These efforts take advantage of the fact that KRAS mutations also have “traveling partners,” especially co-mutations in LKB1 (also known as STK11) and TP53, Dr. Gandara said. Work from the The Cancer Genome Atlas (TCGA) has shown that the frequency of these co-mutations in NSCLC is similar to that of KRAS mutation alone. A very small percentage of patients have three simultaneous mutations. It appears, from preclinical and clinical studies, that a MEK inhibitor plus docetaxel can effectively target these common co-mutations. In a preclinical study, mice were treated with docetaxel alone or with the investigational MEK inhibitor selumetinib.2 The animals harbored the KRAS G12D mutation or KRAS G12D mutation plus a mutation in either TP53 or LKB1, which are considered clinically relevant tumor suppressors. In the study, the concomitant loss

terfall plot among mice harboring these three categories of KRAS-mutated cancer. A rather dramatic change was seen with the MEK inhibitor in combination with docetaxel for all categories except LKB1 loss,” Dr. Gandara noted. The phase II randomized human trial of selumetinib plus docetaxel in KRASmutant NSCLC was also positive for its primary endpoint, progression-free survival: 5.3 months with the combination vs 2.1 months with docetaxel alone.3 Response rates were 37% and 0%, and median overall survival times were 9.4 months and 5.3 months, respectively. “Admittedly, this was totally KRASmutated NSCLC, which is not the typical patient, but the overall survival— though not statistically significant in this phase II study—was almost doubled with the combination,” he pointed out.

Trametinib Trials Dr. Gandara presented a similar phase II study at the 2013 ASCO Annual Meeting for another MEK inhibitor, trametinib (Mekinist) plus docetaxel (with growth factor support) in advanced KRAS-mutant and wild-type KRAS NSCLC.4 Response rates were 28% to the combination among

patients with KRAS-mutated NSCLC, 40% among those with G12C-mutated disease, and 32% among those with wildtype disease, and disease control rates were 60%, 80% and 68%, respectively. “On the waterfall plot, we saw that all patients with G12C-mutated cancers had responses headed in the right direction, even if they did not meet RECIST criteria for a partial response,” he said. While the response rates in the study were similar for patients with KRAS-mutated disease and those with wild-type disease, Dr. Gandara suggested the combination improved responses among those with mutated KRAS, compared to what would be expected with docetaxel alone. Both selumetinib and trametinib are moving forward in development for KRAS-mutated NSCLC, he indicated. These data have led SWOG to initiate the randomized phase II S1408 trial in KRAS-mutated NSCLC, which will evaluate trametinib plus docetaxel or plus an AKT inhibitor (GSK795). The primary endpoint is progression-free survival. Translational studies will evaluate outcomes in patients with the KRAS codon 12 (G12C) mutation vs other KRAS mutations, and for patients with TP53 mutations or LKB1 loss in each study arm. “This will, we hope, lead to subsequent phase III trials,” he added. n

Disclosure: Dr. Gandara has received grants from GlaxoSmithKline and is a consultant for AstraZeneca and Novartis.

References 1. Ostrem JM, et al: K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548-551, 2013. 2. Chen Z, et al: A murine lung cancer coclinical trial identifies genetic modifiers of therapeutic response. Nature 483:613-617, 2012. 3. Jänne PA, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer. Lancet Oncol 14:38-47, 2013. 4. Gandara DR, et al: Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type advanced non-small cell lung cancer: A phase I/IIb trial. ASCO Annual Meeting. Abstract 8028. Presented June 2, 2013.

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International Lung Cancer Congress Thoracic Oncology

SBRT in Early Lung Cancer continued from page 1

is primarily nodal or distant, and toxicity is more likely in the case of centrally located tumors, vs peripheral. This information formed the basis of the well-known Radiation Therapy Oncology Group (RTOG) 0236 trial, which enrolled 59 patients with T1 and T2 peripheral lesions outside of the zone of the proximal tracheobronchial tree.1 The study showed that patients with inoperable NSCLC receiving stereotactic body radiotherapy had a 3-year survival of 55.8%, high rates of local tumor control, and moderate treatment-related morbidity. Only one patient had a primary tumor failure, producing a 3-year primary tumor control rate of 97.6%. Three patients had a recurrence within the involved lobe, producing a 3-year primary tumor and involved lobe control rate of 90.6%. Median overall survival was 48 months. Rates of adverse events were 12.7% for grade 3 and 3.6% for grade 4. More patients died of other causes than of lung cancer. “This study was transformative,” Dr. Decker said. “The findings are probably the best argument I can make for treating some high-risk patients with radiation.” A subsequent population-based analysis from the Netherlands Cancer Registry examined the survival of early-stage NSCLC patients during three time periods, concluding the increase in survival between 2001 and 2009 was at least in part due to the increased use of SBRT over fractionated radiation.2

SBRT vis à vis Surgery The issue of SBRT vs surgery has been examined through several comparative analyses. A retrospective comparison of patients with stage I NSCLC deemed ineligible for lobectomy found no significant difference in outcomes between stereotactic body radiotherapy and wedge resection.3 There were no differences in regional recurrence, locoregional recurrence, distant metastasis, or freedom from any failure. Risk of local recurrence was less with SBRT

(4% vs 20%, P = .07), and while overall survival was higher with resection (87% vs 72%, P = .01), cause-specific survival was identical (94% with wedge, 93% with SBRT). A similar finding was reached in another study of patients with stage I disease, 462 of whom underwent surgery and 76 who had SBRT. A propensitymatched analysis revealed similar rates of local recurrence and disease-specific survival between the two groups. Four-year local control was 90%, and there was no difference in cancer-specific survival.4 Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery and were treated with stereotactic radiotherapy, and found local control rates for T1 and T2 tumors at 5 years to be 92% and 73%, respectively. Five-year over-

are not as favorable, he noted. RTOG 0618 was a small study of 26 patients with T1 and T2 disease in which the 2-year local and lobar failure rate was 19%.6 “This local failure rate is concerningly high,” Dr. Decker commented. “We await the publication, before we know what to make of this.” Japan Clinical Oncology Group ( JCOG) 0403 was a single-arm study of 64 operable patients.7 The 3-year local control rate was 86%, and overall survival rate was 76%. “This local control is not as good as expected, although we do not know how this was defined,” he remarked. Unfortunately several randomized studies comparing surgery to SBRT have closed early due to poor accrual, including ROSEL (lobectomy vs SBRT), STARS (lobectomy vs

In high-risk patients, SBRT appears to offer approximately equivalent control and survival when compared to surgical resection, in retrospective series. I can say that SBRT is approximately as good as surgery. —Roy Decker, MD, PhD

all survival rates for stage IA and IB subgroups were 72% and 62%, respectively. The researchers concluded that the survival rate for SBRT is “potentially comparable to that of surgery.” The most recent data come from a propensity-matched analysis of 64 patients treated with SBRT and 64 treated with minimally invasive surgery.5 PostSBRT locoregional control rates were superior to surgery at 1 year (96.8% vs 86.9%) and 3 years (86.9% vs 82.6%, P = .04), but distant recurrences and overall survival were similar. “None of these studies found that SBRT and surgery were the same, but they do tell us that outcomes with SBRT are in the same ballpark as those we get with surgery,” Dr. Decker concluded.

Prospective Trials Only two prospective trials have been reported for operable patients— and remain unpublished. Their results

Stereotactic Body Radiotherapy for Early-Stage NSCLC ■■ Stereotactic body radiation therapy for early-stage NSCLC (T1) confers a local control rate of 80% to 90%, potentially equivalent to surgery. ■■ Patients with larger tumors can be treated, but local control rates will be lower. ■■ Centrally located tumors can be treated effectively but at higher risk. ■■ In the vast majority of patients, quality of life is preserved.

SBRT with cyberknife) and ACOSOG Z4099/RTOG1021 (sublobar resection vs SBRT).

Pulmonary Function and Quality of Life “The decision could come down to, ‘What’s the effect of SBRT on the patient’s quality of life and pulmonary function?’” Dr. Decker said. “The thoracic surgeon and I discuss whether the patient is a candidate for surgery or SBRT, and we try to parse out what the patient’s life will be like after treatment.” In RTOG 0236, an analysis of patients’ pulmonary function following SBRT found no significant effect overall, but there were nonsignificant declines in both forced expiratory volume (FEV1) and diffusing capacity for carbon monoxide. This is consistent with what retrospective series have shown, and the impact of this could vary among patients, he said. Quality of life has been examined in some studies. One from the Cleveland also revealed small declines in diffusing capacity of the lung for carbon monoxide, but no degradation in quality-of-life, no reductions in 6-minute walking distance, and no increase in patient-reported dyspnea.8

Few ‘Poor Candidates’ for SBRT Not all patients with early-stage lung cancer are optimal candidates for

stereotactic radiotherapy, though even suboptimal patients can have good outcomes, with caveats. “Patients with centrally located tumors can be treated effectively, but they are at higher risk for side effects. And we think it’s safe to treat patients with larger tumors, but we have lower expectations of control,” he said. For centrally located tumors that are small, reduced-dose SBRT can be effective, retrospective studies suggest. Even with a lower dose, however, grade 5 toxicities can occur. In a study from Yale, in which 47 patients with central lesions received stereotactic body radiotherapy, four patients had grade 3 dyspnea and one developed hemoptysis that contributed to respiratory failure and death. Patients who developed grade 3 or more toxicity had larger tumors than those without toxicity (median diameter = 4.3 vs 2.9 cm, P = .02). The 2-year lobar local control rate overall was 94%; this rose to 100% for patients receiving a biologic equivalent dose of 100 Gy or more and diminished to 80% among those receiving a lower dose. The authors concluded that SBRT for central lung tumors seems safe, but treatment of larger tumors carries an increased risk of highgrade toxicity. Accrual is complete for RTOG 0813, which will treat patients at the highest dose levels and should be informative, he predicted. For larger (T2) tumors in general—ie, those that are 4 to 5 cm— evidence is emerging that SBRT is effective, though local control is somewhat less than that seen with smaller tumors. A series of patients treated at Yale showed local control rates to be 75% to 80% in this population. “This is no surprise. With a 5-cm tumor, you won’t get 90% local control,” he added. “If this patient has a good surgical option, that’s a better choice.” Patients with poor pulmonary function at baseline also need not be excluded. A review of 423 patients, stratified by pretreatment pulmonary function, found that pulmonary function declined by 3.6% at 6 months and by 6.8% at 24 months.9 Interestingly, the largest loss was observed among patients with the best pulmonary function pretreatment; pulmonary function actually improved the most among patients with the worst baseline function. n Disclosure: Dr. Decker reported no potential conflicts of interest. continued on page 10

The ASCO Post | SEPTEMBER 1, 2014

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International Lung Cancer Congress SBRT in Early Lung Cancer continued from page 9

References 1. Timmerman R, Paulus R, Galvin J, et al: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303:1070-1076, 2010. 2. Haasbeek CJ, Palma D, Visser O, et al: Early-stage lung cancer in elderly patients: A population-based study of changes in treatment patterns and survival in the Netherlands. Ann Oncol 23:2743-2747, 2012.

3. Grills IS, Mangona VS, Welsch R, et al: Outcomes after stereotactic lung radiotherapy or wedge resection for stage I nonsmall-cell lung cancer. J Clin Oncol 28:928935, 2010. 4. Crabtree TD, Denlinger CE, Meyers BF, et al: Stereotactic body radiation therapy versus surgical resection for stage I nonsmall cell lung cancer. J Thorac Cardiovasc Surg 140:377-386, 2010. 5. Verstegen NE, Oosterhuis JWA, Palma DA, et al: Stage I-II non-small-cell lung cancer treated using either stereotactic abla-

tive radiotherapy or lobectomy by video-assisted thoracoscopic surgery: Outcomes of a propensity score-matched analysis. Ann Oncol 24:1543-1548, 2013. 6. Timmerman RD, Paulus R, Pass HI, et al: RTOG 0618: Stereotactic body radiation therapy (SBRT) to treat operable earlystage lung cancer patients. ASCO Annual Meeting. Abstract 7523. Presented June 1, 2013. 7. Nagata Y, Hiraoka M, Shibata T, et al: A phase II trial of stereotactic body radiation therapy for operable T1N0M0 non-

small cell lung cancer, Japan Clinical Oncology Group ( JCOG0403). 52nd ASTRO Annual Meeting. Abstract 59. Presented November 1, 2010. 8. Videtic GM, Reddy CA, Sorenson L, et al: Support Care Cancer 21:211-218, 2013. 9. Guckenberger M, Kestin LL, Hope AJ, et al: Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol 7:545-551, 2012.

Don’t Miss These Important Reports in This Issue of The ASCO Post Hugo F. Fernandez, MD, on AML see page 20

Jacek Jassem, MD, PhD, on NSCLC see page 57

Visit The ASCO Post online at ASCOPost.com

David Hui, MD, MSc, on identifying impending death see page 65

ASCOPost.com | SEPTEMBER 1, 2014

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News Gynecologic Oncology

September Is Ovarian Cancer Awareness Month

n recognition of September as Ovarian Cancer Awareness month, David A. Fishman, MD, Director of the Mount Sinai Ovarian Cancer Risk Assessment Program and Professor and Fellowship Director in the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Medicine at the Icahn School of Medicine at Mount Sinai, shared the following recommendations and facts in regard to identification and treatment of women with ovarian cancer.

Identifying Women at Risk “There is no effective surveillance technique for the detection of early stage ovarian cancer, so the only effective way to prevent it and save lives is to identify women at risk,” said Dr. Fishman. He recommends that women with a family history of ovarian and breast cancers get a formal genetic evaluation by a boardcertified genetic counselor. For women who have tested positive for a BRCA mutation or are identified to be at a high risk for developing ovarian cancer, Dr.

There is no effective surveillance technique for the detection of early stage ovarian cancer, so the only effective way to prevent it and save lives is to identify women at risk. —David A. Fishman, MD ©The Mount Sinai Hospital.

Fishman recommends that preventive surgery should be considered to remove the ovaries and fallopian tubes before ovarian cancer can develop.

Facts About Ovarian Cancer • About 75% of women with ovarian cancer are diagnosed with late-stage disease. Only 15% to 40% of women survive for 5 years after initial aggressive cytoreductive surgery that is performed to remove cancerous tissue from the abdominal cavity in combination with chemotherapy. • Almost 90% of women who are diag-

THE SIDE OF CANCER YOU’RE NOT SEEING

nosed while the disease is still confined to the ovary (stage I) survive for 5 years. They also require less surgical intervention, may not require chemotherapy and have a better quality of life. • After removal of the ovaries and fallopian tubes, the risk of developing ovarian cancer is close to zero and the incidence of peritoneal cancer is about 1%.

Tips for Ovarian Cancer Prevention • Family and personal history is important to identify women at in-

creased risk: At least 10% of ovarian cancers are attributed to the inheritance of genetic mutations (such as BRCA, HNPCC) that increase the risk of certain cancers (breast, colon, endometrial, thyroid, and melanoma). If you have a history of these cancers in your family (either in men or women), get your risk assessed for ovarian cancer by a board certified genetic counselor. • Take oral contraceptives: Long term use of oral contraceptives reduces the risk of developing ovarian cancer by approximately 50%. • Pay attention to symptoms: Swollen or bloated abdomen, pressure or pain in abdomen, pelvis, back or legs, difficulty eating or feeling full quickly, nausea, indigestion, gas, constipation or diarrhea; fatigue, urinary symptoms, and unusual vaginal bleeding. September is also Prostate Cancer Awareness month. See page 81 for more information. n

The Oncotype DX® assay reveals the unique biology of a tumor, presenting a more complete and individualized picture of the patient’s cancer. It is essential information that can fundamentally change decisions about treatment. With over 440,000 patients tested worldwide, the Oncotype DX portfolio—assays for breast, colon, and prostate—is a world leader in applying genomic science to cancer treatment planning. For more information on using the Oncotype DX assay with appropriate patients, visit OncotypeDX.com/portfolio.

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The ASCO Post | SEPTEMBER 1, 2014

PAGE 12

New Orleans Summer Cancer Meeting Hematology

Treating Multiple Myeloma in 2014 By Sergio A. Giralt, MD

he field of multiple myeloma is rapidly changing, and the shifts that are occurring impact the management of these patients, from initial diagnosis through multiple relapses. At the 9th Annual New Orleans Summer Cancer Meeting, Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York, shared his approach to various patient subgroups.1 The ASCO Post captured his presentation.

How Far We’ve Come In 2001, we had little to offer upfront to a newly diagnosed patient: thalidomide (Thalomid) plus dexamethasone or VAD (vincristine, doxorubicin, and dexamethasone), or pulse dexamethasone. But 4 out of 10 patients receiving these treatments would not respond, and 20% would progress on treatment, which meant a significant proportion did not even get to transplant. For the 60% who responded, the discussion was whether to give high-dose melphalan for consolidation. Post-melphalan, there was no well-established maintenance treatment, except for bisphosphonates. Remember, at that time, the only randomized trial looking at optimal induction was one comparing thalidomide/dexamethasone to VAD. Thalidomide/dexamethasone was associated with improved response rates prior to transplant, but after transplant, the results were similar.2 The question was whether there was an optimal induction regimen for patients undergoing transplant, and the answer was “anything but melphalan,” because melphalan negatively affected stem cell collection In the early 2000s, multiple randomized trials showed the benefit of autologous stem cell transplant, particularly for progression-free survival, and four trials found an overall survival benefit. The problem in using those data now is that they come from old studies, and we no longer use thalidomide/dexamethasone or VAD for induction.

Choice of Induction Regimen The question is whether patients with high-risk vs low-risk features should receive the same induction regimen. The randomized trial by Cavo et al back in 2008 was the first to show that triple therapy is better than double therapy.3 The addition of bortezomib (Vel-

cade) to thalidomide/dexamethasone not only improved response rates after induction, but this translated into improvements in progression-free survival (though no overall survival benefit). The progression-free survival benefit was seen in all risk categories—highrisk and low-risk alike. More recently, at last year’s American Society of Hematology (ASH) Annual Meeting, Cavo et al reported a metaanalysis of the four trials of bortezomib-based induction.4 These were the IFM 2005-1, HOVON-6.5/ GMMGHD4, GIMEMA MM-BO2005, and PETHEMA GEM05MENOS65. In the combined analysis of about 1,000 patients, both progression-free survival (P = .0001) and overall survival (P = .0402) were significantly improved, vs non–bortezomib-based induction before transplant. With these emerging data, one has to be convinced that the optimal induction regimen for transplant-eligible patients includes bortezomib. I am the

low-risk disease also may not need to go to transplant.

Optimal Drug Combinations For improving the induction response prior to transplant, VRD (bortezomib, lenalidomide, and dexamethasone) is commonly used in the United States, partly because this is the only country where lenalidomide has an upfront indication for transplant-eligible patients. I use VRD or CyBorD (cyclophosphamide, bortezomib, and dexamethasone), interchangeably. These regimens have been compared head-tohead in small phase II studies, and the results are equivalent.

Questions About Consolidation Should we use the same consolidation regimen for the patient who obtains a stringent complete remission after four cycles of VTD (bortezomib, thalidomide, and dexamethasone), vs the same patient who has persistent

If you define ‘cure’ as living long enough to die of something else, then I think we are curing patients—just not enough of them. The road to cure goes through complete remission, so we need to work to get them there. —Sergio A. Giralt, MD

first to recognize that this has not been compared to lenalidomide (Revlimid)/ dexamethasone, which we commonly use in the United States. But the preponderance of data suggests that the standard treatment should include bortezomib, and that is what I do in my practice.

Patients Ineligible for Transplant We do not consider patients with poor performance status. This can include the elderly, frail patient, the patient who cannot perform activities of daily living, and the patient with decompensated comorbidities. Other important barriers to transplantation are socioeconomic: lack of a caregiver, distance from the hospital, inability to comply with post-transplant care, and so forth. Age by itself is not a contraindication. Patients with very

disease after this regimen? And who should receive high-dose melphalan and autologous transplant: the patient who achieves a complete remission, the one who does not, both, or neither? This last question is difficult, and can require an hour of consultation with the patient. Fifteen years ago, the conversation about transplant was relatively straightforward. We said, “We gave you the best treatment, and you still have residual disease. Achieving a complete remission makes a difference. We will, therefore, give you high-dose melphalan, which converts residual disease to a complete remission 30% of the time.” You can’t have this conversation with the patient who is already in complete remission, and with modern induction regimens, 20% are in complete remission. In E4A03, patients received lenalidomide/dexamethasone for four cycles,

then either stopped treatment and went to transplant or not, or continued primary lenalidomide therapy beyond four cycles.5 The important finding was this: four cycles, then stopping is not sufficient. The overall survival rate for this group was 55% at 3 years, compared to 80% for patients who continued on lenalidomide and 92% for those who went to transplant (who were also younger). We really need a randomized controlled trial comparing early high-dose therapy and autologous stem cell transplant as consolidation for all patients vs late, ie, high-dose therapy and autotransplant only for patients who relapse after primary therapy. Palumbo et al evaluated MPR (melphalan, prednisone, and lenalidomide) vs high-dose melphalan and tandem transplant as consolidation after lenalidomide induction.6 The response rates were 92% and 97%, respectively, and progression-free survival at 12 months was 91%. So we have at least one trial showing the benefit of high-dose melphalan. The problem is that these patients never got bortezomib, and that makes a difference. Currently, there are two national trials—one in the United States and one in Europe—looking at the optimal induction regimen of VRD, then randomly assigning patients to early vs late transplant followed by maintenance lenalidomide. This should answer the question of whether early transplant is important, or whether we can collect stem cells and hold them until relapse. With regard to the patient who obtains a complete remission after induction, vs the one with residual disease, I think both should go to transplant. The preponderance of the data, at least until the randomized trials are reported, still suggests a benefit for transplant.

Prognostic Factors Can Guide Treatment At last year’s ASH Annual Meeting, Cavo et al presented a multivariate analysis that identified three important prognostic factors: inability to achieve a complete remission with induction, the presence of poor-risk cytogenetics at baseline, and disease stage > 2 by International Staging System (ISS > 2).4 These factors worsen progression-free survival outcomes by 80%, 56%, and 57%, respectively. This information allows us to riskcontinued on page 18

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

LIGHTING A WAY FORWARD Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

VOTRIENT demonstrated signiﬁcant improvement in PFS in a Phase 3 trial1 • VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.260.48; P<0.001)1

Proportion Progression Free

PFS in overall study population (N=369)1

1.6

MONTHS Median PFS

1.0

4.6

VOTRIENT (n=246)

MONTHS Median PFS

Placebo (n=123)

• The efficacy efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

HR 0.35 (95% CI 0.26-0.48) P<0.001

0.8 0.6 0.4 0.2 0.0 0

Months Randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial to evaluate the efﬁcacy and safety of VOTRIENT in patients (N=369) with advanced STS. The Phase 3 trial population excluded patients with adipocytic sarcoma or GIST. Patients were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.1,2

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, VTEs were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal

pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients

undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced STS trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • The most common adverse reactions (≥20%) in patients with advanced soft tissue sarcoma who received VOTRIENT were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

• For additional information on dosing modifications modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

Important Safety Information for VOTRIENT (cont’d) • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group). • Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions.

Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages. www.GSKSource.com ©2014 GSK group of companies. All rights reserved. Printed in USA. 66601R0 June 2014

VOTRIENT.com/HCP/aSTS

The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Data on file. GlaxoSmithKline, 2011.

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.4% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10%

compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) of patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and

lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache

VOTRIENT

Placebo

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 65 13 1 48 4 1 59 5 0 15 1 0 56 3 0 22 2 0 48 4 0 15 0 0 42 7 0 6 0 0 40 6 0 19 0 0 39 0 0 2 0 0 33 3 0 11 1 0 29 8 0 21 7 2 28 0 0 3 0 0 23 1 0 8 0 0

Musculoskeletal pain

Myalgia

Gastrointestinal pain

Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorderb

20 18 17 14 12 12 11 11

5 <1 <1 2 2 0 1 2

<1 0 0 0 0 0 0 0

17 9 12 9 2 1 4 1

5 0 <1 2 0 0 0 0

1 0 0 0 0 0 0 0

Skin hypopigmentation

Stomatitis 11 <1 0 3 0 0 Chest pain 10 2 0 6 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia. Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased Albumin decreased Alkaline phosphatase increased Sodium decreased Total bilirubin increased

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45 34

5 8 <1 1

3 2 0 0

22 18 35 21

2 2 2 0

0 1 0 0

Potassium 16 1 0 11 0 0 increased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

T:13”

B:14.25”

S:12.5”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, shortacting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to

avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and postimplantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/ maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist

of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709

The ASCO Post | SEPTEMBER 1, 2014

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New Orleans Summer Cancer Meeting Treating Multiple Myeloma continued from page 12

stratify patients into those with no highrisk features (13%), one adverse feature (61%), two adverse features (23%), or all three adverse features (3%). Their respective median progression-free survival times are 61 months, 56 months, 36 months, and 26 months. In the context of bortezomib induction, you can tell the patients who lack any high-risk features that they have less than a 50% risk of having to re-treat their disease in the next 5 years. On the other hand, the patient with all three poor-risk factors should consider transplant right away.

Maintenance for (Almost) All Let’s suppose the patient with lowrisk disease has an autotransplant and remains in complete remission, but the patient with high-risk disease still has residual disease after transplant. Should they both get maintenance therapy? This is another difficult discussion. In 2014, while it is still somewhat controversial, the evidence suggests there is a benefit to maintenance lenalidomide. This was shown in the IFM 2005-02 trial, where even patients who achieved a complete remission prior to transplant had prolonged progression-free survival, and many patients with persistent disease converted to complete remission.7 Similar results were reported in

the CALGB 100104 trial, where median progression-free survival was 24 months without maintenance vs 40 months in the maintenance arm.8 CALGB 100104 also showed an overall survival benefit, whereas the French study did not. The potential downside to maintenance is a threefold risk for second malignancies (an increase from 1% to 3%), but this did not affect the survival benefit of these patients. So I think it is reasonable to offer almost all patients maintenance lenalidomide. The one exception is the patient with low-risk disease who is in complete remission prior to transplant. His or her progression-free survival is about 5 years, and it is reasonable to monitor this patient and initiate lenalidomide upon signs of progression. Putting all these approaches together, we await the results of the STaMINA trial, which is evaluating the role of consolidation in the context of highdose melphalan and lenalidomide maintenance. Patients were randomly assigned to a second autotransplant, vs four cycles of consolidation, then maintenance. We will have the results in 2 years.

Possibly, a Cure? The surrogate marker for long-term survival is complete remission—this is what gives the survival advantage. The importance of achieving a complete remission is the same for transplant-eligible and transplant-ineligible

patients. It makes a big difference in both groups. High-dose melphalan has a role in transplant-eligible patients and in my opinion continues to be the standard of care, because it’s the single most effective way of getting a complete remission. Can we cure myeloma? My answer is that 30% of patients who achieve a complete remission remain in remission 10 years down the line, according to data on the Total Therapy protocol from the University of Arkansas for Medical Sciences, Little Rock. If you define “cure” as living long enough to die of something else, then I think we are curing patients—just not enough of them. The road to cure goes through complete remission, so we need to work to get them there. n

Disclosure: Dr. Giralt reported no potential conflicts of interest.

References 1. Giralt S: Multiple myeloma: How to integrate novel agents with stem cell transplantation in the era of targeted therapy. 9th Annual New Orleans Summer Cancer Meeting. Presented July 20, 2014. 2. Macro M, Divine M, Uzunhan Y, et al: Dexamethasone + thalidomide compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma: A randomized trial. Blood (ASH Annual Meeting Abstracts) 108:Abstract 57, 2006. 3. Cavo M, Tacchetti P, Patriarca F, et al: A phase III study of double autotrans-

plantation incorporating bortezomibthalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: Superior clinical outcomes with VTD compared to TD. Blood (ASH Annual Meeting Abstracts) 114:Abstract 351, 2009. 4. Cavo M, Salwender H, Rosinol L, et al: Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: An integrated analysis of patient-level data from phase III European studies. Blood (ASH Annual Meeting Abstracts) 122:Abstract 767, 2013. 5. Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomized controlled trial. Lancet Oncol 11:29-37, 2010. 6. Palumbo A, Cavallo F, Ben Yehuda D, et al: A prospective, randomized study of melphalan, prednisone, lenalidomide versus melphalan (200 mg/m2) and autologous transplantation (Mel200) in newly diagnosed myeloma patients: An interim analysis. Blood (ASH Annual Meeting Abstracts) 114:Abstract 350, 2009. 7. Attal M, Christini C, Marit G, et al: Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol 28(suppl):Abstract 8018, 2010. 8. McCarthy P, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012.

Don’t Miss These Important Reports in This Issue of The ASCO Post David R. Gandara, MD, on targeting KRAS mutations in lung cancer see page 6

Alok A. Khorana, MD, on understanding the impact of CALGB/SWOG 80405 (ASCO 2014 plenary) see page 30

Martin C. Tammemagi, PhD, on lung screening and smoking cessation see page 53

Richard L. Schilsky, MD, on quality cancer care see page 86

Tracy A. Balboni, MD, MPH, on palliative care in radiation oncology see page 44

Eva J. Kantelhardt, MD, on gynecolgic cancer care in resource-challenged Ethiopa see page 76

Anand P. Jillella, MD, and Vamsi K. Kota, MD, on acute promyelocytic leukemia see page 62

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | SEPTEMBER 1, 2014

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New Orleans Summer Cancer Meeting Molecular Biology

Quest for Targeted Therapeutic ‘Cocktails’ Hits Roadblocks By Caroline Helwick

he use of cutting-edge technology and bioinformatics to inform clinical decision-making in oncology is still a ways off, according to Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Oncology and Director of the Stanford Breast Oncology Program, Stanford University, Palo Alto, California. At the 9th Annual New Orleans Summer Cancer Meeting, Dr. Pegram said the “lofty goal” of targeted therapeutic “cocktails”—which will be needed to address the molecular diversity of tumors—is proving hard to achieve.

Circulating Tumor Cells Circulating tumor cells as an alternative to serial biopsies of metastatic lesions has great appeal, but the uptake of this technology has been somewhat anemic. One problem is obtaining a consistent definition of a circulating tumor cell. The cell must be positive for cytokeratin, must have a nucleus, must have a negative control, must be negative for leukocyte

with metastatic disease, and this is correlated with overall survival. “The problem with this assay is that it is not sensitive enough to capture [circulating tumor cells] in early stages of dis-

ease. While enumeration of [circulating tumor cells] is prognostic, let’s be honest: that’s not what we are interested in,” Dr. Pegram said. “We are interested in predicting response to treatment.”

He has observed that while some clinicians are “enamored” of this technology and do use it, others realize that it holds little value over routine restagcontinued on page 20

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MO DEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself.

Mutational events in cancer can yield complex and deranged pathways, but they are still highly functional and they can take the lives of our patients. We need to understand them. —Mark Pegram, MD

cytoplasm (white cell markers), and the nucleus must fit inside the cytoplasm. “These are the things measured using a huge variety of different approaches for defining and capturing [circulating tumor cells],” he said. The most clinically advanced is the CellSearch System, which uses an antibody/ferrofluid combination to attach specifically to circulating tumor cells, and magnets to draw those cells out of the blood sample to be stained and identified. The test enumerates the number of circulating tumor cells in a patient

CLINICAL EXPERTISE More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology. Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

TRANSPLANTATION In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

CLINICAL TRIALS AND RESEARCH Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem • First-in-man clinical trials testing cells for peripheral blood transplants novel therapies and treatment options • Four ICU beds integrated with Carolinas HealthCare System’s • Access to high-quality care, and virtual ICU, which provides 24/7 expertise from physicians who oversight of all patients subspecialize in treating specific • Patient support, including familydiseases friendly patient rooms, an exercise • The ability to enroll patients in room, a laundry room and lounge the newest, most promising trials, • Patient navigation whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

The ASCO Post | SEPTEMBER 1, 2014

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Expert’s Corner Hematology

Emerging Approaches in Acute Myeloid Leukemia A Conversation With Hugo F. Fernandez, MD By Caroline Helwick tation at Moffitt Cancer Center in Tampa, Florida, spoke with The ASCO Post about how he approaches these patients.

Cytogenetics and Molecular Studies

Hugo F. Fernandez, MD

ith the emergence of molecular diagnostics and new therapeutics, the treatment of acute myeloid leukemia (AML) is entering a new era. Hugo F. Fernandez, MD, Associate Chief of Blood and Marrow Transplan-

Targeted Therapeutics continued from page 19

ing with radiographic studies. The assay also reveals little as to what is happening in these cells, and the small number of circulating tumor cells captured—five or so—is insufficient for fully deciphering the tumor, he said. Capturing more cells could help, and that is what microfluidics-based cell separation does. This new, simpler technology passes blood through a membrane, separating larger tumor cells from other blood elements and yielding thousands of cells upon which clinically relevant tests can be performed. “The approaches that have much higher yields will be more useful because they will be informative as to what cells are doing at a molecular level,” he predicted. Even more sophisticated bloodbased technology will someday be better able to capture the genetic heterogeneity of advanced solid tumors at a gene-expression level so they can be compared with the primary tumor. This, however, will present other challenges. “In one blood sample there are multiple populations of [circulating tumor cells] that are different from another. This will pose a diagnostic challenge and a treatment challenge, as well, if we find unique targets within the same patient at the same time,” he said. “Until we can come to terms with the complexity of solid tumor malignancies, we can’t make informed decisions.” At this point, guideline committees

Can you offer a few major requirements in treating AML today? In 2014, we need to know the results of cytogenetics and molecular studies, which should be done on all patients with AML. Cytogenetics has long been a standard diagnostic test, and we classify cytogenetic profiles as conveying a “good (favorable), bad (intermediate), or ugly (unfavorable)” profile. Ten-year overall survival rates have been shown to be 55% to 81% for patients with favorable profiles, 22% to 39% for those with intermediate-risk profiles, and 10% or “have not latched on to [circulating tumor cells] as a ‘must’ in clinical practice,” he indicated, calling circulating tumor cell determination a “consideration,” but one lacking in great value until emerging technologies can interrogate circulating tumor cells at a molecular level.

Genomics and Drug Development The promise of genomics was to identify mutations within a tumor and thus allow the clinician to concoct a tailored therapeutic cocktail. In reality, however, the scenario is infinitely complex. Within a single MCF-7 human breast cancer cell, for instance, 157 chromosomal break points have been found. “We have rich genomic information in a tumor cell, but this does not tell the doctor how to treat the patient,” he said. The Cancer Genome Atlas (TCGA) Network, in its examination of its first 507 breast cancer samples, revealed only four frequently mutated genes out of 50 that were identified: PIK3CA, TP53, MAP3K1, and GATA3. “This was a stunning observation,” commented Dr. Pegram. “We thought we would discover multiple new therapeutic targets in breast cancer and therefore have home runs in drug development, but we found only four, and all four were already known to be common mutations.” Drugs are already targeting PI3K, the other three frequent mutations are

less for those with unfavorable profiles.1 But now we know about a variety of mutations that also confer prognosis. Molecular studies are allowing us to reclassify our patients, which will be important down the road when we can more precisely select optimal treatments. These new molecular assays are important and readily available at academic centers and in commercial laboratories. An important mutational analysis of 18 genes, performed by Patel et al on the Eastern Cooperative Oncology Group (ECOG) E1900 patient population, found that more extensive mutational analysis can better discriminate patients with AML into various prognostic groups.2 The analysis separated patients with AML into three subgroups with very different outcomes: those with a favor-

able mutational risk profile (3-year overall survival rate, 85%), a subgroup with an unfavorable mutational risk profile (3-year overall survival rate, 13%), and a subgroup remaining at intermediate risk (3-year overall survival rate, 42%). The integration of mutational and cytogenetic analyses reduced the proportion of patient with intermediate-risk disease from 63% to 35%. The favorablerisk subgroup increased from 19% to 26%, and the proportion deemed unfavorable increased from 18% to 39%.

not druggable, and the rest of the 50 genes are low-frequency mutations (affecting about 2% of breast cancers) for which pharmaceutical companies are unlikely to invest. “This will pose a challenge because our current models of drug development will not survive this reality,” he predicted. Furthermore, according to Dr. Pegram, deep sequencing identifies even more heterogeneity, revealing individual clones with different mutational profiles within the same tumor. The current next-generation diagnostics are not performing deep sequencing and therefore are not demonstrating the molecular heterogeneity that is critical for selecting the best targeted agent, he said. Even “more sobering,” he continued, is that this complexity is present at the time of diagnosis, with further alterations piled on due to drug resistance. Cancer and genomes are not static; they are a moving target, he reiterated. While the situation is clinically frustrating now, there is the potential to tease apart the molecular evolution of cancers with future sequencing technology, and this “extraordinary” achievement could give insights into prevention strategies.

glycolisation, etc) could be a useful adjunct to genomic information, producing a more “holistic view” of pathway regulation. “The hope is that mixing proteomic work along with genomic work will facilitate our understanding of what is going on in the dynamic tumor cell,” Dr. Pegram said. “But the problem with proteomics is size: the proteome is much larger than the genome, due to alternative splicing and protein modification.” The information desired from proteomics includes all protein-to-protein interactions, protein functions and their regulation, protein modifications, subcellular location, and protein concentrations. Current approaches do not provide all this information. While polymerase chain reaction (PCR) testing determines gene amplification, there is no PCR equivalent for proteomics. Sequencing tools are robust in genomics, but mass spectrometry is still emerging in proteomics. Furthermore, proteomic data is “big data,” and huge servers are needed just to store the data. Novel approaches are currently being pioneered to address these issues, he said. In summary, Dr. Pegram said, “Mutational events in cancer can yield complex and deranged pathways, but they are still highly functional and they can take the lives of our patients. We need to understand them.” n

Adding Proteomic Data Even more complex than genomics is proteomics, the large-scale analysis of protein-expression profiles through mass spectrometry. Proteomic information on post-translational modifications in the tumor (ie, phosphorylation,

Key Mutations What are the key mutations associated with prognosis? In cytogenetically normal patients, there are two abnormalities that genercontinued on page 28

Disclosure: Dr. Pegram reported no potential conflicts of interest.

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

(cont’d)

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Please see next page for adverse events in the NSCLC study. Pancreatic Adenocarcinoma Study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%) • Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

significantly superior ORR in first-line ITT population with advanced NSCLC Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

CATEGORY 1 ABRAXANE + carboplatin %

n=521

(170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin %

n=531

A National Comprehensive Cancer Network ® (NCCN ®) Category 1 recommendation1,2,b,c

(132/531) 95% CI: 21.2%-28.5% 30

First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ORR (%)

ITT=intent-to-treat; ORR=overall response rate. a P value based on chi-square test.

P=0.005a

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

There was no statistically significant difference in overall survival between the 2 study arms.

41% ORR in squamous patients ORR by histology in the phase 3 NSCLC trial 50 45 40

ABRAXANE + carboplatin

41%

ORR (%)

35 30

24%

26% 27

Paclitaxel injection + carboplatin

33% 24% 15%

15%

20 15 10 5 0

94/229

54/221

Squamous cell carcinoma

66/254

71/264

3/9

Carcinoma/adenocarcinoma

2/13

Large cell carcinoma

7/29

5/33

STUDY DESIGN • Multicenter 1:1 randomized, phase 3 study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

Other

Adverse events in the NSCLC study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)]. 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. 2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_ALL_HCP_BSv007 10_2013

The ASCO Post | SEPTEMBER 1, 2014

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Expert’s Corner Hugo F. Fernandez, MD continued from page 20

ally tell us the patient will probably do well: mutations in NPM1 only or isolated biallelic CEBPA. Intermediate-risk disease, on the other hand, is conferred by the c-KIT mutation in core-binding factor leukemia. Poor prognosis is associated with the FLT3-ITD mutation, which we see in about one-third of patients. FLT3 is normally expressed on hematopoietic cells, and regulates the proliferation of early progenitor cells. When mutated, FLT3 constitutively activates leukemia cells so that they never stop growing. The impact of FLT3 is obvious from the study by Patel et al.2 They showed that in patients with intermediate-risk AML, the mutant FLT3-ITD was associated with an adverse outcome regardless of other mutations. In patients with wild-type FLT3, the presence of several additional mutations—DNMT3A, PHF6, ASXL1, MLL, RAS, WT1 and TP53—conferred a worse prognosis. However, these mutations are less frequent and need more study.

Initial Approach What is your initial approach to treatment? AML needs aggressive treatment. Most patients will relapse with conventional therapies, so just getting them through induction is not enough; they also need consolidation. The attainment of a complete response will impact their disease course. Patients with favorable-risk disease generally have excellent outcomes and can be treated with standard chemotherapy. Other genotypes that fall into the intermediate-risk and high-risk groups need more aggressive treatment. It is very important for FLT3-positive patients to receive better therapy, and while we have no real options now, we believe this will change in the near future. A phase II study with sorafenib (Nexavar) was encouraging for patients with FLT3-ITD, and this is the only agent we have available for this purpose. A randomized phase III trial adding the investigational tyrosine kinase inhibitor midostaurin to conven-

tional therapy has been completed and is awaiting maturation. There may be other tyrosine kinase inhibitors that more directly target FLT3, but whether this will be a good thing or not remains to be seen. At least now, we have proof of principle that FLT3 inhibition can positively impact outcomes in these patients.

Induction Therapy What is your induction approach? High-dose anthracyclines must be given to these patients. No patient with AML has benefited from low-dose therapy. Idarubicin and daunorubicin are equivalent at higher doses. If the patient is too ill for this approach, find an alternative, but you still must be aggressive. We also see gemtuzumab ozogamicin (Mylotarg) making a comeback. Early trials were encouraging, but the randomized phase III SWOG trial was negative, partly due to a high incidence of side effects.3 This led to the drug’s

we see less treatment-related morbidity and mortality. We are still not sure whether the drug will come back on the market, and in the future we may be seeing more targeted trials stratified by risk. In the meantime, patients who have core-binding factor leukemia may get some benefit by adding this drug at the lower dose. Moving to consolidation therapy, we can say that prognostic factors and performance status drive treatment. For favorable-risk patients, standard chemotherapy with or without gemtuzumab ozogamicin is the way to go.

Delaying Transplant Can you effectively delay stem cell transplantation to second remission? Although the majority of adult patients with AML will achieve remission with upfront chemotherapy, many patients still relapse. Often, the strategy proposed is to delay transplant until a patient relapses and achieves a second

The future of AML sees us aggressively treating this disease in induction and consolidation. Molecular targets are being discovered, and directed therapy will hopefully improve upon remission rates and overall survival in this deadly disease. —Hugo F. Fernandez, MD

voluntary withdrawal from the market, but gentuzumab ozogamicin has not completely disappeared from our armamentarium. A recent meta-analysis showed that the addition of gemtuzumab ozogamicin to treatment improved relapse-free survival (hazard ratio [HR] = 0.84) and event-free survival (HR = 0.59) but not overall survival (HR = 0.95).4 While the addition of the drug resulted in a 60% higher rate of early mortality in the meta-analysis, improved overall survival was observed in studies using a lower cumulative dose (< 6 mg/m2). So gemtuzumab ozogamicin can be beneficial, especially in patients with favorable- and intermediate-risk disease, but with the issue of side effects, we still have questions. By reducing the dose,

remission. We should not let the “second remission fallacy”—that is, thinking that we can take patients to transplant in their second remission—guide our treatment. Remember that most patients will relapse, and obtaining a second remission is not guaranteed. If the patient relapses within 12 months, the chance of a second remission is only about 15%. Beyond 12 months, it improves to 30% or 40%, but these are still not great numbers. Taking the patient to transplant while in first remission, especially those with intermediate- or high-risk disease, is often beneficial. Allogeneic transplant is preferred for patients with FLT3 mutations. Neither chemotherapy nor autologous transplants helps these patients. Allogeneic

transplant is the only treatment that will level the playing field.

Emerging Treatments What emerging treatments for AML look promising? The cooperative group trials are evaluating a number of new agents in high-risk patients. In patients with corebinding factor leukemia, we are evaluating dasatinib (Sprycel) given with highdose daunorubicin. For FLT3-positive disease, we are looking at sorafenib plus 7+3 chemotherapy (continuous intravenous [IV] cytarabine infusion for 7 days with an anthracycline given by IV push for 3 days). Another trial is comparing high-dose daunorubicin to highdose idarubicin with or without vorinostat (Zolinza). We are also evaluating early allogeneic transplant in high-risk patients. The future of AML sees us aggressively treating this disease in induction and consolidation. Molecular targets are being discovered, and directed therapy will hopefully improve upon remission rates and overall survival in this deadly disease. n

Disclosure: Dr. Fernandez reported no potential conflicts of interest.

References 1. Grimwade D, Hills RK, Moorman AV, et al: Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354-365, 2010. 2. Patel JP, Gönen M, Figueroa MET, et al: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366:1079-1089, 2012. 3. Petersdorf SH, Kopecky KJ, Slovak M, et al: A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121:48544850, 2013. 4. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al: Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: A systematic review and metaanalysis. Br J Haematol 163:315-325, 2013.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 29

Announcements

Charles LeMaistre, MD, and Hans Mark, PhD, Named Chancellors Emeritus by the University of Texas System Board of Regents

wo former Chancellors, Charles LeMaistre, MD, and Hans Mark, PhD, were recently given the honorific title Chancellors Emeritus by the University of Texas System Board of Regents. “Charles LeMaistre and Hans Mark were visionary chancellors who expanded

the University of Texas System from 1984 to 1992. He led the UT System to international prominence in engineering and science, and played a prominent role in bringing the high-tech industry

to Austin and Central Texas. As Chancellor, he presided over a major increase in federal and private funding for UT System institutions and was instrumental in bringing Pan Amer-

Now Charles LeMaistre, MD

Hans Mark, PhD

the UT System into new directions that greatly benefited higher education and the people of Texas,” said current Chancellor Francisco G. Cigarroa, MD. “They were unique, with exceptional careers in their respective fields of medicine and aerospace engineering before bringing their impressive talents to the UT System.”

Charles LeMaistre, MD Dr. LeMaistre is Professor of Internal Medicine who served as the fourth UT System chancellor, from 1971 to 1978. Under his leadership, the UT System expanded to include new health science centers in Houston and San Antonio and new universities in Dallas, Permian Basin and San Antonio. Dr. LeMaistre has devoted much of his professional career to cancer prevention and smoking control. He served on the first U.S. Surgeon General’s Advisory Committee on Smoking and Health in 1964, and later as the National President of the American Cancer Society. He was President of UT MD Anderson Cancer Center from 1978 to 1996 and holds the title President Emeritus.

Enrolling

BLADDER

A Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (UBC) (NCT02108652, Study ID GO29293)

A Phase II study for patients with locally advanced or metastatic UBC who are treatment-naïve and ineligible for cisplatin-based chemotherapy or have failed platinum-containing therapy Primary Endpoint:

N=330

MPDL3280A1 (an engineered anti-PDL1 antibody)

Secondary Endpoints:

• Objective response rate

• Duration of response • Progression-free survival • Overall survival • Safety: incidence of adverse events • Incidence of antitherapeutic antibodies to MPDL3280A • Maximum serum concentration (Cmax) of MPDL3280A

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Documented locally advanced or metastatic • • • • • •

transitional cell carcinoma of the urothelium Representative tumor specimens ECOG performance status of 0-1 Life expectancy ≥12 weeks Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end-organ function Refractory or ineligible for platinum-based chemotherapy

• History of autoimmune disease • Active hepatitis B or hepatitis C • HIV-positive • Administration of a live, attenuated vaccine

within 4 weeks before Cycle 1, Day 1 • Prior treatment with CD137 agonists, or immune

checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1

For more information Visit: clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only)

E-mail: global.rochegenentechtrials@roche.com

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

Hans Mark, PhD Dr. Mark is a physicist and retired Professor of Aerospace Engineering who served as the sixth Chancellor of

ican University into the UT System. Only two other chancellors, Harry Huntt Ransom, PhD (1961–1971) and E. Don Walker (1978–1984), have been named Chancellor Emeritus. n

The ASCO Post | SEPTEMBER 1, 2014

PAGE 30

Expert’s Corner Gastrointestinal Oncology

Understanding the Impact of Results From CALGB/ SWOG 80405 and Other New Data in Colorectal Cancer A Conversation With Alok A. Khorana, MD

Alok A. Khorana, MD

he Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) 80405 trial, presented during the Plenary Session at this year’s ASCO Annual Meeting, demonstrated that cetuximab (Erbitux) and bevacizumab (Avastin) confer similar benefits as first-line treatment with chemotherapy for KRAS wild-type metastatic colorectal cancer.1 The ASCO Post recently spoke to Alok A. Khorana, MD, Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University; and Sondra and Stephen Hardis Chair in Oncology Research, Vice Chair of Clinical Services, and Director of the GI Malignancies Program at Taussig Cancer Institute, Cleveland Clinic, about the study findings and its implications for clinical practice, as well as other important data in colorectal cancer presented at the Annual Meeting

Groundbreaking Abstract What’s your take on the CALGB/ SWOG 80405 study? CALGB/SWOG 80405 had to be the most groundbreaking abstract on colorectal cancer presented at this year’s ASCO Annual Meeting, as reflected by its selection for the Plenary Session. The study took 10 years to complete and asked the question, “What’s the most appropriate first-line treatment in metastatic colorectal cancer?” The reason it took 10 years to complete is that in the first couple of years, new findings suggested that one of the arms should be dropped, so there was an amendment. Additional new findings a couple of years later suggested that only KRAS wild-type patients should be included, so there was a second amendment. The study underwent several iterations before it arrived at the final design. In the end, it was a two-arm study of a

chemotherapy backbone, which was up to the physician, and random assignment to either cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, or bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor. It’s billed as a “negative” study because there was no difference in outcomes between the two arms, but it does have a lot of relevance to clinical practice. We’ve always wondered about the most appropriate first-line treatment in this setting, and the answer for right now is that it could be either one of these agents. The one downside of cetuximab is that there is increased skin toxicity, which was shown in this study as well. However, the skin toxicity did not seem to affect quality of life; the quality-of-life questionnaires were comparable between the two arms.

ment of KRAS wild-type metastatic colorectal cancer. Toxicities appear to be similar, median survival is close to 2½ years, and at 5 years, one-tenth of patients—almost 11% of the patients in this study—do not have cancer with metastatic disease.

Maintenance Chemotherapy What do the new data presented at the Annual Meeting show with regard to the benefit of maintenance chemotherapy? Once you get to about 6 months of therapy, most patients have too much drug-related toxicity and want to scale back their treatment. What options should be chosen at that time? Currently available options include the use of treatment holidays, in which you stop using drug therapy and follow those patients. Alternatively, they can continue

For now, you can use either cetuximab or bevacizumab in first-line treatment of KRAS wild-type metastatic colorectal cancer. Toxicities appear to be similar, median survival is close to 2½ years, and at 5 years, one-tenth of patients—almost 11% of the patients in [CALGB/SWOG 80405]—do not have cancer with metastatic disease. —Alok A. Khorana, MD

The second bit of good news from the study is that the median survival of cancer patients in this study was 29 months—that’s 2½ years. If you go back to the 1990s, the median survival was 12 months, and if you go back to the past decade, it was 20 or 22 months. So 29 months is a phenomenal improvement in median survival for patients with metastatic disease, and I think that is really something to be proud of for the gastrointestinal cancer community. A third takeaway from CALGB/ SWOG 80405 is that there are still findings to be made from this particular clinical trial. In just the past 6 months, we’ve discovered that there are additional RAS mutations that might limit the benefit of cetuximab. Subgroup analysis is underway to find those RAS mutations in this population and to exclude those patients from the general effects observed in the study. That subgroup analysis may yet alter the conclusions of the trial. So for now, you can use either cetuximab or bevacizumab in first-line treat-

on aggressive chemotherapy with more treatment combinations, or scale down chemotherapy to just one or two drugs with the biologic. Multiple abstracts have dealt with these options, and they all point in the same direction: treatment holidays are probably not the best route.2,3 The type of maintenance therapy could be either fluorouracil (5-FU) or capecitabine with bevacizumab, or it could be bevacizumab alone. The three approaches were not statistically significantly different, but if you look at the absolute benefit, there is a clear benefit for the

two-drug combination of either 5-FU/ bevacizumab or capecitabine/bevacizumab. For most patients, that is a gentler regimen. So now that we’ve sorted out the first-line treatment, the maintenance portion is likely not treatment holiday but a combination of a 5-FU–based regimen with an antibody, probably bevacizumab.

Extended RAS Testing What do the data show on the use of extended RAS testing? We’ve seen reports in the past couple of months looking at extended RAS testing, and up to 20% of patients—in one study, up to 30%—who we thought had wild-type disease and would benefit from an anti-EGFR approach, are no longer wild-type.4,5 Yet these patients have been getting an anti-EGFR antibody, they have been experiencing the skin toxicity, and the costs to the system have been very expensive. Data presented at this meeting, particularly the subgroup analysis of the OPUS6 and CRYSTAL7 large clinical trials all show that these patients do not show benefit from antiEGFR therapy, so the new standard of care should be that all metastatic colorectal cancer patients should be screened, not just for KRAS, which has been our standard for close to 10 years, but also with an extended RAS analysis, which includes NRAS and other codons of KRAS. n

Disclosure: Dr. Khorana is a consultant for and receives honoraria from Sanofi and Genentech.

References 1. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wildcontinued on page 31

Three Takeaways in Colorectal Cancer From ASCO 2014 ■■ For first-line therapy, either cetuximab or bevacizumab offer improved median survival and long-term responses in patients with KRAS wild-type metastatic disease. ■■ For maintenance therapy, switching to either 5-FU with or without bevacizumab, or bevacizumab alone—but not to a treatment holiday— appears appropriate. ■■ Extended RAS analysis—not just KRAS screening—should be performed for all patients.

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 31

Journal Spotlight Genitourinary Oncology

Systematic Model Identifies Factors Associated With Adherence in Prostate Cancer Prevention Trial

ealthy men participating in the Prostate Cancer Prevention Trial who actively participate in all steps of the clinical trial are most likely to undergo an end-of-study biopsy, according to a study published in Cancer Epidemiology, Biomarkers and Prevention.1

trial,” said Ellen R. Gritz, PhD, Chair of Behavioral Science at MD Anderson, and lead author on the study.

Study Details The prevention trial was coordinated by SWOG at 219 sites involving more

If we are able to determine which factors are associated with good adherence to study regimens evaluating cancer prevention agents, we may be able to improve the conduct of such large trials by targeting interventions to boost adherence.

cial outcomes, participant health status, participant adherence, and characteristics of the clinical sites at which the study was conducted. ”The biopsy provided the biological specimens that could be tested to see if a man’s prostate cells were cancer-free after 7 years on the trial,” said Carol Moinpour, PhD, of the Fred Hutchinson Cancer Research Center. “That is, the biopsy provided definitive information about which men had prostate cancer 7 years after the study started.”

Factors Associated With Adherence

The Prostate Cancer Prevention Trial was a randomized, double-blind, placebo-controlled trial which tested the efficacy of finasteride (Proscar). Researchers at The University of Texas MD Anderson Cancer Center and the Fred Hutchinson Cancer Research Center used a systematic model to identify factors associated with men adhering to the end-of-study biopsy requirement of the trial. “Our study is unique because it evaluated factors prospectively associated with an invasive biopsy for a cancer prevention trial, not a cancer treatment

than 18,000 men. Participants were randomized into one of two groups; those administered finasteride and those given a placebo. Participants received educational materials about the study and biopsy procedures and were asked to attend regularly scheduled appointments throughout the trial. Funded by the National Cancer Institute, scientists analyzed healthy men over a 7-year period to identify which factors at the 6-year study mark were associated with the willingness of the participant to undergo a biopsy. The factors examined included psychoso-

Researchers were able to assess factors associated with adherence for more than 13,000 men from the trial, and analyzed factors based on whether or not study participants had been prompted for a clinical biopsy by year six of the study. Researchers found participants were more likely to adhere to the end-ofstudy biopsy if 1 year prior to the biopsy they were adherent to the study drug, kept appointments, and underwent required tests and were in good health. Participants who had an end of study biopsy were more likely to be adherent to the study drug at year six (84%). Among participants who were not biopsied, 47% were adherent to the study drug. Results also showed that 98% of men who had an end-of-study biopsy had the digital rectal exam or PSA test done at year six, compared to 75% of

CALGB/SWOG 80405

Presented June 2, 2014. 3. Koopman M, Simkens L, May AM, et al: Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer. ASCO Annual Meeting. Abstract 3504. Presented June 2, 2014. 4. Tejpar S, Lenz HJ, Köhne CH, et al: Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus

FOLFOX4: New results from the OPUS study. 2014 Gastrointestinal Cancers Symposium. Abstract LBA444. Presented January 16, 2014. 5. Stintzing S, Jung A, Rossius L, et al: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract LBA17. Presented September 28, 2013. 6. Bokemeyer C, Kohne CH, Ciardi-

—Ellen R. Gritz, PhD

continued from page 30

type untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. LBA3. Presented June 1, 2014. 2. Arnold D, Graeven U, Lerchenmuller CA, et al: Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): A phase III non-inferiority trial (AIO KRK 0207). ASCO Annual Meeting. Abstract 3503.

men who did not have the end-of-study biopsy. “We also found that participants were more likely to adhere to biopsies if the study site that recruited the participant enrolled more than 200 participants and/or had resources for conducting activities to encourage continued participation in the trial,” said Dr. Gritz. Researchers said monitoring adherence behaviors in clinical trial participants can help identify participants at risk for noncompliance to a study requirement, and help create a model for adherence intervention strategies in future trials. “If we are able to determine which factors are associated with good adherence to study regimens evaluating cancer prevention agents, we may be able to improve the conduct of such large trials by targeting interventions to boost adherence,” said Dr. Gritz. n

Disclosure: The research was supported by the Public Service Health (CA37429) from the Department of Cancer Prevention, National Cancer Institute (NCI), NIH, Department of Health and Human Services. Lead author supported in part by funding from NCI (P30CA16672).

ello F, et al: Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. ASCO Annual Meeting. Abstract 3505. Presented June 2, 2014. 7. Ciardiello F, Lenz HJ, Kohne CH, et al: Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. ASCO Annual Meeting. Abstract 3506. Presented June 2, 2014.

Reference 1. Gritz ER, Arnold KB, Moinpour CM, et al: Factors associated with adherence to an end-of-life biopsy: Lessons from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 23:1638-1648, 2014.

The ASCO Post | SEPTEMBER 1, 2014

PAGE 32

FDA Update

FDA Approves First Noninvasive DNA Screening Test for Colorectal Cancer

he U.S. Food and Drug Administration (FDA) has approved Cologuard, the first stool-based colorectal screening test that detects the presence of red blood cells and DNA mutations that may indicate the presence of certain kinds of abnormal growths that may be cancers such as colon cancer or precursors to cancer.

with positive test results are advised to undergo a diagnostic colonoscopy.

Clinical Trial Results The safety and effectiveness of Cologuard was established in a clinical trial that screened 10,023 subjects.

The trial compared the performance of Cologuard to the fecal immunochemical test, a commonly used noninvasive screening test that detects blood in the stool. Cologuard S:6.75” accurately detected cancers and advanced adenomas more often than the fecal immunochemical

test: 92% of colorectal cancers and 42% of advanced adenomas were detected with stool DNA testing compared with 74% of cancers and 24% of advanced adenomas detected with fecal immunochemical testing. Cologuard was less accurate than

Using a stool sample, Cologuard detects hemoglobin and certain mutations associated with colorectal cancer in the DNA of cells shed by advanced adenomas as stool moves through the large intestine and rectum. Patients

FDA Grants Fast Track Designation to Novel JAK2 Inhibitor for the Treatment of Myelofibrosis

he U.S. Food and Drug Administration has granted Fast Track designation to pacritinib for the treatment of intermediate- and high-risk myelofibrosis, including patients with disease-related thrombocytopenia on other JAK2 therapy or patients who are intolerant to or whose symptoms are suboptimally managed on other JAK2 therapy. Pacritinib is an oral tyrosine kinase inhibitor with dual activity against JAK2 and FLT3.

Expedited Review The Fast Track process is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Pacritinib is currently being evaluated in two phase III clinical investigations: the PERSIST-1 trial, which includes a broad set of patients without limitations on blood platelet counts, and the PERSIST-2 trial, which is limited to patients with low platelet counts. n

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

05/14 [COM-0086]

B:17

T:1

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FDA Update

fecal immunochemical testing at correctly identifying subjects negative for colorectal cancer or advanced adenomas. The stool DNA test correctly gave a negative screening result for 87% of the study subjects, while the fecal immunochemical test provided accurate negative screening results for 95% of the study population.

Proposed CMS Coverage

concurrently review medical devices to help reduce the time between the FDA’s approval of a device and Medicare coverage. “Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as 6 months from the time from study initiation to coverage,” said

Upon the test’s approval, the Centers for Medicare & Medicaid Services (CMS) issued a proposed national coverage determination for Cologuard. Cologuard is the first S:6.75” through a joint product reviewed FDA-CMS pilot program known as parallel review, where the agencies

ancy Stade, Deputy Director for N Policy at the FDA’s Center for Devices and Radiological Health. CMS proposes to cover the Cologuard test once every 3 years for Medicare beneficiaries who are age 50 to 85 years, asymptomatic, and have an average risk of developing colorectal cancer. n

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

1.0

COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

HR=0.28 95% CI: 0.19, 0.40 P<0.0001

0.7 0.5 0.4

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

Probability of patients who are progression free

AE/AS

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

SIGNOFF

Disk

B:11.25”

S:9.75”

COMETRIQ® Placebo

T:10.25”

No. of patients at risk:

PharmaGraphics

0.0

0.1

S&H

7.5”

15”

ASCOPost.com | SEPTEMBER 1, 2014

Cosmos Comm C

27902a

COORDINATED ATTACK

The ASCO Post | SEPTEMBER 1, 2014

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FDA Update

FDA Approves Bevacizumab for Aggressive and Late-Stage Cervical Cancer

he U.S. Food and Drug Administration (FDA) has approved the antiangiogenic agent bevacizumab (Avastin) for the treatment of persistent, recurrent, or metastatic cervical cancer. The new indication is approved for use in combination with paclitaxel and cisplatin or

paclitaxel and topotecan. The FDA reviewed bevacizumab for the treatment of patients with cervical cancer under its priority review program. “[Bevacizumab] is the first drug approved for patients with late-stage cervical cancer since the 2006 approval of

topotecan with cisplatin,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It is also the first biologic S:6.75” agent approved for patients with latestage cervical cancer and was approved in

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

less than 4 months under the FDA’s priority review program, demonstrating the agency’s commitment to making promising therapies available to patients faster.”

Clinical Trial Results The approval was based on the results

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia. 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain. 5 Palmar-plantar erythrodysesthesia syndrome. 1

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FDA Update

PROD ED AE/AS CW CD

The approved retreatment supplemental New Drug Application consisted of a phase II study and other supportive data. The phase II international RETRIEVE trial was a single-arm, open-label trial enrolling 130 adult patients with myeloma who had previously responded to bortezomib-based therapy and relapsed at least 6 months after prior treatment with bortezomib. Patients received a median of two prior therapies, and dexamethasone was administered in combination with bortezomib in 94 patients. The RETRIEVE trial showed an overall response rate of 38.5%, with one patient achieving complete response and 49 achieving partial response. In the 50 responding pateints, the median duration of response was 6.5 months (range, 0.6–19.3 months). The safety profile seen with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed multiple myeloma; no cumulative toxicities were observed upon retreatment. See page 36 for a comprehensive summary of bortezomib retreatment. n

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RETRIEVE Trial

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T:10.25”

he U.S. Food and Drug Administration has approved bortezomib (Velcade) for the retreatment of adult patients with multiple myeloma who had previously responded to bortezomib therapy and relapsed at least 6 months following completion of prior bortezomib treatment. The labeling update includes dosing guidelines as well as safety and efficacy findings for single-agent use or use in in combination with dexamethasone in patients previously treated with bortezomib. Bortezomib retreatment may be started at the last tolerated dose. B:11.25”

S:9.75”

Stage 2: Systolic ≥160 mmHg or Diastolic ≥100 mmHg

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FDA Approves Bortezomib Retreatment in Patients With Multiple Myeloma

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash. • COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking. • COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss. • To contact their healthcare provider before any planned surgeries, including dental procedures. • COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking. • Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water. • Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment. Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

Gastrointestinal perforations (3.2%) and gastrointestinal-vaginal fistulae (8.2%) were also observed in bevacizumab-treated patients, all of whom had prior pelvic radiation. Other grade 3 or greater adverse reactions that were more common in patients receiving chemotherapy plus bevacizumab included venous thromboembolic events, hemorrhage, hypertension, proteinuria, and woundhealing complications. n

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose.

(95% CI = 14.1–19) vs 12.9 months (95% CI = 10.9–15) for those receiving chemotherapy alone. The most common side effects associated with use of bevacizumab in patients with cervical cancer include fatigue, decreased appetite, hypertension, hyperglycemia, hypomagnesemia, urinary tract infection, headache, and decreased weight.

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Results demonstrated a statistically significant improvement in overall survival in patients who received bevacizumab and chemotherapy vs chemotherapy alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.58–0.94, P = .013, log-rank test). The median overall S:6.75” survival of patients receiving bevacizumab and chemotherapy was 16.8 months

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of an international, randomized trial enrolling 452 patients with persistent, recurrent, or metastatic disease. Patients were randomly assigned to receive paclitaxel and cisplatin with or without bevacizumab or paclitaxel and topotecan with or without bevacizumab. Treatment continued until disease progression, unacceptable toxicity, and/or withdrawal of consent.

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In the Clinic Hematology

Bortezomib Retreatment in Multiple Myeloma By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n August 8, 2014, the approved use of bortezomib (Velcade) in multiple myeloma was expanded to include bortezomib retreatment in patients who have previously responded to bortezomib and who relapsed at least 6 months after completing prior bortezomib treatment.1 Retreatment may be started at the last tolerated dose. The drug labeling has been updated to include dosing recommendations and retreatment safety and efficacy data. Bortezomib was previously approved for treatment of patients with multiple myeloma and for treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Supporting Study Approval of retreatment was based on observation of durable responses in a single-arm phase II study in 130 adult patients who had achieved at least partial response on a prior bortezomibcontaining regimen.1,2 Patients had received a median of two prior lines

of therapy (range, 1–7). Patients with peripheral neuropathy or neuropathic pain of grade ≥ 2 were excluded from the study. Treatment was restarted at ≥ 6 months after prior bortezomib treatment at the last tolerated dose of 1.3 mg/m2 (n = 93) or ≤ 1.0 mg/m2 (n = 37) given intravenously on days 1, 4, 8, and 11 every 3 weeks for a maximum of eight cycles with or without dexamethasone. Overall, 83 patients received dexamethasone in cycle 1 and an additional 11 received it in later cycles. European Group for Blood and Marrow Transplantation responses (49 partial and 1 complete) were observed in 50 patients (overall response rate = 38.5%, 95% confidence interval = 30.1%–47.4%). Median duration of response in responders was 6.5 months (range, 0.6–19.3 months).

How It Is Given The recommended starting dose of bortezomib in multiple myeloma is 1.3 mg/m2. It can be given intravenously at a concentration of 1 mg/mL or subcutaneously at a concentration of 2.5 mg/mL. Bortezomib retreatment can be started at the last tolerated dose and should be given twice weekly on days 1, 4, 8, and 11 every 3 weeks for a maximum of eight cycles. Consecutive doses should be separated by > 72 hours. Bortezomib

Expanded Use of Bortezomib in Multiple Myeloma ■■ The approved use of bortezomib (Velcade) now includes retreatment in patients with multiple myeloma who previously responded to bortezomib and relapsed at ≥ 6 months after completing prior bortezomib treatment. ■■ Bortezomib retreatment can be started at the last tolerated dose and should be given twice weekly on days 1, 4, 8, and 11 every 3 weeks for a maximum of eight cycles.

can be administered as a single agent or in combination with dexamethasone.

Safety in Retreatment The most commonly reported adverse events (incidence ≥ 20%) in clinical studies of bortezomib include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. The safety profile of bortezomib in the study supporting retreatment was consistent with the known safety profile of the drug in patients with relapsed multiple myeloma. No cumulative toxicities were observed with retreatment. The most common adverse event of any grade was thrombocytopenia, which occurred in 52% of patients; grade ≥ 3 thrombocytopenia occurred in 24%. Peripheral neuropathy occurred in 28% of

OF NOTE No cumulative toxicities have been observed with bortezomib retreatment.

patients and was of grade ≥ 3 in 6%. Serious adverse events occurred in 12.3% of patients, with the most common being thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events led to discontinuation of treatment in 13%, with reasons including peripheral neuropathy (5%) and diarrhea (3%). Deaths considered to be drug-related occurred in two patients, one due to cerebrovascular accident and one due to sepsis, within 30 days of the last bortezomib dose. Bortezomib carries warnings/precautions for peripheral neuropathy,

OF NOTE The most commonly reported adverse events associated with bortezomib include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

cardiac toxicity, pulmonary toxicity, posterior reversible encephalopathy syndrome, gastrointestinal toxicity, thrombocytopenia and neutropenia, tumor lysis syndrome, hepatic toxicity, and embryo-fetal risk. n References 1. VELCADE® (bortezomib) for injection prescribing information, Millennium Pharmaceuticals, Inc, August 2014. Available at www.velcade.com/files/pdfs/velcade_prescribing_information.pdf. 2. Petrucci MT, Giraldo P, Corradini P, et al: A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol 160:649-659, 2013.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

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ASPHO Annual Meeting Hematology

Advances in Hematopoietic Cell Transplant for Pediatric AML Reduce Toxicity and Expand Access, but Relapse Remains a Problem By Charlotte Bath

dvances in allogeneic hematopoietic cell transplantation for children with acute myeloid leukemia (AML) have resulted in less toxic pretransplant conditioning regimens and expanded access to transplantation, but post-treatment leukemic relapse remains a big problem. The progress and continuing challenges were outlined at the opening Plenary Session of the second annual joint educational meeting of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and the American Society of Pediatric Hematology Oncology (ASPHO) in Chicago.

time. Reductions in transplant-related mortality have been achieved through better human leukocyte antigen (HLA) matching, less toxic conditioning, and

enhanced supportive care, Dr. Horan observed. Survival with well-matched unrelated donors is approaching that with matched related donors, he added.

Relapse is “probably the biggest problem facing us,” Dr. Horan stated. There continued on page 38

We Will

Better Conditioning Regimens “One of the real successes” in using hematopoietic cell transplant for children with AML has been in developing better conditioning regimens and the “reduction in regimen-related toxicity,” noted John Horan, MD, Associate Professor of Pediatrics at Emory University School of Medicine in Atlanta. He reviewed the progression of conditioning regimens from total-body irradiation plus cyclophosphamide in the 1970s and 1980s, to oral busulfan (Myleran) and cyclophosphamide in the 1990s, and thereafter to intravenous busulfan (Busulfex)/cyclophosphamide. A 2013 study demonstrated the superiority of intravenous busulfan/cyclophosphamide over earlier regimens, showing significantly less nonrelapse mortality, a lower relapse rate at 1 year or more post-transplant, and better leukemia-free survival.1 A myeloablative regimen of intravenous busulfan and fludarabine has been associated with reduced toxicity but with survival and nonrelapse mortality similar to intravenous busulfan/cyclophosphamide. This combination is being investigated in clinical trial AAML 1031. A myeloablative regimen of high-dose treosulfan (an investigational alkylating agent) plus fludarabine also showed reduced toxicity and a low incidence of transplant-related mortality2 and is being studied in PBMTC ONC1101. “Thought-provoking results” were provided by a study comparing reducedintensity conditioning regimens and myeloablative conditioning in children with AML undergoing allogeneic hematopoietic cell transplant.3 However, no significant differences in overall survival, disease-free survival, relapse, or nonrelapse mortality were seen, Dr. Horan reported. Trials using unrelated donors to expand access to transplantation have shown improvements in outcomes over

Major Challenge

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The ASCO Post | SEPTEMBER 1, 2014

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ASPHO Annual Meeting Hematology

Protocol Modifications Decrease Toxicity, Increase Event-Free Survival in Children With Down Syndrome Treated for ALL By Charlotte Bath

rotocol modifications to address increased risk of toxicity and excess early mortality among children with Down syndrome being treated for B-cell acute lymphoblastic leukemia (ALL) proved safe for patients with Down syndrome, and these patients had event-free survival similar to those without Down syndrome. Overall survival, however, was still significantly inferior among children with Down syndrome. The results of a study comparing two Children’s Oncology Group (COG) clinical trials were summarized by lead author Kelly W. Maloney, MD,

Associate Professor, Pediatrics-Hematology/Oncology, Children’s Hospital Colorado in Aurora, at the 27th Annual Meeting of the American Society of Pediatric Hematology Oncology (ASPHO) in Chicago. The study was one of two “particularly outstanding” abstracts chosen from among 400 submitted abstracts for presentation at the meeting’s Plenary Session, noted ASPHO’s then-President, A. Kim Ritchey, MD. He is Vice Chair of Clinical Affairs, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center.

More Therapy-Related Toxicities “Children with Down syndrome and acute lymphoblastic leukemia have more toxicities related to their therapy, and this has been pretty well documented and published,” Dr. Maloney noted. These include grade 2–4 gastrointestinal toxicities, grade 3–4 hematologic toxicities, and infections. “In general most of the protocols have shown an increase in infections, sometimes significantly increased over those without Down syndrome undergoing comparable treatment,” Dr. Maloney continued.

Hematopoietic Cell Transplant the pathologic DOT1L-MLL axis in incontinued from page 37

has been “no obvious decrease in relapse over the past 2 decades,” he pointed out, and gains in survival have been more modest than reductions in transplantrelated mortality. “Relapse is the major challenge,” agreed John Perentesis, MD, Director of the Division of Oncology and Cancer Programs at Cincinnati Children’s Hospital Medical Center. “Between onequarter and one-third of patients struggle with relapse,” he said. Important strategies being tested to prevent relapse after bone marrow transplant include enhancing the graft-vs-leukemia effect and targeted post-transplant chemotherapy with sorafenib (Nexavar) for FLT3-mutated blasts, and hypomethylating agents such as decitabine and azacitidine. At high doses, decitabine and azacitidine “work like not very good chemotherapeutic drugs,” Dr. Perentesis said. “They have cytotoxicity. They kill the tumor cells, but they also produce a lot of toxicity to normal cells.” At low doses, they appear to reactivate cellular growth regulatory pathways, and potentially inhibit leukemic stem cell self-renewal and sensitivity to cytotoxic therapies. In a recent small series of pediatric relapsed AML patients, three of eight patients achieved some form of a complete response with low-dose decitabine therapy,4 and several adult studies have indicated feasibility of post-SCT “maintenance” regimens incorporating lowdose decitabine or panobinostat (a histone deacetylase inhibitor). Newer epigenetic modulators with potentially high-specificity targeting of

Targeted agents are being used for AML in the transplant setting to both reduce minimal residual disease and address the problem of post-transplant relapse. One of the challenges is that “AML stem cells share features of hematopoietic progenitors that lead to drug resistance…. AML has a robust system to protect itself from toxic products such as chemotherapeutic agents,” Dr. Perentesis noted. “CD33 is an AML cell surface target,

COG trial ALL0232, a phase III trial for patients with high-risk ALL, was a continued on page 40

Disclosure: Drs. Horan and Perentesis reported no potential conflicts of interest. John Perentesis, MD

cell engaging (BiTE) antibody, in primary AML samples led to T-cell recruitment and expansion, as well as highly potent antibody-mediated cytotoxicity, suggesting efficient therapeutic potential in vivo.5 Findings from another preclinical study cited by Dr. Perentesis suggest that SGN-CD33A, a novel CD33-targeting antibody-drug conjugate, “has CD33-directed antitumor activity and

One of the real successes in using hematopoietic cell transplantation for children with AML has been in developing better conditioning regimens and the reduction in regimen-related toxicity. —John Horan, MD

one of several that has been of great interest. It is a good marker with significant expression of AML blasts, and it is also probably associated with prognostic risk factors,” Dr. Perentesis stated. He cited a study that assessed CD33 expression levels by flow cytometry and found expression in over 99% of AML samples from adult patients. The study also found that targeting CD33 ex vivo using AMG 330, a CD33/CD3-bispecific T-

Excessive Induction Mortality

pathway, and new BLC2 inhibitors engineered to minimize throbocytopenia. “We’ve thought about targetable pathways for a long time,” he noted in closing, but cautioned, “it is likely that you actually have to hit the target directly.” n

fant mixed-lineage leukemias or altered EZH2 activity in leukemia are under active investigation in pediatric AML, with the novel experimental drugs EPZ-5676 and EPZ-6438, respectively.

Surface Antigen– Targeted Therapies

Children with Down syndrome and ALL have “increased mortality during induction, but they are also more likely to suffer death after obtaining remission,” Dr. Maloney said. The mortality rate “can be as high as 28% vs a more standard 2% to 3%, and perhaps even lower in those children who do not have Down syndrome. There is an increased risk of death from relapse as well.”

support clinical testing of this novel therapeutic in patients with AML.”6 This is an exciting time for new prospects to treat AML, as dozens of targeted drugs are in development, Dr. P erentesis said. These include next-generation drugs targeting FLT3-ITD and potential specificity against resistance mutations, new agents targeting the c-Kit and RAS/MEK axes, small molecules with more effective inhibition of the mTOR

References 1. Copelan EA, Hamilton BK, Avalos B, et al: Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 122:3863-3870, 2013. 2. Nemecek ER, Guthrie KA, Sorror ML, et al: Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 17:341-350, 2011. 3. Bitan M, He W, Zhang MJ, et al: Transplantation for children with acute myeloid leukemia: A comparison of outcomes with reduced intensity and myeloablative regimens. Blood 123:1615-1620, 2014. 4. Phillips CL, Davies SM, McMasters R, et al: Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and youg adults. Br J Haematol 161:406-410, 2013. 5. Krupka C, Kufer P, Kischel, R, et al: CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood 123:356-365, 2014. 6. Kung Sutherland MS, Walter RB, Jeffrey SC, et al: SGN-CD33A: A novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122:1455-1463, 2013.

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The ASCO Post | SEPTEMBER 1, 2014

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Pan Pacific Lymphoma Conference Hematology

Best Way to Treat Mediastinal Lymphomas Is Still Unclear By Susan London

variety of treatment options used today can achieve good outcomes in patients with mediastinal lymphomas, according to James O. A rmitage, MD, the Joe Shapiro Professor of Medicine at the University of Nebraska Medical Center in Omaha. He discussed some of the current evidence helping to refine the management of primary mediastinal large B-cell lymphoma and mediastinal gray zone lymphoma at the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii.

Primary Mediastinal Large B-Cell Lymphoma

get over it—and you know that in a relatively short period of time—or they succumb, and unfortunately, salvage therapy has not always been as effective as we would like. So it’s different from other large B-cell lymphomas,” he elaborated. When it comes to treatment, a retrospective analysis of data from patients treated in Vancouver, British Columbia, found that CHOP-R (cyclophosphamide, doxorubicin, vincristine, and prednisone, with rituximab [Rituxan]) was superior to CHOP alone with respect to 5-year overall survival (88% vs 70%).2 Outcomes did not differ signifi-

Is there only one way to treat mediastinal large B-cell lymphoma? I think the answer is no. —James O. Armitage, MD

cantly between patients who did vs did not routinely get radiotherapy (82% vs 89%). Among patients undergoing positron-emission tomography (PET)

“Mediastinal B-cell lymphoma is a unique entity…. It really is different from the rest of the diffuse large B-cell lymphomas,” Dr. Armitage pointed out.1 This tumor initially caught attention in part because of its distinct survival pattern, with nearly all relapses after remission occurring within 3 years. “In this disease, patients either

Table 1: Deauville 5-Point Criteria for PET Scans

Children With Down Syndrome and ALL

COG trial ALL0331 enrolled 5,311 patients with standard-risk ALL, 140 with Down syndrome. The trial used a three-drug induction with dexamethasone for 28 days, vincristine, and pegaspargase. Children with Down syndrome participated in the postinduction randomization to intensified vs standard consolidation, with Capizzi methotrexate as interim maintenance. “Both studies experienced excessive induction mortality for children with

continued from page 38

randomized comparison of 28 days of prednisone vs 14 days of dexamethasone during induction, and high-dose methotrexate with leucovorin rescue vs escalating intravenous methotrexate without rescue plus pegaspargase (Oncaspar) using the Capizzi schedule in interim maintenance. “As planned from the beginning, pa-

1. No uptake 2. Uptake ≤ mediastinum 3. Uptake, but at lower value than in mediastinal blood pool 4. Uptake moderately more than liver uptake, at any site 5. Markedly increased uptake at any site and new site of disease Source: André M, et al: Advances in Hematology, 2011.

We have a similar event-free survival in the Down syndrome children and non–Down syndrome children. We can deliver this therapy safely, but we do have to be mindful [that the children with Down syndrome] need additional supportive care and probably additional attention. —Kelly W. Maloney, MD

tients with Down syndrome participated in the induction steroid randomization, but were not randomly assigned to highdose methotrexate, but were nonrandomly assigned to Capizzi methotrexate,” Dr. Maloney said. This trial enrolled 3,084 patients, 39 with Down syndrome.

[Down syndrome] initially and were modified with expanded supportive care guidelines and leucovorin rescue after intrathecal methotrexate. These modifications successfully eliminated excessive mortality on AALL0331. However, excessive mortality persisted in [high-risk

at the end of CHOP-R, survival was statistically indistinguishable for the PET-positive group given radiotherapy and the PET-negative group not given radiotherapy (95% vs 89%). “It looks like this certainly would provide an argument that if you want to use CHOP-R, you do a PET scan at the end, and if patients are PET-negative, you can follow them, and you end up with roughly a 90% survival, rather than giving radiotherapy to all of these patients. This would be one way to continued on page 41

Down syndrome] ALL on AALL0232 and enrollment to this protocol was halted in 2008,” according to the abstract.

Collective Results Looking at the studies collectively shows that children with Down syndrome had lower 5-year event-free survival and higher morality. Event-free survival for both studies was 80% ± 4% for patients with Down syndrome vs 84.3% ± 0.6% (P = .059) for those without Down syndrome, and overall survival was 82.8% ± 3.8% vs 92.2% ± 0.4% (P < .0001), respectively. Looking at the studies individually confirms that children with Down syndrome had lower event-free and overall survival than those without Down syndrome, but also shows that children with Down syndrome receiving the modified protocol had better 5-year event-free survival than those in the original protocol (86.1% ± 4.2% vs 57.8% ± 8.4%), and better 5-year overall survival (89.2% ± 3.8% vs 60.3% ± 8.3%). With the modified protocol, the 5-year event-free survival was similar for children with and without Down syndrome (86.1% ± 4.2% vs 89.5% ± 0.6%, P = .102), but overall survival was significantly inferior (89.2% ± 3.8% vs 96.1% ± 0.4%, P < .0001). On trial AALL0331, “the induction

A. Kim Ritchey, MD

mortality dropped to 1.7%, which was in line with all the past standard-risk trials and we felt was very acceptable, and postinduction, we did not have any remission deaths,” Dr. Maloney said. “We have a similar event-free survival in the Down syndrome children and non–Down syndrome children. We can deliver this therapy safely, but we do have to be mindful [that the children with Down syndrome] need additional supportive care and probably additional attention,” she noted. n Disclosure: Dr. Maloney reported no potential conflicts of interest.

Reference 1. Maloney K, Larsen E, Devidas M, et al: Event free (EFS) and overall survival (OS) for children with Down syndrome (DS) and B-lymphoblastic leukemia (BALL) in Children’s Oncology Group (COG) clinical trials AALL0232 and AALL0331. ASPHO Annual Meeting. Abstract 4009. Presented May 15, 2014.

ASCOPost.com | SEPTEMBER 1, 2014

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Pan Pacific Lymphoma Conference Mediastinal Lymphomas continued from page 40

try to avoid giving radiotherapy,” Dr. Armitage noted. The German MINT (MabThera International Trial Group) study compared CHOP-like chemotherapy with vs without rituximab in patients with diffuse large B-cell lymphoma, with radiotherapy added for most patients.3 In an analysis looking at tumor subtypes, the 87 patients with mediastinal large B-cell lymphoma had a poorer complete response rate if they did not receive rituximab, and rituximab also yielded a better 5-year overall survival (78% vs 90%).4 A retrospective analysis by the International Extranodal Lymphoma Study Group assessed the prognostic value of various PET cutoffs among patients with mediastinal large B-cell lymphoma who had been treated with rituximab and anthracycline-containing chemoimmunotherapy, and usually also radiotherapy.5 The best discrimination was seen for a Deauville score of 1, 2, or 3 vs a Deauville score of 4 or 5 (Table 1); this cutoff yielded a 99% negative predictive value for progression or relapse. “Remember, PET scans are much more valuable in terms of negative predictive value than positive predictive value. When a PET scan is positive, there are more things than just lymphoma that can be causing it…. But a negative PET scan is more prognostic,” Dr. Armitage noted. Finally, a study of patients with me-

diastinal B-cell lymphoma treated with dose-adjusted EPOCH-R (etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab) but no radiotherapy showed that this regimen achieved excellent outcomes. 6 With a median follow-up of 5 years, patients had an event-free survival of 93% and an overall survival of 97%. However, if it is administered in the hospital, this approach is more inconvenient and more expensive. Current data thus show that a variety of approaches can achieve longerterm survival of approximately 90% in patients with this disease. “So is there only one way to treat mediastinal large B-cell lymphoma? I think the answer is no. However, if the goal is to avoid radiotherapy, this seems to be most likely achieved by using EPOCH-R” he said.

Mediastinal Gray Zone Lymphoma “Mediastinal gray zone lymphoma is a real but confusing entity,” Dr. Armitage commented. “We cannot even agree on how to spell it (gray vs grey). This isn’t composite diffuse large B-cell lymphoma and nodular sclerosing Hodgkin lymphoma. Instead, mediastinal gray zone lymphoma appears to have some characteristics of one type and some of the other,” he continued. “This complicates our management. I can’t imagine that I’m the only one who has been frustrated wondering whether these patients are bet-

A Cautionary Note on Radiotherapy

linicians should use radiotherapy very judiciously in the treatment of mediastinal lymphomas, especially in young patients, recommended Wyndham H. Wilson, MD, PhD, Chief of the Hematological Malignancies Therapeutics Section, Metabolism Branch, Cancer Research Center, of the National Cancer Institute in Bethesda, Maryland., Moreover, longer-term data suggest the prognosis of mediastinal gray zone lymphomas may not be as poor as previously thought in the absence of radiotherapy, he said at the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii

I just wanted to emphasize that radiotherapy in young people is dangerous, dangerous, dangerous. And if there is anything you can do to not use it, I think that would be really wise. —Wyndham H. Wilson, MD, PhD

Who Needs Radiotherapy? “It still stands that they have a significantly worse outcome than that associated with primary mediastinal lymphoma. We still watch them very carefully, and we find that if the Deauville score is 1, 2, or 3, that those people almost never relapse, but if it’s more than that, then radiation is needed,” he said. “I think it is an open question whether or not you want to give all of these patients radiotherapy. I would agree that they do the worst, and if you really want to be extra cautious, then you certainly could radiate them all,” he continued. “But as it turns out, the Deauville score is a pretty good way of identifying those with gray zone lymphoma who really need radiation.” Recent long-term data on patients receiving radiotherapy for Hodgkin lymphoma are “devastating,” Dr. Wilson maintained. “I just wanted to emphasize that radiotherapy in young people is dangerous, dangerous, dangerous. And if there is anything you can do to not use it, I think that would be really wise,” he concluded. n Disclosure: Dr. Wilson reported no potential conflicts of interest.

continued on page 42

EXPERT POINT OF VIEW

ince the presentation on mediastinal lymphoma at the Pan Pacific Lymphoma Conference, Wyndham H. Wilson, MD, PhD, Chief of the Hematological Malignancies Therapeutics Section, Metabolism Branch, Cancer Research Center, of the National Cancer Institute in Bethesda, Maryland, offered The ASCO Post the following considerations: The Vancouver R-CHOP results1 come from a retrospective analysis of patients from multiple centers that employed treatment guidelines. Furthermore, the outcome is presented as overall survival and over estimates the initial “curative potential” of R-CHOP, which is best determined by event-free survival. Importantly, the Vancouver group reported that among 35 pa-

tients who were positron-emission tomography (PET)-negative after R-CHOP and did not receive radiotherapy, 17% recurred.2 In contrast, among 51 patients from the Na-

MINT Trial Reconsidered In addition, Dr. Wilson noted that the retrospective analysis of the primary mediastinal B-cell lymphoma patients from the MINT trial4 only

I think until proven otherwise, DA-EPOCH-R should be considered the standard for [primary mediastinal B-cell lymphoma]. —Wyndham H. Wilson, MD, PhD

tional Cancer Institute and 16 patients from Stanford who received DA-EPOCH-R and no radiotherapy, only 3% recurred, irrespective of the PET scan results.3 Thus, the incidence of treatment failure after R-CHOP alone in PET-negative patients is high.

included patients with an International Prognostic Index score of 0 to 1. “Because patients with advanced stage disease were not included, where the outcome of R-CHOP is particularly poor, these results overestimate the outcome of R-CHOP and radiotherapy in [primary medi-

astinal B-cell lymphoma],” he said. Dr. Wilson continued, “Multiple survivorship studies of radiotherapy in mediastinal Hodgkin lymphoma have shown a very high incidence of second and third cancers. The incidence of breast cancer is especially high, and [primary mediastinal Bcell lymphoma] is more common in young women. While newer radiation techniques may reduce secondary cancers, studies show that there is no safe dose of radiotherapy, and the changes in techniques do not reduce radiation dose in a major fashion.” DA-EPOCH-R is the only immunotherapy treatment that has ever been prospectively studied, he pointed out. All of the other studcontinued on page 43

The ASCO Post | SEPTEMBER 1, 2014

PAGE 42

Pan Pacific Lymphoma Conference CODE: JJ-14-2 B size

PUB/POST: Advertoria

DESCRIPTION: Advertorial Spread Ad (Size B)

Mediastinal Lymphomas continued from page 41

ter off treated like they have a large B-cell lymphoma or like they have a Hodgkin lymphoma,” he added. Some likely good news from the molecular perspective is that these tumors are almost always positive for both CD20, suggesting a role for rituximab, and CD30, suggesting a possible role for brentuximab (Adcetris). At present, data are insufficient to know how best to treat mediastinal gray zone lymphoma, according to Dr. Armitage. In a study of patients given dose-adjusted EPOCH-R without radiation therapy having a median follow-up of 4 years, those with gray zone lymphomas had poorer outcomes than those with primary mediastinal B-cell lymphoma, in terms of progression-free survival (45% vs 90%) and overall survival (75% vs 100%).7 However, with the addition of radiotherapy after chemotherapy, the rate of progression-free survival improved to about 80% in the patients with gray zone lymphomas. “So I believe that when you treat mediastinal gray zone lymphoma, most of these patients should get radiotherapy. That’s what I would recommend to my patients,” he said, while acknowledging that the topic remains controversial. n Disclosure: Dr. Armitage is a consultant for Genentech, GlaxoSmithKline, Roche, Seattle Genetics, Spectrum, and Ziopharm, and a Member of the Board of Directors for Tesaro.

References 1. Cazals-Hatem D, Lepage E, Brice P, et al: Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA (“Groupe d’Etude des Lymphomes de l’Adulte”) study. Am J Surg Pathol 20:877888, 1996. 2. Savage KJ, Yenson PR, Shenkier T, et al: The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. 2012 American Society of Hematology Annual Meeting. Abstract 303. Presented December 10, 2012. 3. Pfreundschuh M, Trümper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379391, 2006. 4. Witzens-Harig M, Ho AD, Kuhnt E, et al: Primary mediastinal B cell lympho-

ma treated with CHOP-like chemotherapy with or without rituximab: 5-year results of the Mabthera International Trial Group (≤MInT) study. 2012 American Society of Hematology Annual Meeting. Abstract 1612. Presented December 8, 2012. 5. Martelli M, Ceriani L, Zucca E, et al: [18F]fluorodeoxyglucose positron emis-

FILE: 02B-006620-02C-770584-B ma.212.237.7000 N Engl J Med 368:1408-1416, 2013.SIZE SPREAD.indd sion tomography predicts survivalDelivery after Support: 7. Dunleavy K, Pittaluga S, Tay K, et chemoimmunotherapy for primary mediastinal large B-cell lymphoma: Results of al: Comparative clinical and biological the International Extranodal Lymphoma features of primary mediastinal B-cell Study Group IELSG-26 Study. J Clin On- lymphoma (PMBL) and mediastinal grey zone lymphoma (MGZL). 2009 col 32:1769-1775, 2014. 6. Dunleavy K, Pittaluga S, Maeda LS, et American Society of Hematology Anal: Dose-adjusted EPOCH-rituximab ther- nual Meeting. Abstract 106. Presented apy in primary mediastinal B-cell lympho- December 6, 2009.

A PERFECT

Connections between intracellular signaling In B-cell malignancies, intracellular dysfunction and external factors enable the disease state.1,2 Intracellular signaling pathways that control survival and proliferation can be dysregulated, resulting in inappropriate survival.1 These internal prosurvival processes are augmented by external signals from supportive cells and factors in the microenvironment such as the lymph nodes and bone marrow.2,3

Intracellular signaling pathways TLR

BCR

CXCR4/5

New research is revealing how intracellular signaling and the microenvironment are involved in B-cell malignancies. Pharmacyclics, Inc. and Janssen Biotech, Inc., are committed to furthering the understanding of these important connections in B-cell malignancies.

For more information, including the new animation “Intracellular Signaling and the Microenvironment in B-cell Malignancies,” visit www.BCellSignals.com.

ASCOPost.com | SEPTEMBER 1, 2014

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Pan Pacific Lymphoma Conference

al Spread Ad (3 Sizes), PRODUCTION: Roseann P.

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Mediastinal Lymphomas continued from page 41

ies are either retrospective analyses and/or include radiotherapy. Finally, Dr. Wilson noted that the cost of R-CHOP and radiotherapy is significantly greater than DA-EPOCH-R

and extends treatment for weeks. “Based on these findings,” he commented, “I think until proven otherwise, DA-EPOCH-R should be considered the standard for [primary mediastinal B-cell l ymphoma].” He added that the data presented

on gray zone lymphoma at the Pan Pacific meeting are older and based on an abstract. “Our full series is now published online with updated and improved outcomes.”5 n Disclosure: Dr. Wilson reported no potential conflicts of interest.

STORM and the microenvironment The microenvironment provides a proliferative, protective niche for malignant cells.2,4-6 The microenvironment supplies survival signals and may contribute to the development of resistance in malignant cells.2,4-6 Internal aberrant prosurvival signaling and increased homing to and retention within supportive microenvironments likewise reinforce the prosurvival signals in malignant B cells,1-3,5 promoting a cycle that maintains disease.

Microenvironment

References 1. Savage KJ, Yenson PR, Shenkier T, et al: The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the RCHOP treatment era. 2012 American Society of Hematology Annual Meeting. Abstract 303. Presented December 10, 2012. 2. Savage KJ, Yenson PR, Shenkier T, et al: The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. 2012 American Society of Hematology Annual Meeting. Abstract 303. Presented December 10, 2012. 3. Dunleavy K, Pattaluga S, Maeda LS, et al: Dose-adjusted EPOCHrituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368:1408-1416, 2013. 4. Pfreundschuh M, Trümper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOPlike chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379-391, 2006. 5. Wilson WH, Pittaluga S, Nicolae A, et al: A prospective study of mediastinal gray zone lymphoma. Blood. July 14, 2014 (early release online).

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland

TLR=toll-like receptor; BCR=B-cell receptor; CXCR4/5=C-X-C (motif) chemokine receptor 4, C-X-C (motif) chemokine receptor 5. Creative representations of select simpliﬁed signaling pathways. Illustrations not to scale. References: 1. Shaffer AL III, Young RM, Staudt LM. Annu Rev Immunol. 2012;30:565-610. 2. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. Blood. 2009;114:3367-3375. 3. Davids MS, Burger JA. Open J Hematol. 2012;3. 4. Burger JA, Kipps TJ. Blood. 2006;107:1761-1767. 5. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Blood. 2009;113:4604-4613. 6. Kurtova AV, Balakrishnan K, Chen R, et al. Blood. 2009;114:4441-4450.

The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms. For more information, visit www.lymphcon.ch/imcl/index.php2

PRC-00437

The ASCO Post | SEPTEMBER 1, 2014

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Palliative Care in Oncology The Role of Integrated Palliative Care in Radiation Oncology A Conversation With Tracy A. Balboni, MD, MPH By Jo Cavallo

hree years ago, Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, launched a Supportive and Palliative Radiation Oncology (SPRO) program to integrate generalist palliative oncology services, including the physical, psychosocial, and spiritual aspects of care, into radiation therapy for patients with advanced cancers. The goals of the program are to improve clinical care for patients and the system of care, including its departmental structure and interface with collaborating services, and

ing interest in integrating palliative care and radiation oncology now, palliative care has not been a focus within radiation oncology historically. We saw this program as an opportunity to establish integrated models of palliative services in radiation oncology care, so our Departments of Radiation Oncology and Psychosocial Oncology and Palliative Care worked together to create a system to provide these services. We see patients at every stage of the trajectory of their disease, from the time

We saw this program as an opportunity to establish integrated models of palliative services in radiation oncology care, so our Departments of Radiation Oncology and Psychosocial Oncology and Palliative Care worked together to create a system to provide these services. —Tracy A. Balboni, MD, MPH

to advance palliative cancer care within radiation oncology through education and research. The ASCO Post talked with Tracy A. Balboni, MD, MPH, Clinical Director of the Supportive and Palliative Radiation Oncology Service and Researcher at the Center for Outcomes and Policy Research at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and Associate Professor in Radiation Oncology at Harvard Medical School, about the program and the integration of palliative services within radiation oncology.

Palliative Care Integration Please talk about the Supportive and Palliative Radiation Oncology service and how radiotherapy for palliation has been integrated into your radiotherapy clinic. Within the practice of radiation oncology, we encounter many patients living with advanced cancer who require palliation for symptom relief and to improve their quality of life. Approximately one-third of treatments that radiation oncology departments deliver are for this purpose, and while there is a grow-

of initial diagnosis to the end of life. Care within each stage presents opportunities to communicate with patients and family members and aid them in their understanding of where they are in their diagnosis, as well as how to intervene with radiation therapy to improve symptoms and control disease.

Program Staff How is the program staffed? We have a team consisting of two nurse practitioners, one attending physician, and one resident. It’s a busy service, and having a dedicated team in place affords us the ability to treat the needs of the whole patient. Attending physicians and residents rotate on the service on a weekly basis and are solely dedicated to SPRO and related patient care for that week. Our nurse practitioners are core members of the SPRO service week-to-week and have training in both palliative care and oncology, which is a critically important combined level of expertise for the service. One of the reasons we decided to launch this service was that by the standard care model, advanced cancer

patients with urgent issues were added to an attending physician’s already full schedule. The physician may not only have inadequate time, but also might not have the support of a resident or nurse practitioner with a dedicated interest in palliative care. This type of isolated care is not an adequate model for patients facing complex issues related to symptomatic advanced cancers, whether those issues arise at the time of initial diagnosis, at disease progression, or at end of life.

New Technologies Are there new radiotherapy technologies available to improve radiotherapy for palliation? Yes, there are. These technologies include the use of more focal therapies to treat regions of symptomatic tumors such as in the brain or within the spine. These technologies can afford greater dose intensity and tumor control of lesions at critical sites while minimizing dose to nearby normal structures. However, technologic advancement within palliative radiotherapy not only includes the application of sophisticated technologies, such as high-dose, stereotactic treatments, but also the more judicious use of radiotherapy, particularly in light of a patient’s disease trajectory. One example is greater use of conventional radiation therapy with a hypofractionated approach (higher dose per treatment, fewer treatment regimens, eg, 8 Gy × 1 for bone metastases) to spare patients protracted time on therapy, especially when life expectancy is short. Furthermore, technologic advancements are needed to better define patients who won’t benefit from palliative radiotherapy based on a short life expectancy. Understanding and disseminating these critical nuances of palliative radiation oncology care requires research as well as the education of radiation oncology clinicians. Along with optimizing patient care, these are the primary goals of the SPRO service.

Spirituality and Religion What role does spirituality and religion play in palliative care? Spirituality frequently plays a critical role for patients in both the curable and incurable setting. Whether in re-

GUEST EDITOR

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is Senior Director of Education, Science and Professional Development Department at ASCO.

ligious or nonreligious forms, spirituality is an avenue by which many patients and family members cope with the stressful circumstances of cancer and find meaning in the midst of the trial of illness. Our studies1,2 of spirituality after an advanced cancer diagnosis have included examining the roles such beliefs play in patient quality of life and medical decision-making, as well as the spiritual struggles patients and families can face as they encounter an illness. Such efforts are one example of palliative care research that attempts to understand patients and families as they face a life-threatening illness and how we as caregivers can provide care in a more holistic way. n

Disclosure: Dr. Balboni reported no potential conflicts of interest.

References 1. Vallurupalli M, Lauderdale K, Balboni MJ, et al: The role of spirituality and religious coping in the quality of life of patients with advanced cancer receiving palliative radiation therapy. J Support Oncol 10:8187, 2012. 2. Phelps AC, Maciejewski PK, Nilsson M, et al: Religious coping and use of intensive life-prolonging care near death in patients with advanced cancer. JAMA 301:1140-1147, 2009.

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 45

Announcements Breast Cancer

Palbociclib Expanded Access Program Open to Eligible Breast Cancer Patients

fizer Inc announced that the company has initiated a multicenter, open-label expanded access program in the United States for the investigational oral CDK 4/6 inhibitor, palbociclib. Through the program, palbociclib is being made available for use in combination with letrozole for postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer for whom letrozole is considered appropriate therapy. “Palbociclib is being evaluated as a potential new treatment for women with hormone receptor–positive, HER2-negative advanced breast cancer,” said Mace Rothenberg, MD, Senior Vice President, Clinical Development and Medical Affairs, and Chief Medical Officer, Pfizer Oncology. “We have completed the submission of a New Drug Application for palbociclib in the United States based on the results of our phase II PALOMA-1 study. With recruitment of new patients to our phase III PALOMA-2 and PALOMA-3 trials now

rolled in the study will receive palbociclib for use in combination with letrozole, and therefore must be deemed appropriate for letrozole therapy. Under its expanded access programs, the U.S. Food and Drug Administration works with companies to allow access to

investigational therapies to patients with serious or life-threatening illnesses who do not otherwise qualify for participation in a clinical trial and for whom there are no satisfactory alternate therapies. Health-care professionals and patients can learn more about the pal-

bociclib expanded access program by visiting www.clinicaltrials.gov (trial number: NCT02142868). U.S.-based health-care professionals seeking more information may also call 1-800-420-6755 or e-mail PalbociclibEAP@parexel.com for further details. n

NOW ENROLLING: New trials for patients with mutant EGFR non-small cell lung cancer

Phase 2 expansion

This [expanded access] program will provide a mechanism by which eligible women who may benefit from treatment with palbociclib can gain access to this investigational therapy at this time.

2nd line and 3rd line+, T790M+ mutant EGFR NSCLC (NCT01526928)

1 prior EGFR TKI

CO-1686

≥2 prior EGFR TKI or chemo

CO-1686

Primary endpoint: ORR

Phase 2

—Mace Rothenberg, MD

complete, Pfizer is initiating the palbociclib expanded access program. This program will provide a mechanism by which eligible women who may benefit from treatment with palbociclib can gain access to this investigational therapy at this time.”

Expanded Access Program The palbociclib expanded access program is a U.S.-only, single-arm, open label study for postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer. Women en-

2nd line T790M+ mutant EGFR NSCLC (NCT02147990)

1 prior EGFR TKI

CO-1686

Primary endpoint: ORR

For more information, visit ClinicalTrials.gov, TIGERtrials.com, or contact clinicaltrials@clovisoncology.com CO-1686 is an investigational product and is not approved in any country. Copyright © 2014 Clovis Oncology.

6/14

1686-001

The ASCO Post | SEPTEMBER 1, 2014

PAGE 46

Direct From ASCO

A Conversation With Lidia Schapira, MD, the New JCO Art of Oncology Editor

Lidia Schapira, MD, FASCO

he popular Art of Oncology (AOO) section of the Journal of Clinical Oncology ( JCO) brings a human perspective to the art and science of practicing oncology. Lidia Schapira, MD, FASCO, Assistant Professor at Harvard Medical School and Massachusetts General Hospital, became the Art of Oncology Editor in November 2013, following in the footsteps of previous AOO Editors Charles L. Loprinzi, MD, FASCO, and David P. Steensma, MD, FACP.

Building a Stronger Community Why is it important for JCO to feature Art of Oncology? Years ago I remember a colleague told me that she first opens the Journal to Art of Oncology. It is the

in order to expand our content and reach. We will build a stronger community of cancer clinicians if we share our experiences—in the same way that researchers share laboratory data and novel observations. I am indebted to Drs. Charles Loprinzi and David Steensma for sharing their clear vision for AOO and for their friendship and mentorship. Charles is a brilliant physicianscientist as well as a humanist and saw the opportunity to start this separate track within the Journal. David invited “new voices,” and as a result, we saw an increase in submissions, including many essays written by residents and fellows. We are training young oncologists to be mindful and reflect on their experiences, and often writing provides a useful mechanism for reflection.

Lessons in Oncology Practice Why do you think AOO articles are so popular? Some readers may find the subjectivity liberating after reading scientific articles. Or perhaps they feel moved by the essayist’s sincerity or by a story that resonates with their lived experience. We admire our colleagues who design brilliant trials that change treatment paradigms, and we also need to have personal heroes who

and I never want to reach the end of his essays. Dr. Romeo Bascioni’s “I’ll Meet You in Your Dreams” taught me a powerful lesson about what can be accomplished with exquisite hospice care. And Dr. Joshua Liao’s “Cancer or No Cancer” makes me feel there will be smart and caring oncologists in years to come to look after all of us.

Any advice or thoughts for aspiring contributors? We would be delighted to read your work. Give us a good story, a personal reflection, a little dose of humor, or even a poem, and I would love to know if readers feel these essays have changed the way they think of themselves or their patients. n

What will be your biggest challenges as an editor? To keep the section relevant and stimulating for readers, find new ways of inviting and inciting reflection, and encourage new writers to submit their work.

Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Interview with Lidia Schapira, MD, New JCO Art of Oncology Editor.” ASCO Connection, May 2014: p 54. All rights reserved.

Volume 7, Issue 3

May 2011

Journal of oncology Practice

Top 5 articles Top 10 most-accessed recently published articles published in 2011 in in Journal of Oncology Practice Journal of Clinical Oncology

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

What’s Hot in

JOP

JOP.ascopubs.org Comorbidity, Chemotherapy Toxicity, and Outcomes Among Older Women Receiving Adjuvant Chemotherapy for Breast Cancer on a

We admire our colleagues who design brilliant trials that change treatment paradigms, and we also need to have personal heroes who inspire and remind us of what is so meaningful about oncology practice. —Lidia Schapira, MD

soul of JCO. It provides a virtual meeting place for oncologists to share experiences or voice their doubts and concerns. Personal essays can have a tremendous impact on readers, leading some to question their assumptions or even make important changes in their practice. What made you interested in the role of editor for AOO? I absolutely love this section of the journal and am keen to invite colleagues and patients from all over the world to contribute their reflections

inspire and remind us of what is so meaningful about oncology practice. Do you have a favorite piece or one that touched you the most from past AOO collections? I was deeply moved by Dr. Steven Grunberg’s “Giving Permission” describing the house call he made to a dying patient to let her know it was her time. I still read Dr. Paulette Mehta’s “He Didn’t Have a Chance” when I feel sad or need a little encouragement to go back to the clinic. Dr. Mikkael Sekeres makes me laugh

Clinical Trial: CALGB 49907 and CALGB 361004 (Alliance) by Heidi D. Klepin, et al

Creation of a Diagnostic Wait Times Measurement Framework Based on Evidence and Consensus by Julie E. Gilbert, et al

Oncologists' Response to New Data Regarding the Use of Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer by Efrat Dotan, et al

Diversity by Race, Hispanic Ethnicity, and Sex of the United States Medical Oncology Physician Workforce Over the Past Quarter Century by Curtiland Deville, et al

Impact of Financial Burden of Cancer on Survivors' Quality of Life by Kathleen M. Fenn, et al

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 47

Direct From ASCO

#WeConquerCancer: Creative Fundraisers From Committed Conquerors

onquer Cancer Foundation donors are a consistently creative bunch when it comes to encouraging others to help conquer cancer: Tyler invited his friends and family to a charity spin class; elementary school students in Malibu, California, sold bracelets in honor of their principal; Steve competed in a half-Ironman and asked loved ones to donate in memory of his father; Jennifer and Sean asked that their guests give donations instead of china at their wedding. The Conquer Cancer Foundation has recently adopted a set of online tools to make it easy for donors to create an online home for their creative fundraising efforts and share it with friends and family. Through the #WeConquerCancer program, fundraisers and event leaders can create a personalized website for their campaign through a simple, stepby-step process, recruit others to join their team, e-mail friends and family about their efforts, track donations, and send personal thank-yous to donors. By creating and sharing an online campaign, fundraisers help to raise awareness and vital support for the Conquer Cancer Foundation’s mission to fund breakthrough research and share cutting-edge knowledge.

not to experience cancer directly, but noted that as a member of the ASCO staff, “I work every day with people who fight to cure and treat it.” “I had read about folks shaving their heads for cancer research, which got

me thinking: What can I do? I’ve had long hair for years—it’s time it was put to good use!” Elizabeth said, and her choice of charity to support was simple. “I can tell you that the Conquer Cancer Foundation makes a real difference

in the lives of both researchers and patients,” she said. Elizabeth created a website as part of a graduate school project, and challenged her family and friends to come continued on page 48

Elizabeth’s Story Elizabeth Ralls had been fortunate

ASCO Experts Discuss the Latest Advances in Breast Cancer Care

he 2014 Breast Cancer Symposium will take place September 4 to 6. Direct your patients to www.cancer.net/blog to listen to ASCO Experts explain some of the research announced prior to the meeting and discuss what this research means for patient care. They can also read a summary of the research highlights. n

Why setle for fuzzy results? Insist on a clearer picture. Intermediate…now what? The answer is MammaPrint®. With binary Low Risk/High Risk classifcatons, MammaPrint provides up to 39% more defnitve results.1 So when you need more clinically actonable informaton, the diference is clear.

Convenient online ordering available at www.agendia.com.

The ASCO Post | SEPTEMBER 1, 2014

PAGE 48

Direct From ASCO #WeConquerCancer continued from page 47

together and donate $100 per inch of hair cut, ultimately raising a total of $500 and donating 10 inches of her hair to an organization that provides wigs for women with cancer.

Jeff’s Story Like so many families, Jeff Sear’s family wasn’t a stranger to cancer, but it wasn’t until his uncle passed away from brain cancer early in 2013 that “it finally hit home.” “Growing up, I didn’t get to know my uncle as well as I would have liked,” Jeff said. “Even when I was old enough to make my own choices, I always figured ‘once I really start to succeed in life, that’s when we’ll be close.’ But I waited too long.” “It’s hard not to experience loss without wanting to do something,” he continued. “The loss made me reex-

amine my lifestyle and my priorities. It made me look at my own health, and I decided to do something about it.” Jeff had heard about others running distance for charity, but found that for

him it didn’t seem like that would be enough. “I wanted a change that people could see,” he said. “Weight is something I, like many of us, struggle with. Making it a challenge about losing weight seemed ideal.” Jeff set a challenge for himself and shared it with family and friends asking that they pledge a $1 donation to the Conquer Cancer Foundation for every pound he lost. “It gave me motivation to work hard. It got the support of not only those affected by cancer, but also tied in people with interest in my health,” he said. Jeff ’s challenge led to great results, both for him and for the Conquer Cancer Foundation. ASCO staff members Kirsten Goldberg (left) and Kristin Ludwig (right) biked a combined 150 miles and raised more than $5,600 for the Conquer Cancer Foundation.

Amy’s Story On the occasion of her 29th birthday, Amy Smith wanted to make her party a “Celebrate Life Soiree.” She created an online fundraiser via #WeConquerCancer to encourage her friends and family to donate $29 to the Conquer Cancer Foundation rather than bringing a gift. She chose to ask her friends to support the Foundation’s Women Who Conquer Cancer program in honor of the women in her family that had faced cancer. “I just said, ‘I’m almost 30, let’s celebrate and put some money towards a good cause!” she said. Amy provided the party, and her

friends enthusiastically answered her call to Celebrate Life—contributing $679 to cancer research.

A Common Cause They come from all different points of view and cancer experiences, but #WeConquerCancer fundraisers have

something in common: they find ways to explore their passions, challenge themselves, and have fun all while raising support and awareness for the vision of a world free from the fear of cancer. n © 2014. American Society of Clinical Oncology. All rights reserved.

September Is Challenge Month at the Conquer Cancer Foundation! During September, Raj Mantena, RPh, will be matching all donations twoto-one, making it the perfect time to set up a personalized online fundraising campaign in honor of a loved one, special event, or athletic endeavor. Visit support.conquercancerfoundation.org to get started!

Save the Date

Conquering

Cancer.

Gastrointestinal Cancers Symposium January 15-17, 2015

Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

Moscone West Building San Francisco, California

Genitourinary Cancers Symposium February 26-28, 2015

DonATe ToDAY! ConquerCancerFoundation.org

Rosen Shingle Creek Orlando, Florida

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 49

Direct From ASCO

A World Free From the Fear of Cancer—Is It Possible? By Clifford A. Hudis, MD, FACP

y every definition, ASCO’s 50th Annual Meeting was a huge success. The halls were buzzing as nearly 35,000 attendees shared excitement about cancer research. This was a banner year for federally funded clinical trials—all four of the abstracts selected for ASCO’s Plenary Session were backed by funding from the National Institutes of Health (NIH), as were so many of the other studies that captured news headlines. But the U.S. clinical research system is facing unprecedented challenges. Today NIH’s purchasing power is 23% lower than it was in 2003. The National Cancer Institute (NCI) plans to cut enrollment in federally funded clinical trials by 15% over the next few years, scaling yearly enrollment back to as low as 17,000 patients in intervention trials.1 Clifford A. Hudis, MD, FACP, is Immediate Past President of the American Society of Clinical Oncology. A longer version of this article originally appeared on ASCO’s CancerProgress.Net website.

Federally funded clinical research answers questions that are critically important to patients—like comparing the effectiveness of two regimens, find-

free of the fear of cancer.” I believe it’s possible, but only if our nation’s investment of resources matches our nation’s need.

A disease that affects one-third to one-half of all Americans garners less than one dollar of every thousand our nation spends. I can’t say that I know the ‘right’ proportion for spending on cancer research, but I do know that this is the wrong one. —Clifford A. Hudis, MD, FACP

ing new uses for generic drugs, and finding new ways to improve patients’ quality of life. These are often trials industry wouldn’t have reason to conduct.

Greater Investment in Cancer Research Needed In my presidential address, I laid out a challenge: creating a “world

In 2013, the U.S. federal budget was almost $4 trillion. Of that, the NCI component was $5 billion. Roughly speaking, just 0.1% of federal spending goes to the NCI. A disease that affects one-third to one-half of all Americans garners less than one dollar of every thousand our nation spends. I can’t say that I know the “right” proportion for

spending on cancer research, but I do know that this is the wrong one. A quote from Lyndon Johnson’s Great Society Speech in 1964, describing his intention to eliminate poverty and racial injustice, rings poignantly true today as we strive to realize a world free from the fear of cancer. He said, we “can afford to win it. We cannot afford to lose it.” I hope you will join me in my call to our nation’s legislators and leaders for greater investment in cancer research—one that is commensurate with our nation’s need, ambition, and intention. We can afford it. And we can’t afford to lose. n © 2014. American Society of Clinical Oncology. All rights reserved. Reference 1. National Cancer Institute: An overview of NCI’s National Clinical Trials Network. May 29, 2014. Available at http://www.cancer.gov/clinicaltrials/nctn. Accessed July 3, 2014.

ASCO Offers Input on 21st Century Cures PCAST White Paper

SCO submitted a letter to the U.S. House Energy and Commerce Committee responding to the committee’s second white paper on its 21st Century Cures Initiative, 21st Century Cures: An Update on the President’s Council of Advisors on Science and Technology (PCAST) 2012 Report on Propelling Innovation. The letter to Representatives Fred Upton (R-MI) and Diana DeGette (D-CO) from ASCO President

Peter P. Yu, MD, FASCO, praises the PCAST report, but notes that the U.S. Food and Drug Administration (FDA) could take “a more coordinated approach to change.” For example, the ASCO letter suggests expanding FDA’s Sentinel Program to collect data on patients provided access to therapies approved under a proposed provisional approval process. ASCO recommendations include supporting federal initiatives such as

ASCO Launches the ASCO in Action Beat

SCO has launched the ASCO in Action Beat, an e-newsletter specifically focused on the latest news and updates related to cancer policy from ASCO in Action. The ASCO in Action Beat provides a snapshot of the most significant news and updates in cancer policy, ASCO’s ongoing advocacy efforts, and opportunities for members to take action

on critical issues affecting the cancer community. All ASCO U.S. members receive the biweekly newsletter. Non-ASCO members can sign up to receive the ASCO in Action Beat at the ASCO Subscription Center at asco.org/subscriptioncenter. n © 2014. American Society of Clinical Oncology. All rights reserved.

the National Center for Advancing Translational Sciences and the Reagan-Udall Foundation, creating a new designation for drugs shown to be safe and effective in a specific subgroup of patients, and improving FDA benefit and risk monitoring tools.

Registration Open for the Community Research Forum Annual Meeting

egistration is open for the ASCO Community Research Forum Annual Meeting, September 28 to 29, 2014, at ASCO headquarters in Alexandria, Virginia. Join fellow community-based researchers to discuss barriers and develop solutions to common challenges faced in the community research setting. This meeting provides a forum to: • Collaborate and network with colleagues • Discuss barriers to conducting research

• Work to develop strategies to effectively conduct community-based research • Influence the direction of ASCO initiatives • Provide input on policy issues impacting clinical research For more information about the Community Research Forum, visit www .asco.org/communityresearchforum. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | SEPTEMBER 1, 2014

PAGE 52

In the Clinic Gynecologic Oncology

Bevacizumab in Persistent, Recurrent, or Metastatic Cervical Cancer By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n August 14, 2014, bevacizumab (Avastin) was approved for the treatment of persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan.1,2 Updated labeling includes changes in warnings and precautions.

Supporting Trial Approval is based on the results of a phase III 2×2 factorial trial in which 452 patients with persistent, recurrent, or metastatic disease were randomly assigned to receive bevacizumab plus chemotherapy consisting of paclitaxel/cisplatin or paclitaxel/topotecan (n = 277) or chemotherapy alone (n = 225).2,3 Patients had a median age of 48 years, Gynecologic Oncology Group performance status of 0 (58%) or 1 (42%), 80% had received prior radiation therapy, and 74% had received prior chemoradiation therapy. Median overall survival was significantly longer with bevacizumab plus chemotherapy vs chemotherapy alone (16.8 vs 12.9 months, hazard ratio [HR] = 0.74, P = .013). There was no significant difference in overall survival between groups receiving paclitaxel/ topotecan with or without bevacizumab (n = 223) vs paclitaxel/cisplatin with or without bevacizumab (n = 229; median 13.3 vs 15.5 months, HR = 1.15, P = .23), but hazard ratios were similar with the addition of bevacizumab to both paclitaxel/cisplatin (HR = 0.72, 95% confidence interval [CI] = 0.51–1.02) and to paclitaxel/topotecan (HR = 0.76, 95% CI = 0.55–1.06). The latter findings suggest that bevacizumab plus paclitaxel/topotecan is an acceptable alternative for women with advanced cervical cancer who are not candidates for platinum therapy.

How It Works Bevacizumab is a recombinant humanized monoclonal IgG1 antibody

that binds vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors (Flt-1 and KDR) on the surface of endothelial cells. Inhibition of this interaction results in inhibition of endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.

How It Is Given The recommended dose of bevacizumab in cervical cancer is 15 mg/kg via intravenous infusion every 3 weeks in combination with paclitaxel/cisplatin or paclitaxel/topotecan. The bevacizumab-plus-chemotherapy regimens used in the supporting trial, repeated every 21 days, were: in-

OF NOTE Bevacizumab carries boxed warnings for gastrointestinal perforation, surgery and wound healing complications, and hemorrhage.

tions requiring medical intervention, serious hemorrhage, severe arterial thromboembolic events, life-threatening (grade 4) venous thromboembolic events including pulmonary embolism, hypertensive crisis or hypertensive encephalopathy, posterior reversible encephalopathy syndrome, and nephrotic syndrome. Treatment should be temporarily suspended ≥ 28 days prior to elective surgery and for severe hypertension not

New Indication for Bevacizumab in Cervical Cancer ■■ Bevacizumab (Avastin) was recently approved for the treatment of persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan. ■■ The recommended dose of bevacizumab in cervical cancer is 15 mg/kg via intravenous infusion every 3 weeks in combination with paclitaxel/cisplatin or paclitaxel/topotecan.

travenous paclitaxel at 135 mg/m2 over 24 hours on day 1 and intravenous cisplatin at 50 mg/m2 plus bevacizumab on day 2; paclitaxel at 175 mg/m2 over 3 hours on day 1 and cisplatin at 50 mg/m2 plus bevacizumab on day 2; paclitaxel at 175 mg/m2 over 3 hours plus cisplatin at 50 mg/m2 plus bevacizumab on day 1; and paclitaxel at 175 mg/ m2 over 3 hours plus bevacizumab on day 1 and topotecan at 0.75 mg/m2 over 30 minutes on days 1 to 3. There are no recommended dose reductions for bevacizumab. Treatment should be discontinued for gastroin-

OF NOTE Bevacizumab is a recombinant humanized monoclonal antibody that prevents interaction of VEGF with its receptors on endothelial cells, thereby inhibiting endothelial cell proliferation and new blood vessel formation.

testinal perforation or fistula formation involving an internal organ, wound dehiscence or wound healing complica-

controlled with medical management, moderate to severe proteinuria, and severe infusion reactions. Treatment should not be started for ≥ 28 days after surgery and until wound healing is complete. Bevacizumab should not be given to patients with serious hemorrhage or recent hemoptysis.

Safety Profile The most common adverse events of any grade in patients receiving bevacizumab and chemotherapy and occurring with a frequency ≥ 5% greater vs the chemotherapy-alone group were fatigue (80% vs 75%), decreased appetite (34% vs 26%), hypertension (29% vs 6%), and hyperglycemia (26% vs 19%). The most common grade 3 or 4 adverse events were fatigue (14.2% vs. 9.9%), abdominal pain (11.9% vs. 9.9%), hypertension (11.5% vs 0.5%), urinary tract infection (8.3% vs 6.3%), and thrombosis (8.3% vs 2.7%). GI perforation occurred in 3.2% of patients receiving bevacizumab and gastrointestinal-vaginal fistulae occurred in 8.2% of bevacizumab patients vs 0.9% of chemotherapy-alone patients. All cases of

GI perforation and GI-vaginal fistulae occurred in patients who had received prior pelvic radiation. Other grade 3 or 4 adverse events that were more common in patients receiving bevacizumab included hemorrhage, proteinuria, and wound healing complications. Bevacizumab carries boxed warnings for gastrointestinal perforation, surgery and wound healing complications, and hemorrhage (including severe or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, and vaginal bleeding). It also carries warnings/ precautions for gastrointestinal perforation or fistula and nongastrointestinal fistula, arterial thromboembolic events, venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure. Patients must undergo routine monitoring of blood pressure and urine protein. Women of reproductive potential must be informed of the risk of ovarian failure. n References 1. U.S. Food and Drug Administration: Bevacizumab solution. Available at www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm410128.htm. 2. AVASTIN® (bevacizumab solution for intravenous infusion) prescribing information, Genentech, Inc, August 2014. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2014/125085s301lbl.pdf. 3. Tewari KS, Sill MW, Long HJ III, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734-743, 2014.

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 53

Journal Spotlight Thoracic Oncology

Lung Screening–Detected Abnormalities Other Than Cancer Result in Smoking Cessation: National Lung Screening Trial Analysis By Matthew Stenger

n a study reported in the Journal of the National Cancer Institute, Martin C. Tammemägi, PhD, of Brock University, Ontario, and colleagues assessed smoking cessation rates among participants undergoing chest x-ray or computed tomography (CT) screening for lung cancer in the National Lung Screening Trial (NLST). Among patients without a subsequent diagnosis of lung cancer, they found that screening abnormalities were significantly associated with smoking cessation.1 This finding suggests that lung cancer screening programs may provide opportunities to reduce smoking rates.

Study Details In the study, data from participants in the NLST (2002–2009) were used in multivariable longitudinal regression models to predict annual smoking cessation in 15,489 subjects who were current smokers at study entry and did not receive a diagnosis of lung cancer during the study. Screening occurred at years 0, 1, and 2, with annual followup at years 3 to 7. The NSLT showed that annual low-dose CT screening reduced lung cancer mortality by 20% compared with chest x-ray screening Overall, at study year 3, 23.5% of subjects were no longer smoking. The highest proportions of subjects who remained smokers at ≥ 1-year intervals after a screening were those with normal screening results, followed in order by those with a screen showing a minor abnormality not suspicious for lung cancer, those with a major abnormality not suspicious for lung cancer and those with a screen that was suspicious for lung cancer but was unchanged from the previous screen, and those with a screen suspicious for lung cancer that represented a new or changing finding.

Year-to-Year Impact Among subjects with a normal finding at year 0 screening, 87.4% remained smokers at year 1 screening. By comparison, rates were significantly lower among patients with major abnormality not suspicious for cancer (85.0% still smokers, odds ratio [OR] = 0.81) and among those with an abnormality suspicious for lung cancer (81.7% still smokers, OR = 0.64).

Among subjects with a normal finding at year 1 screening, 83.1% remained smokers at year 2 screening. By comparison, smoking rates were significantly lower in those with findings suspicious for lung cancer but stable from year 1 screening (79.2%, OR = 0.78) and those with a new finding suspicious for lung cancer (74.8%, OR = 0.61). Among subjects with a normal finding at year 2 screening, 78.3% remained smokers at year 3. By comparison, significant reductions in smoking rates were found among subjects with an unsuspicious minor abnormality at year 2 (76.3%, OR = 0.89), those with an unsuspicious major abnormality (73.3%, OR = 0.76), those with a stable suspicious finding (73.9%, OR = 0.79), and those with a new/changed suspicious finding (71.9%, OR = 0.71).

Effect of Longer Durations Among subjects with normal findings on year 2 screening, 73.6% remained smokers at year 4 follow-up.

Screening and Smoking Cessation ■■ Progressively more significant screening abnormalities were associated with increasing reductions in smoking rates during follow-up. ■■ Screening abnormalities were independent predictors of smoking cessation on multivariate analysis.

finding. Among those with a new/ unstable suspicious finding at year 2 screening, decreases in smoking rates compared with those with normal findings were significant at year 5 (63.6%, OR = 0.82), year 6 (58.1%, OR = 0.76), and year 7 (56.7%, OR = 0.81).

Screening Abnormalities Predict Cessation A final multivariable logistic model included adjustment for sociodemographic factors (age, sex, race/ethnicity, education as an indicator of socioeconomic circumstance, and marital status), exposures (alcohol consumption; cigarette, cigar, and pipe smoking histories; and second-hand smoke

Smoking cessation is statistically significantly associated with screendetected abnormality. Integration of effective smoking cessation programs within screening programs should lead to further reduction in smoking-related morbidity and mortality. —Martin C. Tammemägi, PhD, and colleagues

By comparison, there were significant reductions in smoking rates at year 4 among those with an unsuspicious minor abnormality (71.8%, OR = 0.91), those with an unsuspicious major abnormality (68.4%, OR = 0.77), those with a stable suspicious finding (69.9%, OR = 0.83), and those with a new/unstable suspicious finding (68.0%, OR = 0.76). At years 5, 6, and 7, the smoking rates among subjects with normal results at year 2 screening decreased from 68.1% to 61.8%. By comparison, rates nonsignificantly decreased from 67.4% to 60.7% in subjects with an unsuspicious minor abnormality, from 64.5% to 60.9% in those with an unsuspicious major abnormality, and from 65.4% to 58.1% in those with a stable suspicious

exposures), and medical history (body mass index, family history of lung cancer, personal history of cancer, history of comorbidities), as well as for study year, study center, and randomization group (x-ray or CT screening). By this model, compared with normal screening findings, findings of an unsuspicious minor abnormality (OR = 0.91, P = .005), an unsuspicious major abnormality (OR = 0.81, P < .001), a stable suspicious abnormality (OR = 0.78, P < .001), or a new/unstable suspicious finding (OR = 0.66, P < .001) were independently predictive of smoking cessation. Other significant predictors for not smoking were increasing age, mixed race (vs white), increased education level, married status, higher body mass

index, lower smoking intensity and duration, absence of secondhand smoke at home, and past or present pipe and cigar smoking.

Outcomes by X-ray or CT Screening Analysis according to randomization group showed that compared with subjects in the x-ray group with normal findings, there was a significant reduction in smoking among those with an unsuspicious minor abnormality (adjusted OR = 0.86, P < .001), a borderline significant reduction in those with an unsuspicious major abnormality (OR = 0.81, P = .06), and significant reductions in those with a stable suspicious finding (OR = 0.72, P = .02) and those with an new/unstable suspicious finding (OR = 0.71, P < .001). Compared with subjects in the CT group with a normal finding, there was a nonsignificant increase in smoking (adjusted OR = 1.01, P = .88) among those with an unsuspicious minor abnormality, a borderline significant decrease in those with an unsuspicious major abnormality (OR = 0.87, P = .06), and significant reductions in those with a stable suspicious finding (OR = 0.84, P = .01) or a new/unstable suspicious finding (OR = 0.69, P <.001). The investigators concluded, “Smoking cessation is statistically significantly associated with screendetected abnormality. Integration of effective smoking cessation programs within screening programs should lead to further reduction in smoking-related morbidity and mortality.” The National Cancer Institute is the funding source for the NLST. n

Disclosure: Dr. Tammemägi and his coauthors reported no potential conflicts of interest.

Reference 1. Tammemägi MC, Berg CD, Riley TL, et al: Impact of lung cancer screening results on smoking cessation. J Natl Cancer Inst 106:dju084, 2014.

The ASCO Post | SEPTEMBER 1, 2014

PAGE 54

Announcements

AACI Members Elect New Leadership, Members to Board of Directors

he Association of American Cancer Institutes (AACI) has announced the election of Stanton L. Gerson, MD, as Vice-President/ President-Elect for a 6-year term, effective in October 2014. Dr. Gerson is the Asa and Patricia Shiverick- Jane Shiver-

members, Dr. Gerson said that in his new AACI leadership role, he will prioritize three critical aspects of the nation’s cancer centers program by: (1) encouraging the centers to work more closely together to lower health-care costs and improve outcomes through nationally

coordinated research and translation, (2) expanding the use of cancer patient data to further health improvements and research discoveries, and (3) making optimal use of the cancer center director and administrative leader network, including partnering with fund-

ing agencies, to set the policy agenda for cancer research, dissemination of discoveries, and cancer health care. Drs. Gerson, Loehrer, and Seller’s terms will commence on October 27 during the AACI/CCAF Annual Meeting in Chicago. n

Stanton L. Gerson, MD

ick (Tripp) Professor of Hematological Oncology, Director of the National Cancer Institute (NCI)-Designated Case Comprehensive Cancer Center, in Cleveland, Founding Director of the National Center for Regenerative Medicine, and Distinguished University Professor at Case Western Reserve University. He is also Director of University Hospitals Seidman Cancer Center in Cleveland and a member of the NCI Board of Scientific Advisors. The Association also announced that Patrick J. Loehrer, Sr, MD, and Thomas A. Sellers, PhD, MPH, have been elected to AACI’s Board of Direc-

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Patrick J. Loehrer, Sr, MD

Thomas A. Sellers, PhD, MPH

tors. Dr. Loehrer is Director of the Indiana University Melvin and Bren Simon Cancer Center, in Indianapolis. Dr. Sellers is Director and Executive Vice President of the Moffitt Cancer Center and Research Institute, in Tampa.

Priorities for Term In a statement submitted to AACI

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 55

Announcements

Leaders in Health Disparities Honored

he W. Montague Cobb/National Medical Association (NMA) Health Institute (Cobb Institute) was established by the National Medical Association to develop, evaluate, and implement strategies to promote wellness and eliminate health disparities

and racism in medicine. The Institute recently celebrated its 10th anniversary during the 112th Annual Convention of the NMA and recognized three leaders in health disparities with awards. John Ruffin, PhD, former Director of the National Institute on Minority Health

and Health Disparities, whose life-long career and innovations have had a significant impact on society, received the W. Montague Cobb Lifetime Achievement Award for his exceptional contributions to the field of African American Medicine. Alvin Poussaint, MD, Professor of

Psychiatry and Director of the Office of Recruitment and Multicultural Affairs at Harvard Medical School, received the 2014 Cato T. Laurencin Lifetime Research Award. The award recognizes an individual who has demonstrated more than 20 years of consistent, long-lasting contributions to benefit African Americans and to reduce health disparities through recog-

John Ruffin, PhD

Alvin Poussaint, MD

Advertisement not displayed in digital edition at advertiser’s request Thomas LaVeist, PhD

nized research and leadership. Thomas LaVeist, PhD, Director of the Hopkins Center for Health Disparities Solutions was named the 2014 W. Montague Cobb Lecturer for his significant contributions as a pioneer in health disparities research. “These distinguished individuals have been tireless champions for the elimination of health disparities and advancing minority health. Being selected for the Cobb Awards speaks to their exemplary leadership and service,” said Cato T. Laurencin, MD, PhD, Chair of the Cobb Institute Board of Directors and University Professor at the University of Connecticut. n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

The ASCO Post | SEPTEMBER 1, 2014

PAGE 56

Journal Spotlight Thoracic Oncology

Phase III Trial of Figitumumab Plus Chemotherapy in Advanced NSCLC Stopped Early for Futility and Increased Harm By Matthew Stenger

n the first phase III trial assessing the combination of an insulin-like growth factor 1 receptor (IGF-1R) inhibitor with chemotherapy as first-line treatment for advanced nonadenocarcinoma non– small cell lung cancer (NSCLC), the addition of the fully human immunoglobulin G2 monoclonal antibody figitumumab to paclitaxel/carboplatin did not improve overall survival over chemotherapy alone. The study, reported by Corey J. Langer, MD, of University of Pennsylvania, and colleagues in Journal of Clinical Oncology, was stopped early due to futility and an increased frequency of serious adverse events, including treatment-related death, in patients receiving figitumumab.1 When the trial was begun, it was thought that IGF-1R played a role in squamous cell NSCLC, in which it is more commonly expressed than in adenocarcinoma, and analysis of phase II data suggested increased efficacy of figitumumab in patients with this histology. A randomized phase II study in patients with treatment-naive advanced NSCLC showed improved objective response rate with the addition of figitumumab to full-dose paclitaxel/carboplatin (54% vs 42%). However, the failure of the phase III trial prompted a thorough review of the phase II data, which were subsequently retracted when reanalysis showed lower response rates in both groups.2

Study Details In the open-label phase III trial, 681 patients with stage IIIB/IV or recurrent NSCLC with nonadenocarcinoma histology from 25 countries were randomly assigned between April 2008 and September 2009 to receive figitumumab at 20 mg/kg plus paclitaxel at 200 mg/m2 and carboplatin at area under the concentration-time curve = 6 mg • min/mL (n = 342) or paclitaxel/carboplatin alone (n = 339) once every 3 weeks for up to six cycles. The primary endpoint was overall survival. The figitumumab and chemotherapy groups were generally balanced for age (median, 62 years in both), sex (76% and 77% male), ethnicity (78% and 80% white, 16% and 17% Asian), Eastern Coopera-

tive Oncology Group performance status (0 in 33% and 34%, 1 in 66% and 64%), disease stage (IIIB in 11% and 12%, IV in 88% in both), smoking status (10% never in both, 42% current in both), histology (squamous cell in 86% and 85%, large cell in 8% in both, adenosquamous in 4% and 6%), and prior treatment (surgery in 21% and 18%, radiation in 13% and 11%, and adjuvant chemotherapy in 4% in both).

No Benefit After median follow-up of 23.1 months, median overall survival was 8.6 months in the figitumumab-plus-chemotherapy group vs 9.8 months in the chemotherapy-alone group (hazard ratio [HR] = 1.18, P = .06). One-year overall survival rates were 34% vs 39%. The effect of figitumumab on overall survival was similar across subgroups for sex, per-

8.2 vs 9.7 months (HR = 1.26, P =. 05) in those with HbA1c ≥ 5.7%. Median progression-free survival was 4.7 vs 4.6 months (HR = 1.10, P = .27). Objective response rates were 33% vs 35%.

Adverse Events Adverse events of any grade that were more common in the figitumumab plus chemotherapy group included decreased appetite (38% vs 23%), diarrhea (30% vs 14%), vomiting (25% vs 14%), hyperglycemia (23% vs 5%), and decreased weight (20% vs 9%). Grade 3 or 4 adverse events that occurred more frequently in the figitumumab group included hyperglycemia (12% vs 1%), fatigue (8% vs 4%), decreased appetite (7% vs 2%), dehydration (6% vs <1%), and diarrhea (5% vs 1%). Serious adverse events occurred in 66% of the figitumumab group vs 51% of

[O]ur current phase III study involving nonadenocarcinoma patients failed to show any benefit and unexpectedly suggested a possible detrimental effect. —Corey J. Langer, MD

formance status, nonsquamous histology, smoking status (never, current), stage, and HbA1c < vs ≥ 5.7%. Exploratory analysis based on baseline total IGF-1 with a cutoff of 120 ng/mL indicated that median overall survival was 7.0 vs 10.4 months in figitumumab recipients and 10.1 vs 9.4 months in chemotherapyalone recipients patients with low vs high IGF-1. Overall survival was significantly shorter for figitumumab vs chemotherapy patients with low IGF-1 (HR = 1.37, P = .01) and did not differ between patients with higher IGF-1 (HR = 0.93, P = .67). Hyperglycemia appears to be a class effect of IGF-1R inhibition. Median overall survival was 8.7 months in the figitumumab group and 10.2 months in the control group (HR =1.07, P = .65) among patients with baseline HbA1c < 5.7% and

Figitumumab in Non–Small Cell Lung Cancer ■■ The addition of figitumumab to chemotherapy did not improve overall survival. ■■ The addition of figitumumab was associated with a higher frequency of serious adverse events and treatment-related death.

the chemotherapy group (P < .01) and were considered possibly related to treatment in 22% vs 12%. Apart from disease progression events, the most common serious adverse events were pneumonia (6% vs 4%), dehydration (4% vs 1%), asthenia (3% vs 1%), and hyperglycemia (3% vs < 1%). Adverse events led to discontinuation of figitumumab in 7% of patients and to discontinuation of chemotherapy in 9% of patients in each group.

Treatment-Related Deaths Grade 5 adverse events not related to disease progression occurred in 13% vs 10% of patients (P = .22), with the most common in figitumumab patients being pulmonary hemorrhage and pneumonia (2% each). Grade 5 adverse events were considered to be treatment-related in 5% of figitumumab patients vs 1% of chemotherapy patients (P < .01); those observed in the figitumumab group consisted of hemoptysis, pneumonia, unknown cause reported only as death, septic shock, cardiorespiratory arrest, decrease of performance status, neutropenic sepsis, toxicity to

various agents, renal failure, hemorrhage, and hypovolemic shock and those in the chemotherapy-alone group consisted of unknown cause reported as death, pneumonia, septic shock, and dehydration. Baseline IGF-1 was not related to overall frequency or type of adverse events. However, grade 5 adverse events were more likely to occur among figitumumab patients with lower vs higher IGF-1 levels (56% vs 38%), with no such difference in risk observed in the chemotherapy group. As stated by the investigators, “Although additional studies are required, these data suggest that low baseline total IGF-1 may be a safety biomarker that identifies a subset of patients for whom IGF-1R inhibition is particularly harmful.” Rates of adverse events did not vary markedly by HbA1c level, but the rate of grade 3 or 4 events among patients with no grade 5 events was slightly lower in those with baseline levels <5.7% in the figitumumab group (30% vs 36%; 33% vs 35% in chemotherapy group). The investigators concluded: [T]hough the phase II trial suggested an [objective response rate] advantage for adding figitumumab to standard chemotherapy in advanced NSCLC, our current phase III study involving nonadenocarcinoma patients failed to show any benefit and unexpectedly suggested a possible detrimental effect. This may be a class effect and should be assessed in current and future trials examining IGF-1R inhibitors. Further clinical development of figitumumab is not being pursued. n Disclosure: The study was supported by a grant from the National Cancer Institute and by Pfizer. Dr. Langer reported a consultant or advisory role with and research funding from Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.

References 1. Langer CJ, Novello S, Park K, et al: Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non–small-cell lung cancer. J Clin Oncol 32:2059-2066, 2014. 2. Karp DD, Paz-Ares LG, Novello S, et al: Retraction: Phase II study of the anti– insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 30:4179, 2012.

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 57

Perspective

Failure of IGF-1R Inhibitor Figitumumab in Advanced Nonadenocarcinoma Non–Small Cell Lung Cancer By Jacek Jassem, MD, PhD

he vast majority of non–small cell lung cancer (NSCLC) patients present with advanced disease, and many will develop metastases after primary curative therapy. Until recently, despite its low efficacy, chemotherapy remained the only treatment modality in metastatic NSCLC. Within the past decade, the management of advanced NSCLC has dramatically changed as a result of the development of several targeted anticancer agents. Currently, some of them constitute standard of care in this malignancy and have replaced chemotherapy in genetically selected patients. The most effective compounds include the small epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib, gefitinib (discontinued in the United States), and afatinib (Gilotrif) and the ALK inhibitors crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (investigational). However, the activity of these treatments, as well as the activity of the anti–vascular endothelial growth factor (VEGF)-A antibody bevacizumab (Avastin), is virtually restricted to lung adenocarcinoma. Molecular features of other subtypes of NSCLC, particularly squamous cell carcinoma, are far less defined. In the absence of validated targetable alterations, there are virtually no approved targeted therapies specific for squamous cell carcinoma; for more than a dozen years, patients with squamous cell carcinoma have been receiving the same, barely effective conventional chemotherapy. Squamous cell carcinoma is the second most common pathology subtype of lung cancer, comprising 20% to 30% of newly diagnosed NSCLC in the United States and a greater proportion in Europe and Asia. Thus, closing this therapeutic gap between two main lung cancer subtypes remains one of the sore needs of contemporary oncology. Dr. Jassem is Head of the Department of Oncology and Radiotherapy, Medical University of Gdańsk. Dr. Jassem was an investigator in and is an author of the article reporting the phase III trial of figitumumab.

Targeting the IGF Pathway The insulin-like growth factor (IGF) pathway is one of the most extensively studied signaling pathways in cancer. IGF-1 and its receptor, IGF1R, have been implicated in tumor cell proliferation, survival, and invasiveness. IGF-1R protein expression has been detected in 40% to 80% of NSCLC specimens and appears to be more common in squamous cell carcinoma. Hence, the IGF pathway was considered a promising therapeutic target in this subtype. These hopes were heightened when a randomized phase II study demonstrated that the addition of figitumumab, a fully human anti-IGF-1R G2 monoclonal antibody, to a stan-

ing the control arm—an outcome that was an unpleasant surprise and a great disappointment.

Reasons for Failure The reasons for this failure are unclear and can only be speculated upon. First, a reanalysis of the preceding phase II study did not confirm its promising results, leading to their retraction.2 Hence, inhibition of the target by figitumumab may not be strong enough to induce disease response in nonadenocarcinoma patients, a likely explanation in view of negative results of a parallel phase III study (ADVIGO 1018, a combination of figitumumab with erlotinib in a similar population).

Closing this therapeutic gap between two main lung cancer subtypes remains one of the sore needs of contemporary oncology. —Jacek Jassem, MD, PhD

dard chemotherapy doublet (carboplatin/paclitaxel) resulted in a higher response rate and trends for superior progression-free survival and overall survival. Most important, a subgroup analysis of this study indicated a particularly high benefit of figitumumab in squamous cell carcinoma patients. Based on these data, and in view of a strong preclinical rationale for targeting IGF-1R, a phase III study was enthusiastically launched for patients with nonadenocarcinoma histology (mostly squamous cell carcinoma), a group with a particular need of new successful therapies.1 The study—reported by Langer and colleagues in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post—was terminated early after a planned interim analysis demonstrated a hazard ratio that crossed the futility boundary favor-

Indeed, IGF-1R signaling may activate other downstream signaling pathways (for example mTOR), and some of them may become constitutively activated to overcome disruption of the IGF-1R axis. Most likely, owing to the genetic complexity of lung cancer, targeting of multiple signaling pathways may be necessary to induce a therapeutic effect. Second, despite there being a clearly defined therapeutic target, this study did not use predictive biomarkers for patient selection. Notably, there are very few molecularly targeted anticancer therapies that are effective in unselected patient populations. A post hoc biomarker analysis of our study showed no overall survival difference in a subset of patients with elevated (> 120 ng/mL) baseline total IGF-1 serum levels and an apparently detrimen-

tal effect of figitumumab in patients with low IGF-1, constituting around two-thirds of the tested population. Importantly, IGF-1 levels did not correlate with treatment outcomes in patients receiving chemotherapy alone, suggesting specific predictive value of this biomarker for figitumumab treatment. Unfortunately, at the time the phase III study was developed, these correlations had not been analyzed in serum samples collected from patients participating in the phase II study. Therefore, no biomarkerbased patient selection was employed. Another factor that might have contributed to the negative results of our study was an unexpectedly high toxicity (not reported in the phase I/ II studies) of figitumumab. IGF-1R shares structural homology with the insulin receptor; thus, its inhibition (likely as a class effect) may affect vital physiologic functions. Interestingly, low baseline total IGF-1 serum level not only identified patients with detrimental effect of figitumumab, but was also a marker of its particularly high toxicity. Although Pfizer has decided to terminate the figitumumab program in NSCLC, these observations may be exploited in the clinical development of other IGF-1R inhibitors. n

Disclosure: Dr. Jassem reported no potential conflicts of interest.

References 1. Langer CJ, Novello S, Park K, et al: Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non–small-cell lung cancer. J Clin Oncol 32:2059-2066, 2014. 2. Karp DD, Paz-Ares LG, Novello S, et al: Retraction: phase II study of the anti–insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 30:4179, 2012.

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Bone metastases?

First sign of symptoms?

Start

to extend survival

1,2

Important Safety Information • Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigotreated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care • Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have

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07/14

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• In the ALSYMPCAa exploratory updated analysis,b median overall survival was 14.9 months for Xofigo (95% confidence interval [CI]: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8) [hazard ratio (HR)=0.695; 95% CI: 0.581-0.832]1 • In the ALSYMPCA prespecified interim analysis, median overall survival was 14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2) [P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)]1

30% reduction in the risk of death vs placebo1

ALSYMPCA was a phase 3, randomized, double-blind, controlled trial that evaluated Xofigo plus best standard of care (n=614) vs placebo plus best standard of care (n=307).1

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

To learn more, visit www.xofigo-us.com

not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see brief summary of full Prescribing Information on following pages.

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were

radium Ra 223 dichloride INJECTION

Xoﬁgo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations. Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination. Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing. 19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is Renal and urinary disorders recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go. 8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

The ASCO Post | SEPTEMBER 1, 2014

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Debates and Didactics in Hematology and Oncology Conference Hematology

Program Offers Unique Intervention for Acute Promyelocytic Leukemia By Caroline Helwick

f Anand P. Jillella, MD, has his way, no future patient with acute promyelocytic leukemia (APL) will experience a delay in treatment or lack for an expert consult—and few, if any, will die of this condition. Mortality from APL is much higher than most oncologists think, especially during the first 30 days, and these early deaths can be prevented, according to Dr. Jillella, Professor of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, who has developed an algorithm and an intervention program that will be

ence in Sea Island, Georgia, Dr. Jillela presented an APL patient-care strategy that has two components: use of a simplified algorithm, and prompt and frequent consultation with his team of experts.

of the outcome in the general population. The death rate of 5% to 10% is a gross underestimate. And mortality is not just a problem in small community practices but also in big, sophisticated cancer centers,” he emphasized.

Mortality Greatly Underestimated

Risk Greatest in First 30 Days

Dr. Jillella pegged the populationwide survival rate at around 65%— much worse than the generally accepted figure of 85% to 90% demonstrated in large cooperative group trials. “These numbers are for highly se-

If you suspect this diagnosis, there is no downside to treating it immediately. You can always step back, but withholding treatment will be detrimental to the patient. —Anand P. Jillella, MD

validated in a trial by the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network (ECOG/ACRIN). As a result of his passion and personal quest, and having examined the problem of APL-related mortality for 8 years, Dr. Jillella has become a foremost expert on APL. “I’m really a transplant doctor,” he said in an interview with The ASCO Post, “but I’ve become obsessed with APL.” Dr. Jillella shares credit with his colleague, Vamsi K. Kota, MD, Assistant Professor of Hematology and Medical Oncology at Emory, who is co–principal investigator with Dr. Jillella on the upcoming ECOG/ACRIN trial. APL was first described in 1950 as a hyperacute fatal illness associated with a hemorrhagic syndrome. The condition remained highly fatal until its genetic profile was identified and all-trans retinoic acid (ATRA, aka tretinoin) became the established treatment. While APL is now largely curable, too many patients still die, he said. “Early deaths from APL can and should be prevented. Anything short of this is totally unacceptable,” Dr. Jillella commented. At the recent Debates and Didactics in Hematology and Oncology confer-

lected patients treated under a protocol and perhaps by experts. This is not what happens to these patients in the real world,” he pointed out. Misconceptions about APL occur because the condition is uncommon, affecting fewer than 1,000 patients a year in the United States. The average oncologist/hematologist rarely if ever sees these patients, and this lack of experience can be fatal for the patient, he suggested. “A single mistake can result in the demise of the patient because APL is hyperacute, and there are often nuances that need to be identified. If you don’t know what you are doing right away, you can kill the patient,” he noted. Surveillance, Epidemiology, and End Results (SEER) data, recently analyzed by researchers at The University of Texas MD Anderson Cancer Center, Houston, opened the eyes of the medical community to the seriousness of APL.1 The analysis over time showed 5-year survival to be 18% between 1975 and 1990, improving to 52% between 1991 and 1999, and to 64% for the years 2000 to 2008; for the most recent period, 1-year survival was 71%. “Still, the survival rate of 90% in multicenter trials is not a reflection

Researchers worldwide have examined early deaths in APL (days 1 to 30), showing fairly consistent mortality rates in the 30% range. “One in three patients dies within the first month, even in countries with sophisticated health care and good record-keeping, such as the United States and Sweden,” he pointed out. Patients are most likely to die from internal bleeding (70%), differentiation syndrome (ie, treatment toxicity, 20%), and infection (10%). Very few patients die as a result of relapse. The first 30 days are critical, and risk diminishes thereafter. “If we get patients through the first month, it’s basically a ‘home run,’” he said. He believes that improvements in survival rates will come not through drug development but through the reduction in early deaths. Success in reducing early mortality could push survival estimates into the 90% range, he predicted.

Finding a Plan of Action Dr. Jillella’s particular interest in APL began while he was Chief of Hematology/Oncology at the Medical College of Georgia (now Georgia Regents University). His team treated 19

I had an external consultant review my death charts, to see if we were doing things right. It seemed no one else was seeing this problem: either they were not looking, or they did not acknowledge it,” he continued. “We found a proactive way of treating APL and preventing complications, rather than worrying about them once they occur,” he said. Dr. Jillella and colleagues created a “culture of awareness” in the states of Georgia and neighboring South Carolina. They simplified what was once a 15-page document, creating a 1.5-page checklist, based on standards of care, to guide management. The strategy involves rapid diagnosis and initiation of therapy, aggressive management of coagulopathy, prevention of differentiation syndrome, and prophylaxis and aggressive treatment of infection. What makes this protocol really effective is its emphasis on prompt and frequent consultation with an APL expert. “We function as a resource for the physician caring for the patient. And we call the doctor; we don’t wait for the doctor to call us. We have gotten good at this, and we can predict what’s going to happen to the patient tomorrow, and 2 days from now. That’s a big help to physicians who infrequently see APL,” he said. “We are currently helping to manage three patients, and we are in constant contact with their doctors.” Dr. Kota added that this arrangement allows very sick patients to be

By collaborating and co-managing patients, we have done much better in APL. I think we can replicate this model in other diseases. —Vamsi K. Kota, MD

patients with APL between 2005 and 2009, of whom 7 died. The 11 survivors are now in remission and presumed cured. “We admitted we were not doing well with these patients. Our goal in 2009 was to fix the problem that we saw,” he said. “I reviewed the literature and conference abstracts. I attended national meetings. I talked to experts.

treated locally. “This is intensive treatment, and patients need to be close to their families. Bringing them to a specialized center may not be appropriate from the patient’s point of view.” APL is a medical emergency that should be immediately treated with ATRA, the physicians emphasized. “If you suspect this diagnosis, there is no downside to treating it immediately.

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Debates and Didactics in Hematology and Oncology Conference You can always step back, but withholding treatment will be detrimental to the patient,” Dr. Jillella added. The algorithm alone “is not a panacea,” he emphasized. “It’s extremely important to call someone who treats APL on a day-to-day basis.”

Implementing the Plan Dr. Jillella and Dr. Kota disseminated their protocol by actually visiting every oncology practice throughout Georgia and South Carolina. They urged any oncologist/hematologist to immediately alert the Emory program when APL is suspected, where they could receive an immediate consultation and frequent telephone follow-up. “We literally went to every practice, and we mailed out flyers with our protocols and our pictures,” Dr. Jillella said. “We think that 90% of practitioners in two states (and a few other practices in Florida and North Carolina) know about us, and they call us as soon as a patient is seen—or even before one is transferred to their center. They have our cell phones and we have been available 24/7 for the past 4 years.” Dr. Kota estimated that the program helps an average of three new patients per month. The 37% mortality rate that Dr. Jillella observed among his own patients prior to instituting the algorithm (median follow-up, 2,358 days) was greatly improved after 2009. He and his colleagues have now treated 61 patients, of whom only 3 died (median follow-up, 255 days), for a mortality rate of 4.9%. Commenting on his protocol, he said, “When we had treated nine patients and none died—while three should have—we knew we were onto something.”

Program Will Expand Drs. Jillella and Kota have sought funding to expand his program and to more rigorously validate the intervention. They received a grant from the Leukemia & Lymphoma Society through its Therapy Acceleration Program, for work in two states. That program began accruing July 1, 2013, and will enroll 120 patients over 3 years. More recently ECOG/ACRIN signed on to help expand the program’s scope. The goal of EA9131 is to prospectively assess 30-day mortality and to collect survival data using the ECOG/ACRIN mechanism. Physician education, use of the algorithm, and consultations with national experts in several sites will be key com-

ponents of the study. They hope this study will be expanded nationwide. “We are tremendously excited about this program and this study,” Dr. Jillella said. “We think it will change the outcome in these patients, and that our model will evolve into a global paradigm whereby a physician in South Korea, for instance, can text us and get

an immediate reply.” Dr. Kota proposed an even larger objective: that the APL program serve as a model for other challenging diseases. “By collaborating and co-managing patients, we have done much better in APL,” he noted. “I think we can replicate this model in other diseases.” n Disclosure: Drs. Jillella and Kota received

Now

OAK

grant funding from the Leukemia & Lymphoma Society.

References 1. Chen Y Kantarjian H, Wang H, et al: Acute promyelocytic leukemia: A population-based study on incidence and survival in the United States, 1975-2008. Cancer 118:5811-5818, 2012.

Enrolling

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

MPDL3280A1 Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

(an engineered anti-PDL1 antibody)

N=850

Randomized 1:1

Docetaxel

Primary Endpoint:

Secondary Endpoints:

• Objective survival

• Safety: incidence of adverse events • Overall response rate • Progression-free survival • Duration of response

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Locally advanced or metastatic NSCLC • • • •

• History of autoimmune disease

(stage IIIB, stage IV, or recurrent) Representative FFPE tumor specimens Disease progression during or following platinum-containing treatment regimen Measurable disease, defined by RECIST v1.1 ECOG performance status of 0-1

• Active hepatitis B or hepatitis C • Prior treatment with docetaxel, CD137 agonists,

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

For more information Visit: clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only)

E-mail: global.rochegenentechtrials@roche.com

The ASCO Post | SEPTEMBER 1, 2014

PAGE 64

Awards

ASTRO Awards $35,500 in Individual Grants to 43 Researchers

he American Society for Radiation Oncology (ASTRO) has selected 43 recipients to receive a total of $35,500 for the 2014 Annual Meeting Abstract Awards. The awardees will be recognized at ASTRO’s 56th Annual Meeting. ASTRO’s 56th Annual Meeting, takes place San Francisco’s Moscone Center, September 14-17,

Bruce G. Haffty, MD, FASTRO

2014, and will be led by ASTRO President Bruce G. Haffty, MD, FASTRO. The theme of the 2014 Meeting is “Targeting Cancer: Technology and Biology.” Watch future issues of The ASCO Post for coverage of ASTRO 2014.

Resident Clinical/Basic Science Research Abstract Award The Resident Clinical/Basic Science Research Abstract Award recognizes the top three resident authors of the leading abstracts in radiation and cancer biology, clinical practice, and radiation physics (one award in each category). Award winners will receive $1,500 and a trophy during the scientific session in which their abstract is presented. Recipients are: Radiation and Cancer Biology • Andrew Sharabi, MD, PhD, Johns Hopkins University, Baltimore Radiation Physics • Madhu Sudhan Reddy Gudur, PhD, Stanford University, Stanford Clinical Practice • Stephanie Markovina, MD, PhD, Washington University School of Medicine, St. Louis

Resident Digital Poster Recognition Award The Resident Digital Poster Recognition Award honors the three highest rated abstracts selected for digital poster discussions by residents who are the lead author. Awards are presented for one abstract in each category: radiation and cancer biology, clinical practice, and radiation physics. Awardees are: Radiation and Cancer Biology • Pranshu Mohindra, MD, University of Wisconsin School of Medicine and

Public Health, Madison, Wisconsin Radiation Physics • Adam Gladwish, MD, University of Toronto, Toronto Clinical Practice • Kim Cao, MD, Institut Curie, Paris

Resident Poster Viewing Recognition Award The Resident Poster Viewing Recognition Award recognizes the highest rated, resident-submitted abstracts selected for paper poster presentations. The top three resident authors in each category (radiation and cancer biology, clinical practice, and radiation physics) are awarded this recognition. The 2014 Resident Poster Viewing Recognition Award recipients are: Clinical Practice • 1st place: Steven Sckolnik, MD, University of Arizona, Tuscon, Arizona • 2nd place: Jessica Zhou, MD, University of Michigan, Ann Arbor, Michigan • 3rd place: Thomas Mullen, MD, PhD, University of Washington, Seattle Radiation and Cancer Biology • 1st place: Nils Nicolay, MD, PhD, Heidelberg University Hospital, Heidelberg, Germany • 2nd place: Kate Barrett, MD, Princess Margaret Cancer Centre, Toronto • 3rd place: Chi Zhang, MD, PhD, Columbia University Medical Center/New York Presbyterian Hospital, New York Radiation Physics • 1st place: Paul Romesser, MD, Memorial Sloan Kettering Cancer Center, New York • 2nd place: Roohi Gupta, PhD, Fox Chase Cancer Center, Philadelphia • 3rd place: Ziad Simon Fawaz, MD, University of Montreal Health Centre, Montreal

Basic Science Abstract Award The Basic Science Abstract Award recognizes up to 10 basic scientists (lead authors) of abstracts selected for presentation at the 2014 ASTRO Annual Meeting, in the biology or physics categories, with a $1,000 grant and a certificate. Up to five awards are available in each category. Junior investigators must have completed an ACGME-accredited residency or PhD program no more than 4 years prior to the deadline, and senior investigators must be biologists or physicists 4 to 10 years post-PhD or

Board certification, whichever comes later. Recipients of the 2014 Basic Science Abstract Award are: Radiation and Cancer Biology • Masayuki Matsuo, MD, PhD, National Institutes of Health, Bethesda • Everett Moding, BS, Duke University, Durham, North Carolina • Ngoc Pham, BS, The University of Texas MD Anderson Cancer Center, Houston • Corey Speers, MD, PhD, University of Michigan Health System, Ann Arbor • Daniel Spratt, MD, Memorial Sloan Kettering Cancer Center, New York Radiation Physics • Ganiyu Asuni, PhD, Cancercare Manitoba, Winnipeg • Jeremy Booth, PhD, Northern Sydney Cancer Centre, Sydney • Fiona Hegi-Johnson, MBBS, University of Sydney, Sydney • Xia Li, PhD, University of Nevada, Las Vegas • Yana Zlateva, MS, McGill University, Montreal

Annual Meeting Scientific Abstract/Travel Award The Annual Meeting Scientific Abstract/Travel Award recognizes outstanding abstracts submitted by early career scientists, biologists, and physicists. Up to 15 awards of $1,000 each are given (five in each category) to help offset travel expenses to attend ASTRO’s Annual Meeting. Awardees are the lead authors of high-scoring abstracts selected for presentation at the 2014 ASTRO Annual Meeting. They include: Clinical Practice • Kamran Ahmed, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa • Ben Creelan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa • Clement Ho, MD, MS, University of Calgary, Calgary, Alberta • Anthony Paravati, MD, MBA, University of California, San Diego • John Vargo, MD, University of Pittsburgh Cancer Institute, Pittsburgh Radiation and Cancer Biology • Miran Blanchard, MD, Mayo Clinic, Rochester • Nevine Hanna, MD, MPH, University of California, Irvine • Amanda Walker, MD, Johns Hopkins University, Baltimore • Christopher Wright, BS, Thomas Jefferson Medical School, Philadelphia

• Zachary Zumsteg, MD, Memorial Sloan Kettering Cancer Center, New York Radiation Physics • Olivia Kelada, MS, BS, Yale University School of Medicine, New Haven • Yilin Liu, PhD, Duke University, Durham • Jan Schuemann, PhD, Massachusetts General Hospital, Boston • Almut Troeller, MS, Beaumont Health System, Royal Oak, Michigan • Stephen Yip, PhD, Brigham and Women’s Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston

International–U.S. Annual Meeting Scientific Abstract Award The International–U.S. Annual Meeting Scientific Abstract Award provides a $4,000 grant to a radiation oncologist from a developing country to attend ASTRO’s Annual Meeting and to spend one week at a comprehensive cancer center in the United States. The award fosters continuing medical education, assists in career development, and aids in establishing relationships with ASTRO members who may serve as scientific mentors to the award winner. Recipients are the lead author of an abstract selected for presentation at the 2014 ASTRO Annual Meeting and have a letter of support from the Chair/Mentor of the U.S. institution that will host the awardee at their cancer center. The awardee must submit a written summary of their Annual Meeting participation and the experience garnered at the host cancer center. The recipient of the 2014 International – U.S. Annual Meeting Scientific Abstract Award is: • Yun Chiang, MD, National Taiwan University Hospital, Taipei, Taiwan

Annual Meeting Nurse Abstract Award The Annual Meeting Nurse Abstract Award honors the two highest rated abstracts with a nursing designation. Award candidates must be nurses who are the lead author or co-author of an abstract selected for presentation at the 2014 ASTRO Annual Meeting. Awardees will be recognized with a $1,000 grant and certificate at the Nurses’ Luncheon. The 2014 Annual Meeting Nurses’ Abstract Award recipients are: • Chiaki Fujioka, RN, Tane General Hospital, Osaka, Japan • Diane Serra, MS, RN, Mount Sinai Beth Israel Medical Center, New York n

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 65

Expert’s Corner Issues in Oncology

Identifying Impending Death Helps Patients and Caregivers A Conversation With David Hui, MD, MSc By Ronald Piana

Difficult Clinical Situation

David Hui, MD, MSc

ignificant weight loss, cachexia, and being bedbound signal that a cancer patient is dying. However, identifying the specific signs that give physicians the ability to predict death is not well described in the literature. To better understand why predicting death is an important part of the care continuum, The ASCO Post spoke with palliative care specialist and medical oncologist, David Hui, MD, MSc, Assistant Professor in the Departments of Palliative Care/Rehabilitation Medicine and General Oncology at The University of Texas MD Anderson Cancer Center, Houston. Dr. Hui and his colleagues recently completed a study in this underreported area of palliative care.

Why is it important to be able to identify the clinical signs of impending death? For a number of reasons. Clinical decisions at the end of life, such as discharging patients and ending and beginning medication schedules, are dependent on a patient’s prognosis. In patients who are actively dying, we need to focus all our efforts on comfort measures that prevent suffering. The key question becomes: how can we as oncologists tell when our patients are actively dying? This is not a subject without controversy. In many countries, there is an intense debate about the medical propriety in the use of integrated care pathways for patients who are imminently dying, such as the United Kingdom’s Liverpool Care Pathway for the Dying Patient. Part of this controversy stems from the fact that, to date, we still do not have a lot of clinical confidence to determine when a patient has entered this irreversible phase and will die within a few days. That lack of knowledge creates

caregivers, and they can plan their lives around the dying process. For instance, if a father is admitted to the hospital and his son lives in another state, it’s important to be able to know if the patient is in the final days of life so his son can make appropriate travel plans for a peaceful closing and to say goodbye.

Overestimating Survival In your work, you indicate that physicians tend to overestimate survival time in their terminally ill cancer patients. Why is this? A body of literature from our group at MD Anderson, as well as from other institutions, shows that doctors and nurses routinely overestimate survival, and this is largely due to our lack of accurate prognostic tools. Moreover, we often lean on the side of overcaution when breaking bad news to patients and their families; there are so many implications to a diagnosis of imminent death that doctors often avoid the conversation altogether. Caution is understandable, but honesty based on

Having tools that help predict impending death will make the stressful process easier for the patient, the doctor, and the family and caregivers who need to prepare for the end. —David Hui, MD, MSc

Study Details Please describe the trial design. It was a prospective longitudinal observational cohort study designed to identify the physical signs of impending death. It involved the MD Anderson Cancer Center in Houston and the Barretos Cancer Hospital in Brazil. We basically followed the cancer patients from the day of admission to an acute palliative care unit. We documented clinical signs of interest twice a day, every day until they were discharged from the unit or they died. We were able to tell how often certain systems occurred prior to death. After aggregating and analyzing the data, we identified a number of physical signs that allow us to predict death within 3 days.

unease about frank discussions about care in this very difficult clinical setting. Plus, if we cannot predict with certainty that the patient is imminently dying, then it opens the door for critics of the pathway to say that option was taken away from patients still eligible for lifesustaining therapy.

Family Considerations How does having a better way to predict death affect the patient’s family? Families of terminally ill cancer patients often want to know when to expect death so they can appreciate the process and understand what their loved one is going through. This information can also help their efforts as

accurate information is needed in this difficult setting.

Role of Hospice Is this an area of inquiry that might help hospice workers? We looked at patients in MD Anderson’s acute palliative care unit, because they are being carefully monitored, in the inpatient setting. We suspect what we learned might be applicable to other settings such as hospice; however, this would need to be further tested. Our next step is to conduct a larger validation study to further confirm our findings. We could then develop a diagnostic tool to help clinicians and caregivers identify the specific signs of impending death.

Key Symptoms What were the symptoms that best predicted impending death? There were 10 clinical signs leading to the death of patients we followed in the palliative care unit. Built on our findings, we were able to divide the signs into two groups based on the frequency of occurrence, their onset relative to death, and their predictive value for impending death. The early signs are decreased level of consciousness, decreased performance status, and dysphagia. Most patients who die have these signs, which occur about a week before death. These signs have only moderate predictive value in telling us that the patient has 3 days left. The later signs that we documented were pulselessness of the radial artery, apnea, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, respiration with mandibular movement, and decreased urine output. These signs occur due to bodily changes seen with very decreased level of consciousness—perhaps activity in the brainstem or decreased cardiovascular profusion. These signs usually occur in the last 3 days of life. They are not always present in patients who die within 3 days, but when they are present, they are strongly predictive of impending death. So with simple bedside observations, a clinician can predict what is going to happen to the patient by detecting the signs, such as respiration with mandibular movement, which essentially means the jaw drops during breathing. This is a telltale sign that the patient will die in the next few days. Having tools that help predict impending death will make the stressful process easier for the patient, the doctor, and the family and caregivers who need to prepare for the end. As mentioned, our next step is more research from which we can design a tool to help clinicians predict when death is imminent. n Disclosure: Dr. Hui reported no potential conflicts of interest.

Visit The ASCO Post website at ASCOPost.com

Does your ovarian cancer patient have a BRCA mutation? Only testing will tell.

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation. Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9 BRCAm Ovarian Cancer Patients by Age at Diagnosis8

NCCN, SGO, and ASCO guidelines recommend that all patients with epithelial ovarian cancer be considered for BRCA testing, regardless of family history, age, or ethnicity.2-4

39% 29

The Society of Gynecologic Oncology encourages the medical community to offer hereditary cancer risk assessment to all women with ovarian, fallopian tube and peritoneal carcinoma.” - SGO Clinical Practice Statement, March 2014 3 In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients. 8,9 Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no significant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCABRCAm Ovarian Cancer Patients by Family History Status8

53%

47% No relevant family history Relevant family history

32%

71%

of patients with ovarian cancer and a BRCA mutation are aged 50 or older at diagnosis.8 <50 50-59 >60

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity, yet BRCA testing is not as common in women of non-European descent.10 Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a significant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair deficiencies and therefore are particularly sensitive to DNA-damaging agents.13 Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13 Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefit for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES: 1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 4;2013. 3. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. March 2014. http://www.sgo.org/clinical-practice/ guidelines/genetic-testing-for-ovarian-cancer/. Accessed June 13, 2014. 4. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. ©2014 AstraZeneca. All Rights Reserved. 3011508 Last Updated 07/14

The ASCO Post | SEPTEMBER 1, 2014

PAGE 68

Book Review

A New Book Explores an Old Subject: Aging By Ronald Piana

eath is the universal experience shared by Earth’s 7 billion or so inhabitants, from street beggars in Mumbai to Wall Street investment bankers. Another common human experience is our determination to forestall death. However, while humans strive to live as long as possible, there’s also a common dread of losing youthful vigor as life’s journey moves into its later years—the human paradox of wanting to live forever but not grow old. Aside from X’s on a calendar, wrinkled skin, and forgetfulness, what is aging and why do we fear it? This big philosophical question has been tackled in a captivating new book, Lighter as We Go: Virtues, Character Strengths, and Aging, by Mindy Greenstein, PhD, and Jimmie Holland, MD, both of Memorial Sloan Kettering Cancer Center in New York.

About the Authors In 1977, Dr. Holland took a position at Memorial Sloan Kettering, where she developed the first psychological and psychiatric services center in a cancer center. Her groundbreaking work would mature into the subspecialty of psycho-oncology practice. Since cancer is largely a disease of aging, Dr. Holland’s life’s work informed the writing of this intriguing book. Similarly, her coauthor and Memorial Sloan Kettering colleague, Dr. Greenstein, is a clinical psychologist with extensive experience talking with emotionally vulnerable cancer patients facing an uncertain future. Dr. Holland turned 85 during the writing of this book. Dr. Greenstein is 50, and in the introduction, the readers learn that she is a breast cancer survivor, having been diagnosed at the age of 49. Book collaboration is difficult and can strain the best of colleagues, but the authors’ voices are seamlessly woven throughout the narrative, and even before finishing the introduction, you will come to like these smart and compassionate women. They bring erudition and hard-earned experiential knowledge to the pages of their book.

Character-Building Experiences Lighter as We Go is about social science and the results of research that shed light on the way people experience life as they move from youth to old age and how, if we pay attention, we can in-

tegrate the character-building lessons of aging into other parts of our society— and into cancer care, too. Also, in the words of the authors, “From our different vantage points, we can both see how much society needs an attitude adjustment when it comes to aging.” Divided into three sections and 13 chapters, Lighter as We Go asks difficult questions and then explores the answers using anecdotal and researchbacked narratives. For instance, in chapter 1, “The Oak Tree and The U-Bend,” the authors ask, “So, what is this me?” This me can be defined and realized by the term character, which has fallen into disuse in the contemporary psychiatric community. But Drs. Holland and Greenstein argue that character is an essential component of the healthy aging process, especially in a youth-oriented society that enforces negative stereotypes that “scare the young and make elders feel worse about themselves. Midlifers fear becoming old, and young adults fear becoming mid-lifers, like

Bookmark Title: Lighter as We Go: Virtues, Character Strengths, and Aging Authors: Mindy Greenstein, PhD, and Jimmie Holland, MD Publisher: Oxford University Press Publication date: September 2014 Price: $27.95; Hardcover, 320 pages bourne, psychologists who developed what is called “identity balance theory,” which suggests that there are processes that help us keep a balanced sense of who we are, even as we age and change in appearance. They explain that the idea of identity balance comes from the fact that not every new experience leads to changing fundamental qualities or how you define yourself. And even when major

From our different vantage points, we can both see how much society needs an attitude adjustment when it comes to aging. —Mindy Greenstein, PhD, and Jimmie Holland, MD

one long cascading domino effect of the fear of aging.” For help on this issue, they refer to psychologist James Hillman, who noted that it takes a lot of living to develop character, and it only emerges in elders. “How we age, the patterns we regularly perform, and the style of our image show the character at work. As character directs aging, aging reveals character.”

Identity Balance The authors’ use of stimulating analogy is shown early in the book when citing research by Joel Sneed and Susan Whit-

changes in one’s life occur, there is still a core identity underpinning those changes. Professional athletes, whose personal identity is forged to their sport, experience a radical change of life because their careers are cut so short by age. The authors use legendary Cleveland Indians pitcher Bob Feller as an example of how character withstands upheaval and enhances the aging process. After retiring as one of history’s most notable pitchers, Feller built a successful insurance company and became a licensed pilot, living a long and fulfilling life. “While some core aspects of his identity changed over

the years, other core aspects stayed the same, and he could experience himself as a coherent whole, despite the dramatic changes,” the authors write.

‘U-Bend’ Phenomenon In an absorbing discussion, Drs. Holland and Greenstein look at a phenomenon that consistently finds its way into the social science literature called the “U-Bend” of life. According to the authors, research has surprisingly shown that the age group that feels the greatest sense of well-being is the 82- to 85-yearold group. Eighteen year olds have a very high sense of enjoyment of life, but those feelings begin sliding, reaching bottom around the early 50s. After that, feelings of well-being bend upward rather rapidly, peaking in the early 80s—hence, the U-Bend phenomenon, which is not completely understood. “So, what might be going on, and what can we learn from it?” the authors ask. To that end, they discuss a 2009 Yale study that found people who have negative stereotypes of aging when they are young are more likely to have serious chronic illnesses as they get older, compared with those with a more positive view of aging. One possible explanation (that’s examined in chapter 9) is that people with more positive expectations about old age might be more likely to develop healthier lifestyles. Therefore, teaching the young to embrace aspects of their own aging could lead to better health outcomes for future generations of elderly. Mixing social science with anecdotal forays into the personal experiences of real people can be tricky, and if done with too heavy a hand, downright deadly to a serious book such as this. But Drs. Holland and Greenstein are natural storytellers, and they put human continued on page 72

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL WITH ZELBORAF Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)† 100

HR=0.47 (95% CI, 0.35-0.62), P<0.0001

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001) —78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months) —Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Significant improvement in PFS ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis. Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | SEPTEMBER 1, 2014

PAGE 72

Advocates in Oncology How Pharmaceutical Companies Are Partnering With Patient Advocates to Ensure Access to Oncology Care A Conversation With Thomas P. Sellers, MPA By Jo Cavallo

homas P. Sellers, MPA, has been a tireless advocate for patients’

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

8 3 <1 1 1 2 0 0 <1 0

2 4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

Mr. Sellers said it was his mother’s death from lung cancer when she was 51, fol-

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)]. • ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)]. • Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)]. • Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)]. • ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)]. • Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)]. • ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)]. • Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)]. • ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

lowed by the death of his father from glioblastoma multiforme that led him to a career in patient advocacy. Over the past 2 decades, Mr. Sellers held the positions of Chief Financial Officer for the American Cancer Society New England Division and CEO of the National Coalition for Cancer Survivorship. He

Book Review continued from page 68

faces on each topic they engage. For example, Nancy Miller, a 63-year-retired engineer says, “People over 60 have less to lose. Their striving is over, and now you can take risks. It’s time to be generative. You have to go out of your way to connect with people.” That’s a powerful sentiment, shared by millions of Americans. The authors seize on the complicated notion of being generative. Citing the psychologist Erik Erikson, who in 1950 theorized that mid-life was the time in our life to generate and nurture the next generation. And quite poetically, psychiatrist George Vaillant “refers to us [mid-lifers] as society’s ‘keepers of meaning,’ a role we will continue into older age.”

Important Lesson Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

rights for more than 20 years. A 15-year Safety:7" prostate cancer survivor and only child,

Along with deep and thoughtful explorations of aging that will assuredly enlighten their audience, the authors give even more, such as chapter 4, “Older Age in the Olden Days: A History of Aging in the Western World.” This chapter details the history of our very complicated relationship with age and mortality, from antiquity to present day. The authors sum up this edifying section thusly: “Perhaps one of the most important lessons of history is the importance of learning to reconcile the good with the bad, the things we can control with the things we can’t, the older with the younger.” Lighter as We Go does not glorify old age. But by explaining the multilayered physical and psychological processes of aging, the book defends the old against crass ageists that populate much of our pop culture. More important, without being the least bit didactic, Drs. Holland and Greenstein have open-mindedly explored and discussed a societal topic that still remains sorely misunderstood, partly out of our universal fear of aging. This bold and liberating book should be on everyone’s reading list, regardless of age. n

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Advocates in Oncology is currently Senior Director for Patient Advocacy and Corporate Philanthropy for Millennium, The Takeda Oncology Company. His overarching goal at Millennium is to ensure that patients have access to the most effective therapies available and that the company develops programs to address the unmet needs of patients with cancer and their caregivers, including giving them a greater role in drug and clinical trial development. The ASCO Post talked with Mr. Sellers about the increasing collaboration among patients, patient advocacy groups, and the pharmaceutical industry in the funding of new oncology therapies and in the facilitation of clinical trial design and patient recruitment, and how these relationships are having an impact on drug development and approval.

therapies, such as treatment effectiveness and side effects. We also have meetings with representatives from the American Cancer Society and the Patient Advocate Foundation to ensure that we are aware of every concern patients have, including their financial concerns. We are really focused on building relationships in which there is mutual value for patients, caregivers, and us.

Changing Relationship Please talk about the evolution of patient involvement in drug development. How has the relationship changed between

With the advent and emphasis on patient-focused drug development and through initiatives like 21st Century Cures, patient groups are having more influence across the entire drug development continuum, from discovery and approval to market.

Advocacy Collaborations How does Millennium collaborate with patient advocates in its drug development process? We strategize and engage with patient advocacy groups—such as the International Myeloma Foundation (IMF), the Multiple Myeloma Research Foundation (MMRF) and the Leukemia & Lymphoma Society (LLS)— that are very involved in and have a significant amount of knowledge and experience in the design of clinical trial concepts and protocols to consult with our oncology research division about patient concerns. We are also currently looking at additional ways to directly involve patient advocates who are highly trained in the clinical trial process. In addition, we convene meetings with patient advocacy leaders involved in cancers we do not currently have a lot of drug development in, such as the Ovarian Cancer National Alliance, LUNGevity, Lung Cancer Alliance, and Melanoma Research Foundation, because we want the voices of all active participants in the cancer community around the table. Several years ago, we formed the Cancer Advocacy Council, which is made up of patient advocates and thought leaders in the patient community, and each year we convene one or two meetings to address a specific topic of concern to patients, with the goal of advancing our knowledge of patient needs—for example, easier access to therapies or patient education about their cancer. We also want to know about patients’ experience with their

relationship grew from having a strong patient advocacy function within Millennium. Another example is our collaboration with the IMF to identify myeloma patient preferences.

—Thomas P. Sellers, MPA

Greatest Concerns What are some of patients’ greatest concerns? Their number 1 concern is having access to drugs, and that access can include everything from getting the drug to transportation to and from the cancer clinic, lodging, and other financial impacts of having cancer, including not being able to work or their caregivers not being able to work. One of the ways we try to mitigate the financial burden of having cancer is by supporting the patient assistance programs of organizations like the LLS or the Patient Advocate Foundation and CancerCare’s transportation program.

Therapeutic Advances How is Millennium partnering with patient advocacy groups to advance cancer therapies? One example is MMRF’s 10-year CoMMpass study in multiple myeloma. Millennium was the first company to collaborate with MMRF to both fund and participate in the study. But our involvement is more than just writing a check. We want to partner with patient advocacy groups and private foundations to be part of the entire process to learn how patients respond to therapies. Patients and the pharmaceutical industry will greatly benefit from the work that CoMMpass is doing. Millennium’s Translational Medicine Department is involved in that study, but the

with patient groups on individual diseases to develop a structured approach to evaluating and regulating drugs based on benefit and risk.

Clinical Trial Funding Is there more emphasis now on patient advocacy groups directly funding specific clinical trials? Yes. There are many patient groups directly funding clinical trials and engaged in helping with the recruitment or the design and organization of clinical trials. Patient advocacy groups are also involved in key government agencies to present the patient perspective to advance cancer research. For example, the National Cancer Institute has an Office of Advocacy Relations and also includes patient advocates who sit on clinical trial and grant review committees and have helped write patientfriendly templates for clinical trial consent forms, among other things.

Major Accomplishments patients and pharmaceutical companies? It has changed significantly and in multiple ways. Five years ago, the extent of pharmaceutical companies’ involvement with patient groups seemed to be limited to the drugs serving the needs of patients involved in those groups. With the advent and emphasis on patient-focused drug development and through initiatives like the U.S. House of Representatives Committee on Energy and Commerce’s 21st Century Cures, which is studying the gap between the science of cures and drug regulation, patient groups are having more influence across the entire drug development continuum, from discovery and U.S. Food and Drug Administration (FDA) approval to market. For example, the MMRF’s Multiple Myeloma Research Consortium is serving as an incubator for clinical trials, and the MMRF has invested a lot of money in the development of new myeloma therapies. Other patient organizations such as the LLS are supporting early drug discovery in preclinical and clinical studies. And there are lots of other groups getting involved earlier and earlier in the drug development process. There is also more patient involvement in government regulatory agencies, including the FDA and the Prescription Drug User Fee Act, which plays an important role in expediting new drug approval. The FDA has started holding a series of public meetings

What significant accomplishments have you seen as a result of patient involvement in drug development at Millennium? One of the initiatives that came out of our Cancer Advocacy Council is a more accurate way to measure patient outcomes. We brought a group of prostate cancer advocates in to talk about issues they wanted to address in collecting patient reported outcomes and improved the clarity, appropriateness, validity, and usefulness of survey questions.

Ethical Issues What are the ethical boundaries pharmaceutical companies have to adhere to when working with patient groups? Most importantly, we must have transparent and open communication characterized by integrity and mutual respect, with clear expectations about our shared goals and objectives. Also, patient groups independently develop their own content for patient education materials or patient education programs that may have costs offset by unrestricted educational grants we provide. Another way Millennium operates to preserve the integrity of the process is to rarely be the sole sponsor on a project or program. We prefer to work with other companies to fund work for the benefit of patients in a particular area. n Disclosure: Mr. Sellers is Senior Director for Patient Advocacy and Corporate Philanthropy for Millennium, The Takeda Oncology Company.

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; SEPTEMBER 1, 2014

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Clinical Trials Resource Guide Genitourinary Oncology

Ongoing Clinical Trials Actively Recruiting Patients With Kidney Cancer Compiled by Jo Cavallo

he information in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with kidney cancer. The list includes a pilot study and observational, randomized, and nonrandomized phase II and phase III studies evaluating new therapies, combination therapies, surgical techniques, and contrastenhanced ultrasound diagnostics. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.go

KIDNEY CANCER Study Type: Interventional/singlegroup assignment Study Title: A Prospective Pilot Study Evaluating Renal Lesions Through Contrast-Enhanced Utrasound in Patients With Renal Cancer and in Those With a Risk Factor for Renal Malignancy Study Sponsor and Collaborators: University of North Carolina Lineberger Comprehensive Cancer Center Purpose: This pilot study is designed to evaluate the accuracy of contrast-enhanced ultrasound when used to evaluate renal lesions in two different populations: patients with known renal tumors (cohort 1) and patients with a risk factor for renal malignancy in whom their screening ultrasound shows an indeterminate or possibly malignant renal mass (cohort 2). Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Feasibility of using contrast-enhanced ultrasound in diagnosing renal malignancy in patients with known renal disease and in patients with a risk factor for renal malignancy diagnosed with suspicious or indeterminate lesions (time frame: 12 months) Principal Investigator: Kimryn Rathmell, MD, University of North Carolina Lineberger Comprehensive Cancer Center. Contact: Gayle Grigson, RN; 919-966-4432; gayle_grigson@med.unc.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01751529

Study Type: Phase II/interventional/nonrandomized Study Title: A Phase II Multi-Center Study of Bevacizumab in Combination With Ixabepilone in Subjects With Advanced Renal Cell Carcinoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To determine whether the combination of ixabepilone, a member of the class of drugs called epothilones, and bevacizumab (Avastin) is effective in treating kidney cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Response rate per RECIST Principal Investigator: Antonio T. Fojo, MD, National Cancer Institute; 301-496-2831; fojot@mail.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00923130 Study Type: Phase II/observational Study Title: A Phase II Metastasectomy Study for Patients With Renal Cell Carcinoma Study Sponsor and Collaborators: MD Anderson Cancer Center Purpose: To learn if the surgical removal of the primary tumor or the parts of the cancer that has spread to other parts of the body is a good method for treating patients with kidney cancer. Only the parts of the cancer that has spread will be removed during the surgery. Ages Eligible for Study: N/A Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: 24week progression-free/relapse-free survival time (time frame: every 3 months for the first year; 4 months during the second year; every 6 months in the third through fifth year) Principal Investigator: Eric Jonasch, MD, The University of Texas MD Anderson Cancer Center; 713-792-2830 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00918775 Study Type: Phase II/interventional/randomized Study Title: A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothelial Growth Factor Therapy in Patients With Renal Cell Carcinoma Who Have

Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate how well trebananib (AMG 386) with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients with kidney cancer that has spread to other places in the body Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Overall tumor response rate defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by Response Evaluation Criteria in Solid Tumors version 1.1 criteria (time frame: up to 8 weeks) Principal Investigator: Thomas J. Semrad, MD, University of California at David Cancer Center; 916-734-3771; thomas.semrad@ucdmc.ucdavis.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01664182 Study Type: Interventional/singlegroup assignment Study Title: A Prospective Pilot Study Evaluating Renal Lesions Through Contrast-enhanced Utrasound in Patients With Renal Cancer and in Those With a Risk Factor for Renal Malignancy Study Sponsor and Collaborators: University of North Carolina Lineberger Comprehensive Cancer Center Purpose: This pilot study is designed to evaluate the accuracy of contrast-enhanced ultrasound when used to evaluate renal lesions in two different populations: patients with known renal tumors (cohort 1) and patients with a risk factor for renal malignancy in whom their screening ultrasound shows an indeterminate or possibly malignant renal mass (cohort 2). Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Feasibility of using contrast-enhanced ultrasound in diagnosing renal malignancy in patients with known renal disease and in patients with a risk factor for renal malignancy diagnosed with suspicious or indeterminate lesions (time frame: 12 months) Principal Investigator: Kimryn

Rathmell, MD, University of North Carolina Lineberger Comprehensive Cancer Center. Contact: Gayle Grigson, RN; 919-966-4432; gayle_grigson@med.unc.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01751529 Study Type: Phase II/interventional/randomized Study Title: A Phase II Study of Bevacizumab Alone or in Combination With TRC105 for Advanced Renal Cell Cancer Study Sponsor and Collaborators: National Cancer Institute Purpose: To evaluate how well bevacizumab with or without monoclonal antibody therapy works in treating patients with metastatic kidney cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Progression-free survival (time frame: the duration of time from start of treatment to time of progression or death, assessed at 12 weeks) Principal Investigator: Tanya B. Dorff, MD, University of South Carolina Norris Comprehensive Cancer Center; 323-865-3900; dorff@usc.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01727089 Study Type: Phase II/interventional/randomized Study Title: Randomized Phase II Study Comparing Cabozantinib (NSC #761968) With Commercially Supplied Sunitinib in Patients With Previously Untreated Locally Advanced or Metastatic Renal Cell Carcinoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To study how well cabozantinib-s-malate works compared to sunitinib malate in treating patients with previously untreated kidney cancer that has spread to nearby areas of the body Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Progression-free survival (time frame: up to 5 years) Principal Investigator: Toni K. Choueiri, MD, Alliance for Clinical Tri-

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Clinical Trials Resource Guide

als in Oncology; toni_choueiri@dfci. harvard.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01835158 Study Type: Phase II/interventional/randomized Study Title: A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal Cell Carcinoma With Sarcomatoid Features Study Sponsor and Collaborators: Eastern Cooperative Oncology Group; National Cancer Institute Purpose: To investigate giving sunitinib malate together with or without gemcitabine hydrochloride to determine how effective they are in treating patients with advanced kidney cancer that cannot be removed by surgery Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Response rate Principal Investigator: Naomi S. Balzer-Haas, MD, Abramson Cancer Center of the University of Pennsylvania. Contact: Clinical Trials Office of the Abramson Cancer Center of the University of Pennsylvania at 800-4749892 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01164228 Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Efficacy Trial of Pazopanib in Non-Clear Cell Metastatic Renal Cell Cancer (mRCC) PINCR Study Sponsor and Collaborators: Mayo Clinic Purpose: To study how well pazopanib hydrochloride works in treating patients with metastatic kidney cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Overall survival time (time frame: 12 months) Principal Investigator: Brian A. Costell, MD, Mayo Clinic. Contact: Mayo Clinic Clinical Trials Referral Office: 507-538-7623 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01767636 Study Type: Phase II/interventional/single-group assignment

Study Title: Phase II Trial of Moderate Dose Bolus Interleukin-1 in Metastatic Kidney Cancer Study Sponsor and Collaborators: Western Regional Medical Center Purpose: To determine whether interleukin-2 at the dose and schedule used in this study helps increase tumor shrinkage

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Progression-free survival of patients with metastatic kidney cancer who have had disease progression on at least one prior therapy or who have not been treated

(time frame: 9 weeks) Principal Investigator: Walter Quan, MD, Western Regional Medical Center. Contact: Marci Pierog, RN, 623-207-3000; marci.pierog@ctcahope.com For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01702909 n

For HR+, early-stage invasive breast cancer

Confidence begins with a highly accurate risk assessment

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1 • Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today. Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy. Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients. © 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

Proceed with confidence

The ASCO Post | SEPTEMBER 1, 2014

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Gynecologic Oncology

Gynecologic Cancer Care: Collaboration With Resource-Challenged Ethiopia By Ronald Piana

ver the past 40 years, largely because of universal Pap screening, cervical cancer deaths have been drastically reduced in the United States and other wealthy industrialized countries. However, cervical cancer is still a leading cause of cancer death among women in resource-challenged areas of the developing world, such as subSaharan Africa. The ASCO Post recently spoke with Eva J. Kantelhardt, MD, a gynecologist at Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany, whose clinical research focus is on gynecologic oncology and breast cancer. Among other things, she spoke about her ongoing research in cervical cancer in Ethiopia.

Rewarding Beginnings Please tell the readers a bit about yourself, where you were born and raised. I was born in Mount Kisco, New York. My parents are both German, but my father, a physicist, was in the United States doing a 1-year postdoctoral program at the IBM research laboratories in New York State. My early schooling was mainly in the western part of Germany in the small town of Schwerte, as well as high school in Göttingen. Since my father had sabbatical leaves every 4 years, we spent 6-month periods in different parts of the United States as a family. This was a great experience as a child, as I discovered the cultural differences and learned English. It is a rewarding situation to begin school as the new foreigner in class and to then be welcomed and make new friends.

Path to a Medical Career Please describe your early education and college, as well as any influences on your decision to pursue a career in medicine. My grandmother studied medicine in the 1920s in Germany and Austria, one of the first women to do so. Having Jewish family members and given the growing political turmoil in Germany, in 1938 she applied to work as a doctor in Latin America. Her request was denied, however, since the organization coordinating this effort thought women were unable do this type of work.

Fortunately, the family found another opportunity to emigrate from Germany to Brazil, where my grandmother practiced obstetrics. I still have her notes and some of her instruments. Even though I never met her personally, her example encouraged me to go into medicine. My mother was born in Brazil, and parts of the family still live there. My cousin is a plastic surgeon in São Paulo. When I was 16, I saw a report from a pediatrician who was a missionary in South Africa and worked there during the Apartheid era. This impressed me

Altogether, the experience there encouraged me to become a gynecologist and to focus on improving health care for women in settings with limited resources. I learned that this could only be done by analyzing the situation, generating evidence, and finding ways to improve the situation as a team.

berculosis, and malaria. We started with three German students in Addis Ababa in 2010. They documented pathology reports and patients’ disease course, and did interviews in the countryside. One by one, colleagues from pathology, public health, surgery, and gynecology at Addis Ababa University joined the group to collect data on female cancer in Ethiopia. More students from Germany and Ethiopia worked together. Visiting conferences like the AORTIC (African Organization for Research and Treatment in Cancer) raised spirits on the interdisciplinary team. We somehow convinced the German Ministry for Research and Education to provide a grant for our activities, including the start of a populationbased cancer registry in Addis Ababa in 2011. Now there are three radiation oncologists working there, and Mathewos Assefa, MD, is our main collaborator. We often faced bureaucratic challenges, technical problems, lack of essentials like water or Internet access, and many other unexpected events. But after working together for some time, I can quote my colleague Adamu Addissie, MD, MPH, MA, from the public health sector: “This is part of the experience!” And it truly is a wonderful experience and a privilege to work with my colleagues from Ethiopia and Germany to improve female cancer care.

Ethiopian Experience

No Quick-Win Strategies

Please tell us about your current career and your epidemiologic research in cervical cancer in Ethiopia. In 2007, a very good Ethiopian nurse friend of mine was diagnosed with breast cancer during her pregnancy. This led me to Solomon Bogale, MD, the only oncologist in Addis Ababa at the only oncologic center (with one cobalt radiotherapy machine) in the country at that time. In the end, we treated my friend in Germany because there was less of a wait there. However, I started visiting Dr. Bogale and collaborating with him. He was very open to collaboration, since few people were interested in his work in cancer. As we discovered, research funding was available mainly for HIV, tu-

As an oncologic specialist and global researcher, what is your outlook for reducing the cancer burden in developing nations? The World Health Organization says: “Do not drink, do not smoke, participate in sports, and maintain a normal weight.” These recommendations are of course essential, but there are difficulties in promoting them even in countries with highly educated people. For female cancer in Africa, we need more evidence-based strategies. Much progress has been made in surveillance, with 20 African countries currently submitting data to the International Agency for Research in Cancer, for example, in the GLOBOCAN Project (led by Donald Maxwell Parkin, MD). Prevention measures, such as HPV vac-

in smaller regional hospitals, without a research background. When I had finally finished my first 4 years of medicine, I went to the South African North West province, for an extended 6-month elective. The pediatrician, Angelika Krug, MD, arranged for me to start my elective where life starts: in the obstetrics ward of a small rural hospital. This was a very positive experience, but I also saw three maternal deaths in only 2 months. I realized that the accumulation of small mistakes can lead to catastrophes and that medicine does have its limitations.

Forming a collaborative team is the only way forward to tackle a complex issue like oncologic care in these resource-challenged areas. —Eva J. Kantelhardt, MD

very much. I asked her, if I study medicine, might I go and spend half a year working with her. She said yes, but not to come before the fourth year of studies.

From the Lab to the Clinic Please describe medical school and what influences led you to specialize in gynecologic oncology. The medical school at Georg-August University in Göttingen is known for very good natural sciences and preclinical education. I decided to spend time in the biochemistry laboratory of Kurt von Figura, MD, who later became the University President. Our group worked with one of the first transgenic mice, which I had to take care of even on weekends. Seeing accurate lab research and vigorous collaboration was very memorable. After finishing the thesis before my internship, I decided not to stay in the lab full-time, but rather to work with patients and do clinical research as well. I did my residency at a university hospital to make sure research would be included. It’s worth noting that doing a residency in Germany is also possible

ASCOPost.com | SEPTEMBER 1, 2014

cination and optimization of early-detection strategies for cervical cancer, have been started nationwide now in Rwanda, with other countries following suit. Downstaging breast cancer through awareness campaigns is on the way. Hospital-based care must be expanded as well, since there is no option for preventing breast cancer, for example. Oncology centers must become available throughout these countries. The fact that about half the countries in Africa do not offer radiotherapy represents a serious health-care gap. For noncommunicable diseases

like cancer, there will be no quick-win strategies. A multidisciplinary approach requiring tertiary-level institutions needs, first of all, political commitment with careful and wise planning. When governments start thinking about buying linear accelerators, they also have to think about stable electrical current and radiotherapy technicians who can handle the machines.

Looking Ahead Any last thoughts about your future direction? My future direction is to continue in

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clinical work and research, with a focus on Africa, striving to realize benefits for patients from translational medicine and transnational collaborative efforts. I am sure that high-quality research can be done in resource-challenged countries like Ethiopia. Having joint projects at an eye-to-eye level with colleagues in Africa is the basis for progress in the laboratory and the clinic. I am aiming to continue surveillance and epidemiologic studies, look at best practices, do operational research, and in the long term, set up capacities for conducting clinical trials in

Africa. Several international collaborations for improving oncologic care in Ethiopia are working together with the Addis Ababa University and the Ethiopian Ministry of Health. Forming a collaborative team is the only way forward to tackle a complex issue like oncologic care in these resource-challenged areas. This will be to the benefit of colleagues in Africa who are the ones facing such a magnitude of patients, and who will ultimately change patients’ lives for the better. n Disclosure: Dr. Kantelhardt reported no potential conflicts of interest.

NIH Awards Two New Grants to Explore the Understanding of Genomics Research in Africa

wo grants totaling more than $300,000 will support studies on genomic literacy among Africans as it relates to research conducted in Africa by African investigators. The 3-year grants are part of the Human Heredity and Health in Africa (H3Africa) program, funded by the National Institutes of Health’s Common Fund in partner-

“These grants will help us begin to get a better sense of what people in two different African countries understand about genomics concepts,” said H3Africa Program Director Ebony Madden, PhD, an Epidemiologist in the Division of Genomic Medicine at the National Human Genome Research Institute (NHGRI), part of

NIH. “We hope that what we learn from this work will lead to more effective informed consent discussions with potential research participants and to new culturally appropriate educational strategies about genomics.”

tability and genomics are understood in local languages. They will assess the participants’ perception and satisfaction with the informed consent form currently in use, and compare it to a new consent form the researchers will develop. The new form will include language that they hope will better explain genomics terms based on feedback they receive from the interviews and focus groups. The researchers plan to test this on participants enrolling in a diabetes study. The Nigeria project could impact how consent forms for genomics-related projects are written, especially for populations unfamiliar with the concepts of heritability and genomics.

Institute of Human Virology, Nigeria

Addis Ababa University, Ethiopia

The Institute of Human Virology, Nigeria, has been awarded a grant of $162,000, with Clement Adebayo Adebamowo, MD, ScD, serving as Principal Investigator. Dr. Adebamowo and his colleagues will conduct interviews with community leaders and focus groups in rural and urban populations to gauge how concepts on heri-

Addis Ababa University, Ethiopia, has been awarded a grant of $161,151, with Getnet Tadele, PhD, serving as Principal Investigator. Dr. Tadele and his colleagues are assessing young people’s (ages 15 to 24 years) understanding of how genes and the environment interact to cause podoconiosis, an infectious condition prevalent in north-

Both studies will increase our knowledge of how to tailor informed consents and educational materials based on linguistic and cultural needs so that genomic concepts are better understood. —Ebony Madden, PhD

ship with Britain’s Wellcome Trust. One of the grants will support a research project to understand cultural and language concepts of genomics in Nigeria. The goal is to develop a participant consent form for a diabetes study that better relays genetic concepts in terms that people from both rural and urban environments in Nigeria understand. The other grant will support a project to determine Ethiopians’ understanding of gene-environment interactions, with a goal of also increasing awareness about disease susceptibility. Both grants are part of the Ethical, Legal and Social Implications (ELSI) component of H3Africa. The program has disbursed approximately $78 million to date.

Clement Adebayo Adebamowo, MD, ScD

ern Ethiopia. The disease is caused when people with certain genetic variants are exposed to volcanic soil. An estimated one-fifth of Ethiopians carry the genetic variants that result in the debilitating disease. Researchers will then develop educational strategies and a resource to improve the understanding of these concepts in African communities. Dr. Madden said both research projects could lead to broader applications. “Both studies will increase our

Getnet Tadele, PhD

knowledge of how to tailor informed consents and educational materials based on linguistic and cultural needs so that genomic concepts are better understood,” Dr. Madden said. “Many times, even though we try to write on a young elementary school student level, we are still using terms that certain cultures may not be able to relate to. These studies will teach us how to truly inform participants and/or educate the public about genetic concepts that they may only have a vague idea about.” n Disclosure: These awards are supported by NIH grants 1U01HG007654-01 and 1U01HG007628-01.

Continue treatment.* 1-4 Extend survival. For patients with advanced nonsquamous† NSCLC Median Overall Survival: 13.9 months with ALIMTA® (pemetrexed for injection) single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02 * Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent. After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA continuation maintenance showed extended overall survival with a safety profile consistent with previously reported ALIMTA single-agent trials

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

Select Important Safety Information Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Premedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

Clinically relevant differences in survival probability as compared with placebo in certain patients* with advanced nonsquamous† NSCLC 1,4,5

a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy. b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety Information Warnings and Precautions ALIMTA can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Frequent blood monitoring is required with ALIMTA therapy. Dose adjustments, modifications, or suspension of therapy may be necessary based on hematologic and nonhematologic toxicities. Monitor renal function during ALIMTA therapy. ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

See the complete data at ALIMTAhcp.com/data See the Important Safety Information and Brief Summary for ALIMTA on the following pages. References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Data on file, Eli Lilly and Company. ONC20120911A.

Indications for ALIMTA® (pemetrexed for injection) ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities. Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function. Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/ desquamation (10% vs 3%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

PM_HCP_ISI_NSCLC1M_17OCT2012

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

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Announcements

September Is Prostate Cancer Awareness Month

n recognition of September as Prostate Cancer Awareness Month, The ASCO Post is pleased to share the following reminders, adapted in part from the American Cancer Society: • Prostate cancer is the second most common cancer among men, behind

skin cancer, and it affects one in seven men in his lifetime. • Prostate cancer is the second leading cause of cancer death in American men, behind only lung cancer. • In 2014, approximately 233,000 new cases will be diagnosed in the United

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer — Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information. 2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)]. Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)]. Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3.

75% of previous dose (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose ALIMTA® (pemetrexed for injection)

PV 8927 AMP

States; about 29,480 men will die of prostate cancer this year in the U.S. • Prostate cancer occurs mainly in older men. The average age at the time of diagnosis is about 66. • Most men diagnosed with prostate cancer do not die from it.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.) Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

NCI Common Toxicity Criteria (CTC). Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity b

Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. 5 WARNINGS AND PRECAUTIONS 5.1 Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0]. Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)]. 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the ALIMTA® (pemetrexed for injection)

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5

PV 8927 AMP

PRINTER VERSION 1 OF 4

• African American men have the highest prostate cancer incidence in the world. • Over 90% of all prostate cancers are discovered while they are localized or regional. The 5-year survival rate for men diagnosed with prostate tumors discovered at these stages is nearly 100%. n

The ASCO Post | SEPTEMBER 1, 2014

PAGE 82

Announcements

Peter Pisters, MD, Appointed President and Chief Executive Officer, University Health Network, Canada

r. John Mulvihill, Chair of the Board of Trustees of University Health Network (UHN), Canada, and Chair of the Board’s Selection Committee for the President and CEO, recently

announced that Peter Pisters, MD, will serve as UHN’s next President and CEO, beginning January 1, 2015. Dr. Pisters is currently Vice President of The University of Texas MD Anderson

Cancer Center’s Regional Care System and Professor of Surgery. He has held a number of clinical, administrative, and leadership positions at MD Anderson from 1994 to the present, with his most

recent executive responsibilities being the management of six MD Anderson centers for care across metropolitan Houston. Prior to his current role, he was Medical Director of the regional can-

3 3 platelet is ≥100,000 cells/mm , and creatinine clearance is ≥45 mL/min [see platelet count is ≥100,000 cells/mm , andcount creatinine clearance is ≥45 mL/min [see Dosage Incidence 1%Dosage to 5% Incidence 1% to 5% Body as a Whole — febrile neutropenia, pyrexia Body asinfection, a Whole — febrile neutropenia, infection, pyrexia and Administration (2.4)]. and Administration (2.4)]. lacrimatio General Disorders — dehydrationGeneral Disorders — dehydration Inc 5.6 Pregnancy Category D 5.6 Pregnancy Category D Metabolism and Nutrition — increased AST, increased ALT — increased AST, increased ALT Metabolism and Nutrition Based on its action, ALIMTA can cause fetal harm when administered Based on its mechanism of action, ALIMTA canmechanism cause fetalofharm when administered — creatinine failureclearance decrease, renal failure Renal —renal creatinine to a pregnant woman. Pemetrexed administered intraperitoneally Renal to mice during clearance decrease, to a pregnant woman. Pemetrexed administered intraperitoneally to mice during Special — conjunctivitis Special Senses — conjunctivitis was embryotoxic, andthan teratogenic thanSenses 1/833rd organogenesis was embryotoxic,organogenesis fetotoxic and teratogenic in micefetotoxic at greater 1/833rd in mice at greater Incidence Less than 1% Incidence Less than 1% recommended If ALIMTA used during pregnancy, or if the patient the recommended human dose.theIf ALIMTA is usedhuman duringdose. pregnancy, or ifisthe patient Cardiovascular — arrhythmia Cardiovascular — arrhythmia while taking drug, ofthethepatient should be apprised of the potential becomes pregnant while taking becomes this drug,pregnant the patient should be this apprised potential General Co hazard to the fetus. Women of childbearing potential should be advised to avoid Disorders becoming — chest pain General Disorders — chest pain hazard to the fetus. Women of childbearing potential should be advised to avoid becoming Metabolism and Nutrition — increased GGT and Nutrition — increased GGT Metabolism Ind pregnant. Women should be advisedmeasures to use effective contraceptive measures to prevent pregnant. Women should be advised to use effective contraceptive to prevent Tab during treatment ALIMTA (8.1)]. [see Use in Specific PopulationsNeurology (8.1)]. — motor neuropathy Neurology — motor neuropathy pregnancy during treatment withpregnancy ALIMTA [see Use in Specificwith Populations Non-Small Cell Lung Cancer (NSCLC) – Maintenance Non-Small Cell Lung Cancer (NSCLC) – Maintenance of the 500 ADVERSE REACTIONS 6 ADVERSE REACTIONS 6 ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based maintenanI Therapy Therapy Th 6.1 Clinical Trials Experience6.1 Clinical Trials Experience provides the frequency and severity of adverse reactionsand reported in >5% of reactions reported Table 5 provides the frequency severity of adverse doses ofin Becauseunder clinical trialsvarying are conducted under widely varying Table 5 conditions, adverse Because clinical trials are conducted widely conditions, adverse 438 patients NSCLC ALIMTAwith maintenance the 218 patients with 438 patients NSCLC whoand received ALIMTA maintenance and thereductions 218 patie reactions ratesto cannot directly compared to rates in otherthe clinical trials andwith may not whothereceived reactions rates cannot be directly compared rates inbeother clinical trials and may not NSCLC who received placebo following platinum-based induction therapy. NSCLC awho received placebo following a platinum-based induction therapy. the placeb reflect the rates observed in clinical practice. reflect the rates observed in clinical practice. All patients received following platinum-based patients received study4 cycles therapyofimmediately following 4 cycles arm of platinum and 1 In clinical trials, the most common≥20%) adverseduring reactions (incidence ≥20%) duringstudy therapyAllimmediately In clinical trials, the most common adverse reactions (incidence treatment for locally advanced ortreatment metastaticforNSCLC. study arms werePatients fully in both study locally Patients advancedin orboth metastatic NSCLC. acidarms andwv therapy with a single-agent were fatigue, and anorexia. Additional therapy with ALIMTA as a single-agent wereALIMTA fatigue,asnausea, and anorexia. Additionalnausea, supplemented with folic vitamin B12. with folic acid and vitamin B12. common≥20%) adverse reactions ≥20%) during with ALIMTA when usedacid in andsupplemented common adverse reactions (incidence during therapy(incidence with ALIMTA when usedtherapy in Table combination cisplatin leukopenia, included vomiting, anemia, stomatitis/ combination with cisplatin included vomiting,with neutropenia, anemia,neutropenia, stomatitis/ leukopenia,Table Table 5: Adverse in Patients Receiving ALIMTA versus Placebi 5: Adverse Reactions in Patients ReceivingReactions ALIMTA versus Placebo ALIMTA a a pharyngitis, thrombocytopenia, and constipation. pharyngitis, thrombocytopenia, and constipation. in NSCLC in NSCLC Following Platinum-Based Following Platinum-Based Induction Therapy Induction Therapy Non-Small Cell inLung Cancer (NSCLC) – ALIMTA in Combination with Cisplatin Non-Small Cell Lung Cancer (NSCLC) – ALIMTA Combination with Cisplatin ALIMTA Placebo ALIMTA Placebo Adverse 4 provides the frequency andthat severity of adverse reactions that have been Table 4 provides the frequency Table and severity of adverse reactions have been (N=438) (N=218) (N=438) (N=218) Reactionb Reactionb Syst in >5% 839 randomized patients withtoNSCLC whoreceived were randomized to study and received reported in >5% of 839 patientsreported with NSCLC whoofwere study and Grades Grade Grade3-4 3-4 All Grades Grad ALIMTA plus and were 830 patients withtoNSCLC ALIMTA plus cisplatin and 830 patients with cisplatin NSCLC who randomized study who and were randomized to study and All Grades Grade 3-4 AllAllGrades Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxic received gemcitabine plusstudy cisplatin. All as patients received gemcitabine plus cisplatin. All patients received therapy initial received treatmentstudy therapy as initial treatment Toxicity (%) Toxicity (%) Toxicity All Adve locallyand advanced NSCLCgroups and patients in both treatment groups were fully for locally advanced or metastaticforNSCLC patientsorinmetastatic both treatment were fully All66Adverse Reactions 37 All Adverse Reactions 16 3766 416 Laborat supplemented with folic acid andsupplemented vitamin B12. with folic acid and vitamin B12. Laboratory Laboratory Hemat TableSupplemented 4: Adverse Reactions in Fully Supplemented Table 4: Adverse Reactions in Fully Hematologic Hematologic Anem a a Receiving NSCLC Patients Receiving ALIMTA plusPatients Cisplatin in NSCLCALIMTA plus Cisplatin in Anemia 13 6 615 3 15 Anemia Neutro 03 0 06 3 6 Neutropenia Neutropenia ALIMTA/cisplatin Gemcitabine/cisplatin ALIMTA/cisplatin Gemcitabine/cisplatin Clinical 12 1 16 2 6 Leukopenia Leukopenia (N=839) (N=830) (N=839) (N=830) Reactionb Reactionb Constit Hepatic Hepatic Sympto Grades Grade Grade3-4 3-4 All Grades Grade 3-4 All Grades Grade 3-4 AllAllGrades Increased ALT 0 4 Increased ALT (%) 10 410 00 Fatigu Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxicity Toxicity (%) Toxicity (%) Toxicity Increased AST 0 4 Increased AST 8 48 00 Gastro All 91 53 All Adverse Reactions 90Adverse Reactions 37 9190 5337 Clinical Clinical Nause Laboratory Laboratory Constitutional Constitutional Vomit Hematologic Hematologic Symptoms Symptoms Mucos 10 106 46 4633 6 33 Anemia Anemia Fatigue 11 Fatigue 25 5 1125 15 Genera 27 2715 38 3829 15 29 Neutropenia Neutropenia Gastrointestinal Gastrointestinal Edem 8 85 21 2118 5 18 Leukopenia Leukopenia 11 6 a 619 1 19 Nausea Nausea 13 134 27 2710 4 10 Thrombocytopenia Thrombocytopenia Adverse 02 5 519 2 19 Anorexia Anorexia adverse Renal Renal 00 1 19 0 9 Vomiting Vomiting Creatinine elevation 7 1 Creatinine elevation 10 1 710 11 01 2 b to those 27 1 7 Mucositis/stomatitis Mucositis/stomatitis NCI CTC 01 3 35 1 5 Diarrhea Diarrhea Clinical Clinical Ad Constitutional Constitutional Infection 2 Infection 5 2 25 02 erythropoi Symptoms Symptoms Neurology Neurology factors (6% Fatigue 45 5 Fatigue 43 7 4543 57 Neuropathy-sensory 4 Neuropathy-sensory 9 1 49 01 Th Gastrointestinal Gastrointestinal frequently Dermatology/Skin Dermatology/Skin 4 47 53 5356 7 56 Nausea Nausea Inc Rash/Desquamation 3 Rash/Desquamation 10 0 310 00 6 66 36 3640 6 40 Vomiting Vomiting a a 24 12 2427 2 27 Anorexia Anorexia Foroffthe purpose of thisfortable a cut off of events 5% waswhere used the for inclusion of all events w For the purpose of1this table a cut of 5% was used inclusion of all 0 a possible relationship 01 20 considered 2021 1 21 Constipation Constipation reporter considered reporter to ALIMTA.a possible relationship to ALIMTA. Inc b b 12 01 1214 1 14 Stomatitis/Pharyngitis Stomatitis/Pharyngitis Refer CTCAE Criteria version 3.0 for each Grade of toxicity. Refer to NCI CTCAE0 Criteria version 3.0toforNCI each Grade of toxicity. 2 21 13 No clinically relevant 1312 1 12 Diarrhea Diarrhea NoGrade clinically differenceswere in Grade 3/4patients adverse reactions were seen in differences in 3/4 relevant adverse reactions seen in 0 ethnic origin, 00 6 on age, gender, 65 0 5 Dyspepsia/Heartburn Dyspepsia/Heartburn basedoronhistology age, gender, origin, or histology except based exceptethnic a higher incidence of Grade 3/4a higher incidence of G fatigue for patients compared non-Caucasian fatigue for Caucasian patients compared to Caucasian non-Caucasian patients (6.5%toversus 0.6%). patients (6.5% versus 0 Neurology Neurology Safety was assessed by exposure for one patients by exposure for patients who received at least dosewho of received at least one Neuropathy-sensory Neuropathy-sensory 9 0 12 Safety was assessed 1 129 10 (N=438). The incidence of adverse reactions ALIMTA of adverse reactions was evaluated for patients whowas evaluated for patie Taste Taste disturbance 8 disturbance 0c 9 (N=438). The 0c incidenceALIMTA 98 0c0c ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of received ≤6 cycles of ALIMTA, andreceived compared to patients who received >6 cycles of ALIMTA. No Dermatology/Skin Dermatology/Skin in adverse reactions (all grades) werehowever observednowith longer exposure; how Increases in adversecreactions (allIncreases grades) were observed with longer exposure; Alopecia Alopecia 12 0c 21 1 2112 1c0c clinically in Grade clinically relevant differences in Grade 3/4relevant adversedifferences reactions were seen.3/4 adverse reactions were seen. increased Rash/Desquamation Rash/Desquamation 7 8 Consistent with 1 the higher incidence 0 87 10 Ada Consistent with(all thegrades) higher incidence of anemia (all grades) on the ALIMTA of anemia on the ALIMTA arm, use Sep a a For purpose of thisfortable a cut off of events 5% waswhere used the for inclusion of all events(mainly where RBC) the andof erythropoiesis For the purpose of this table a cut offthe of 5% was used inclusion of all transfusions (mainly RBC) agents and erythropoiesis stimulating agents (ESAs; eryth of transfusions stimulating (ESAs; erythropoietin Eso reporter considered reporter considered a possible relationship to ALIMTA.a possible relationship to ALIMTA. andALIMTA darbepoetin) were higher in the ALIMTA compared to the placebo arm (tran and darbepoetin) were higher in the arm compared to the placebo armarm (transfusions b NCI CTC Criteria version 2.0 for each Grade of toxicity.9.5% versus 3.2%, ESAs 5.9% versus Refer to NCI CTC Criteria versionb Refer 2.0 fortoeach Grade of toxicity. 6.2 Po 9.5% versus 1.8%). 3.2%, ESAs 5.9% versus 1.8%). c c According to NCI CTC Criteria version 2.0,only thisbe adverse event term should only be reported According to NCI CTC Criteria version 2.0, this adverse event term should reported following reactions were observed in patients withThno The following additional adverse The reactions wereadditional observedadverse in patients with non-small ALIMTA. B as Grade 1 or 2. as Grade 1 or 2. cell lung cancer who received ALIMTA. cell lung cancer who received ALIMTA. size, it is relevant differences in patients No clinically relevant differencesNoin clinically adverse reactions were seen in adverse patients reactions based were seen Incidence 1% to 5% Incidence 1% based to 5% relationsh on histology. on histology. Dermatology/Skin — alopecia, pruritus/itching Dermatology/Skin — alopecia, pruritus/itching Gastrointestinal — constipation Gastrointestinal — constipation Th to thetoxicity lower incidence of hematologic toxicity on the ALIMTA and cisplatin In addition to the lower incidenceInofaddition hematologic on the ALIMTA and cisplatin General edema, fever (in the absence of neutropenia) General (in theDisorders absence — of neutropenia) combinati arm, use ofand transfusions (RBC growth and platelet) wasDisorders lower in — edema, fever arm, use of transfusions (RBC and platelet) hematopoietic factorsand washematopoietic lower in growth factors Hematologic — thrombocytopenia — thrombocytopenia Blo the ALIMTA andgemcitabine cisplatin arm the gemcitabine and cisplatin Hematologic arm. the ALIMTA and cisplatin arm compared to the andcompared cisplatin to arm. — decreased de Renal decreased creatinineRenal clearance, increasedcreatinine creatinine,clearance, decreasedincreased creatinine, Ga following reactions were observed in patients with— non-small The following additional adverse The reactions wereadditional observedadverse in patients with non-small glomerular filtration rate glomerular filtration rate Ge celltolung cancer randomly cell lung cancer randomly assigned receive ALIMTA plus assigned cisplatin. to receive ALIMTA plus cisplatin.

ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection)

PV 8927 AMPfor injection) ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed

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PM HCP BS NSCLC1M 18Nov2013 PV8927 VERSION ALIMTA PM HCP BSALIMTA NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5BRF SUM 6.5 x 9.5 PRINTER VERSION PRINTER 2 OF 4 ALIMTA P

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 83

Announcements

Peter Pisters, MD

cer centers, Clinical Consultant for the Center for Global Oncology (now known as MD Anderson Cancer Network), and Section Chief for Sarcoma Surgery. Dr. Pisters was with Memorial Sloan Kettering Cancer Center’s Department of Surgical Oncology from 1985 to 1992. He completed his internship and residency at New York University

School of Medicine Center, Bellevue Hospital. He holds an MSc degree in Health Care Management from Harvard University. “I know I speak for everyone on the Board and all members of the Selection Committee when I say how delighted we are that Dr. Pisters has agreed to return home to Canada to

Injury, poisoning, and proceduralrecall complications Injury, poisoning, and procedural complications — Radiation has been — Radiation recall has been Special Senses — ocular surface disease (including conjunctivitis), increased Special Senses — ocular surface disease (including conjunctivitis), increased reported received in patients who have previously received radiotherapy. reported in patients who have previously radiotherapy. lacrimation on Respiratory — interstitial pneumonitis Respiratory — interstitial pneumonitis Incidence Less than 1% cidence Less than 1% SkinStevens-Johnson — Bullous conditions, including Stevens-Johnson Skin — Bullous conditions, including syndrome and toxic epidermal syndrome and toxic epidermal Cardiovascular Cardiovascular — supraventricular arrhythmia — supraventricular arrhythmia necrolysis. Some cases were fatal.necrolysis. Some cases were fatal. Dermatology/Skin — erythema multiforme Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity General Disorders — febrile neutropenia, allergic reaction/hypersensitivity DRUG INTERACTIONS 7 DRUG INTERACTIONS 7 Neurology — motor neuropathy Neurology — motor neuropathy 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Renal — renal failure Renal — renal failure Although (400 mg fourthetimes a day)ofcan decrease the clearance of Although times ibuprofen a day) can decrease clearance ALIMTA ALIMTA as Maintenance Following ALIMTA Plus ibuprofen Platinum(400 mg four ontinuation of ALIMTA as Continuation Maintenance ofFollowing Plus Platinum pemetrexed, it caninbepatients administered with ALIMTA in patients with normal renal function pemetrexed, it can be administered with ALIMTA with normal renal function Induction Therapy duction Therapy clearance ≥80 mL/min). No dosewith adjustment of ALIMTA is needed with concomitant (creatinine clearance ≥80 mL/min).(creatinine No dose adjustment of ALIMTA is needed concomitant Table 6 provides the frequency severityinof>5% adverse reactions reported in >5% ble 6 provides the frequency and severity of adverse reactionsand reported NSAIDs in patients with normal renal function NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].[see Clinical Pharmacology (12.3)]. of the 500 patients non-squamous who received at least one cycle of ALIMTA 0 patients with non-squamous NSCLC whowith received at least oneNSCLC cycle of ALIMTA should NSAIDs be usedconcurrently when administering NSAIDs concurrently with ALIMTA Caution should be used when Caution administering with ALIMTA Induction (n=333) or placebo (n=167) ontrial. the continuation maintenance trial. mild to moderate nce (n=333) or placebomaintenance (n=167) on the continuation maintenance to patients with mild to(creatinine moderate clearance renal insufficiency to patients with renal insufficiency from 45 to(creatinine clearance from 45 to Theadministered median of maintenance cycles administered receiving one or more he median of maintenance cycles to patients receiving one or moreto patients 79 mL/min). 79 mL/min). nmaintenance >5% of doses4 of therapy was on botharms. the pemetrexed and NSAIDs placebo with arms.short Doseelimination NSAIDs therapy was on maintenance both the pemetrexed and 4placebo Dose short elimination half-lives (e.g., half-liveswith (e.g., diclofenac, indomethacin) shoulddiclofenac, indomethacin) should ents reductions for adverse events occurred 3.3%andof 0.6% patients ALIMTA arm and 0.6% in s forwith adverse events occurred in 3.3% of patients in the ALIMTAinarm in in the a period 2 daysfollowing before, the day of, and 2 days following administration be avoided for a period of 2 daysbe avoided before, theforday of, andof2 days administration placebo arm.occurred Dose delays for adverse events of patients in the ALIMTA bo arm. Dose delays forthe adverse events in 22% of patients in theoccurred ALIMTA in 22% of ALIMTA. of ALIMTA. m-based and 16% in the placebo in bothwith studyfolic arms were supplemented withof folic 16% in the placebo arm.arm Patients in both study arms arm. werePatients supplemented In the absence of data regarding potential interaction In the absence data regarding potential interaction between ALIMTA and NSAIDs withbetween ALIMTA and NSAIDs with were fully acid and vitamin B12. vitamin B12. half-livespatients (e.g., meloxicam, patients taking these NSAIDs should interrupt longer half-lives (e.g., meloxicam,longer nabumetone), taking thesenabumetone), NSAIDs should interrupt least2 days 5 daysfollowing before, the day of, and 2 days following ALIMTA administration. If for at Receiving least 5 days before,dosing the dayforof,atand ALIMTA administration. If Table 6:b Occurring Selecteda in e 6: Selecteda Adverse Reactions Adverse Occurring in ≥5%dosing of Patients ≥5% ofReactions Patients bReceiving bo concomitant administration of NSAIDs is necessary, patients concomitant administration is necessary, patients should be monitored closely for should be monitored closely for ALIMTA in Nonsquamous Following ALIMTA Plus Cisplatin Induction Therapy of NSAIDs in Nonsquamous NSCLC Following ALIMTA Plus NSCLC Cisplatin Induction Therapy toxicity, especially myelosuppression, toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.renal, and gastrointestinal toxicity. ALIMTA Placebo ALIMTA Placebo 7.2 Nephrotoxic Drugs 7.2 Nephrotoxic Drugs (N=333) (N=167) (N=333) (N=167) e Reaction Organ Adverse Reaction Organ ALIMTA is renally primarilyaseliminated ALIMTA is primarily eliminated unchanged a result of unchanged glomerular renally filtrationas a result of glomerular filtration a tem and Term System and Term All Grades Gradesa a Grades Grade3-4 3-4aa All Gradesa Grades 3-4a Grade 3-4a AllAllGrades and tubular secretion. Concomitantdrugs administration of nephrotoxic drugs could result in and tubular secretion. Concomitant administration of nephrotoxic could result in de 3-4 Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity delayed clearance of ALIMTA. Concomitantthat administration delayed clearance of ALIMTA. Concomitant administration of substances are also of substances that are also city (%) All53Adverse Reactions 34 secreted 4.8 erse Reactions 17 3453 4.817 tubularly (e.g., probenecid) potentially result in delayed clearance of ALIMTA. tubularly (e.g., probenecid) couldsecreted potentially result in delayedcould clearance of ALIMTA. 4 Laboratory tory 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS Hematologic tologic 8.1 Pregnancy 8.1 Pregnancy Anemia 4.8 4.8 0.6 mia 15 4.8 4.815 0.6 Teratogenic Effects - Pregnancy Category D(5.6)]. [see Warnings and Precautions (5.6)]. Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions 1 Neutropenia 0.6 0 openia 9 3.9 0.69 03.9 Based on its action, ALIMTA can cause fetal harm when administered Based on its mechanism of action, ALIMTA canmechanism cause fetalofharm when administered 0 Clinical a pregnant are nostudies adequate and wellin controlled studies of ALIMTA in to a pregnant woman. There areto no adequatewoman. and wellThere controlled of ALIMTA 1 Constitutional tutional pregnant women. fetotoxic, Pemetrexed embryotoxic, fetotoxic, pregnant women. Pemetrexed was embryotoxic, andwas teratogenic in mice. In and teratogenic in mice. In Symptoms oms mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis 0 Fatigue 4.5 11 fetal malformations 0.6 ue 18 4.5 1118 0.6 caused ossification fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd caused (incomplete of talus and skull bone; about 1/833rd 0 2 the recommended intravenous dosepalate on a (1/33rd mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m basis),human and cleft Gastrointestinal ointestinal recommended human dose on a was mg/m2 basis). Embryotoxicity was the2.4recommended 0intravenous the human dose on aintravenous mg/m2 basis). Embryotoxicity 00.3 2.412 0.3 12 Nausea ea characterized increased characterized by increased embryo-fetal deathsbyand reducedembryo-fetal litter sizes. Ifdeaths ALIMTAandis reduced used litter sizes. If ALIMTA is used 0 00 1.8 1.86 0 6 Vomiting ting during pregnancy, or if while the patient while taking this drug, the patient during becomes pregnant taking becomes this drug,pregnant the patient 0 if the patient 00.3 2.4 pregnancy, or 2.45 0.3 5 Mucositis/stomatitis sitis/stomatitis 1 should be apprised of theWomen potential hazard to thepotential fetus. Women of childbearing potential should be apprised of the potential hazard to the fetus. of childbearing General Disorders al Disorders be advised to use effective contraceptive measures should be advised to use effectiveshould contraceptive measures to prevent pregnancy during the to prevent pregnancy during the Edema 3.6 with ALIMTA. 0 ma 5 0 3.65 00 treatment with ALIMTA. treatment 1 a reactions of any severity (all grades) more frequently (≥5%) orMothers Grade 3-4 reactions of any severityAdverse (all grades) occurring more frequently (≥5%) occurring or Grade 3-4 0 8.3 Nursing Mothers 8.3 Nursing reactions more frequently in ALIMTA-treatedIt patients reactions occurring moreadverse frequently (≥2%)occurring in ALIMTA-treated patients(≥2%) compared 0 It is ornotitsknown whetherareALIMTA metabolites are excreted in human is not compared known whether ALIMTA metabolites excretedor inits human to those receiving placebo receiving placebo 0 milk. Because manymilk, drugs excreted milk, milk. Because many drugs are excreted in human andarebecause of inthehuman potential forand because of the potential for b CAE 0 Criteria version 3.0 NCI CTCAE Criteria version 3.0 serious adverse ALIMTA, serious adverse reactions in nursing infants fromreactions ALIMTA, ina nursing decisioninfants should from be made to a decision should be made to of RBC (13%versus versus0.6%) 4.8%)transfusions, and platelet (1.5% versus 0.6%) transfusions, dministration of RBC (13% versusAdministration 4.8%) and platelet (1.5% discontinue nursinginto or discontinue drug, taking intodrug account the importance of the drug discontinue nursing or discontinue the drug, taking account the the importance of the 0 (12%colony versusstimulating 7%), and granulocyte colony stimulating for the mother. iesis stimulating agentserythropoiesis (12% versusstimulating 7%), and agents granulocyte for the mother. (6% versus were higher in the ALIMTA % versus 0) were higherfactors in the ALIMTA arm0)compared to the placebo arm.arm compared to the placebo arm. 8.4 Pediatric Use 8.4 Pediatric Use additional or 4 adverse he0 following additional Grade The 3 orfollowing 4 adverse reactionsGrade were3 observed more reactions were observed more Efficacy of in pediatric patients has not Efficacy of ALIMTA in pediatric patients hasALIMTA not been demonstrated. ALIMTA wasbeen demonstrated. ALIMTA was y in the ALIMTA arm. frequently in the ALIMTA arm. intravenous 10 cycle minutes administered as an intravenous administered infusion over as 10anminutes on Dayinfusion 1 of a over 21 day to on Day 1 of a 21 day cycle to Incidence 1% to 5% cidence 1% to 5% 0 patients with recurrent solidpatients) tumors and in a aPhase pediatric patients with recurrent pediatric solid tumors in a Phase 1 study (32 Phase1 study (32 patients) and a Phase Blood/Bone Marrow — thrombocytopenia Blood/Bone Marrow — thrombocytopenia 2 study (72 pretreatment patients). All with patients received pretreatment 2 study (72 patients). All patients received vitamin B12 and folic acid with vitamin B12 and folic acid where the General Disorders — febrile neutropenia General Disorders — febrile neutropenia supplementation and dexamethasone. dosedetermined escalation in the Phase 1 study determined supplementation and dexamethasone. The dose escalation in the PhaseThe 1 study Incidence Less than 1% cidence Less than 1% 2 the1910 maximum 1910 mg/mfor2 and the maximum tolerated dose was mg/mtolerated this dose (or 60 mg/kg for patients and thisdose dosewas (or 60 mg/kg patients Cardiovascular — ventricular tachycardia, syncope <12 months old) was evaluated in<12 months Cardiovascular — ventricular tachycardia, syncope wasofevaluated in therelapsed Phase 2orstudy of patients with relapsed or refractory the Phase 2old) study patients with refractory n patients General Disorders — pain General Disorders — pain osteosarcoma,PNET, Ewing sarcoma/peripheralneuroblastoma, PNET, rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma/peripheral rhabdomyosarcoma, Grade 3/4 Gastrointestinal Gastrointestinal — gastrointestinal obstruction — gastrointestinal obstruction ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. 0.6%). Neurologic — depression Neurologic — depression No responses were observed among theThe 72 patients in this Phase 2 trial. The most common No responses were observed among the 72 patients in this Phase 2 trial. most common e dose of Renal — renal failure Renal — renal failure toxicities reported were hematological (leukopenia,anemia, neutropenia/granulocytopenia, anemia, toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, ents who thrombocytopenia, lymphopenia), liver function abnormalities (increased ALT/AST), thrombocytopenia, and lymphopenia), liver functionandabnormalities (increased ALT/AST), fVascular ALIMTA. — pulmonary embolismVascular — pulmonary embolism No relevant effect for ALIMTA due toexcept gender was identified, except an fatigue, and nausea. owever relevant due to gender or race wassafety identified, anor race fatigue, and nausea. no effect for ALIMTA safety increasedcompared incidence to of women (16%). rash in men (24%) compared to women (16%).The single dose pharmacokinetics d incidence of rash in men (24%) The single dose administered pharmacokinetics of ALIMTA of ALIMTA in doses rangingadministered in doses ranging Additional dditional Trials Experience Across Clinical Trials from 400 to 2480 mg/m from 400 to 2480 mg/m2 were evaluated were themales Phaseand 1 trial in 22 patients (13 males and in the Phase 1 2trial in evaluated 22 patientsin(13 arm, useExperience Across Clinical which in insome cases was 1% fatal,ofoccurred of patients. psis, which in some cases wasSepsis, fatal, occurred approximately patients. in approximately females)age aged to 18 Pemetrexed years (average age 12(AUC years). 9 females)1% aged 4 to 18 years 9(average 12 4years). exposure and Pemetrexed exposure (AUC and hropoietin Esophagitis occurred in less than 1% of patients. ophagitis occurred in less than 1% of patients. Cmax) appeared Cmax) appeared to increase proportionally to increase proportionally with dose. The average pemetrexed clearance with dose. The average pemetrexed clearance nsfusions 2 (2.30 L/h/m2) and half-life (2.3 (2.30 ) and half-life in pediatric patients were comparable to values hours)L/h/m in pediatric patients(2.3 werehours) comparable to values 6.2 Postmarketing Experience ostmarketing Experience reported in adults. use of reported in adults. adverse during reactions have been use identified post-approval heon-small following adverse reactionsThe havefollowing been identified post-approval of during Because these reactions are reportedof voluntarily uncertain 8.5 Geriatric Use Because these reactionsALIMTA. are reported voluntarily from a population uncertain from8.5a population GeriatricofUse it is not alwaystheir possible to reliably estimate their frequency orALIMTA establish a causal not always possible tosize, reliably estimate frequency or establish a causal ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse is known to be substantially excreted by the kidney, and the risk of adverse hip to drug exposure. relationship to drug exposure. reactions to thiswith drugimpaired may be greater in patients with impaired renal function. Renal function reactions to this drug may be greater in patients renal function. Renal function occurred ALIMTA when as a single-agent and in withmonitoring hese reactions occurred withThese ALIMTAreactions when used as awith single-agent and inused monitoring is recommended administration of ALIMTA. is recommended administration of ALIMTA. Nowith dose reductions other than No dose reductions other than combination therapies. ion therapies. those all patients areofnecessary for patients those recommended for all patients arerecommended necessary for for patients 65 years age or older [see 65 years of age or older [see Dosage and Administration (2.4)].Dosage and Administration (2.4)]. Blood and Lymphatic Systemanemia – Immune-mediated hemolytic anemia ood and Lymphatic System – Immune-mediated hemolytic ecreased 3,946across patients ≥65) trials studied[see across the five clinical trials [see Clinical Of 3,946 patients (34.0% ≥65) Of studied the(34.0% five clinical Clinical Gastrointestinal — colitis, pancreatitis astrointestinal — colitis, pancreatitis Studies 14.2, 14.3,onand 14.4)],was the similar effect ofinALIMTA the (14.1, effect of ALIMTA survival patientson survival was similar in patients General and—Administration Site Conditions —Studies edema (14.1, 14.2, 14.3, and 14.4)], eneral Disorders and Administration SiteDisorders Conditions edema

27(pemetrexed AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP for injection)

PV 8927 AMPfor injection) ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed

PV 8927 AMP

N 2 HCP OF 4BSALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 PM NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5BRF SUM 6.5 x 9.5 PRINTER VERSION PRINTER 3 OF 4 VERSION 3 OF 4

take on the role of President and CEO of UHN,” said Mr. Mulvihill. “His background as a clinician-researcher and his commitment to patients as partners in their care will ensure that Dr. Pisters will feel at home at UHN and that the organization will continue to grow, innovate, and lead health care in Canada and beyond our borders.” n

The ASCO Post | SEPTEMBER 1, 2014

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Announcements

Mark Del Beccaro, MD, Named Senior Vice President, Chief Medical Officer of Seattle Children’s Hospital

eattle Children’s has announced that Mark Del Beccaro, MD, has been appointed as Senior Vice President and Chief Medical Officer (CMO) effective October 1, 2014. Dr. Del Beccaro,

who currently serves as Vice President of Medical Affairs, will replace David Fisher, MD, who is retiring. “Mark has made many significant contributions to Seattle Children’s

over the course of his career,” said Thomas N. Hansen, MD, CEO of Seattle Children’s. Dr. Del Beccaro started his career at Seattle Children’s in 1979 after gradu-

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients. 8.9 Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients. 10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. • Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. • Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia. • Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. • Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch. Additional information can be found at www.AlimtaHCP.com

PV 8927 AMP

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5

Mark Del Beccaro, MD

ating from Stanford University. He moved to Seattle with the intention of attending the University of Washington School of Medicine. Having a desire to work in pediatrics, and wanting to become a Washington state resident, Dr. Del Beccaro started working as a nursing aid at what was then Children’s Orthopedic Hospital. He later transitioned to the position of mental health specialist within the Inpatient Psychiatric Unit.

Long History at Seattle Children’s Dr. Del Beccaro entered medical school at the University of Washington in 1981 and started his pediatric residency at Seattle Children’s in 1985. Three years later, he was appointed chief resident. He joined the faculty of Seattle Children’s Emergency Department in 1989 and was appointed Pediatrician-in-Chief in 2007. A professor at the University of Washington School of Medicine, Del Beccaro became Vice President of Medical Affairs in 2012. During his time at Seattle Children’s, Dr. Del Beccaro played an integral role in the design, preparation, and completion of Building Hope, the hospital’s new state-of-the-art cancer, critical and emergency care building. In his new role, Dr. Del Beccaro said he will continue the work that Dr. Fisher started, namely the support of hospital medical staff and faculty, and efforts to continually improve patient safety. He also will advocate for completion of a fully electronic medical record that reaches community partners and families, further the development and integration of clinical standard work, and ensure the care provided is affordable and of the highest quality. “Mark’s passion, dedication, leadership and commitment to our patients, families and his colleagues make him an outstanding candidate to serve as CMO,” Dr. Hansen said. “He is in a great position to lead Seattle Children’s into the next era.” n

PRINTER VERSION 4 OF 4

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Patient’s Corner

Cancer Has Given Me Courage

Despite enduring three cancers over 3 decades, I know how lucky I am and I’m grateful for every day. By Lori Piggott, as told to Jo Cavallo

n 1986, I was pregnant with my third child and excited to be interviewing for a job on the assembly line at a General Motors plant near my home in Brodhead, Wisconsin. Hiring requirements included a physical examination and a chest x-ray, which was done by my obstetrician to avoid any radiation harm to the fetus. I was young, just 29, and thought I was in excellent health, so when I got a call from my doctor telling me I had a large mass in the middle of my chest and that he thought it was cancer, I was shocked. A biopsy of a swollen lymph node confirmed I had Hodgkin lymphoma. I saw an oncologist at a large medical center and was advised to terminate my pregnancy and start treatment immediately. But by then I was 5 months pregnant and refused the advice. My cancer treatment would have to wait. I knew the next few months would be difficult. The cancer made it impossible for me to take the job at General Motors, and that meant that my husband Tom, who was already working 6 to 7 days a week as a mechanic, would be under even greater pressure to provide for our growing family. My illness also meant that he would have to take on the additional responsibility of caring for our children once I started treatment. Although I had some fearful moments, once I made the decision not to be treated until after the baby was born, I felt at peace and had a sense that I was going to be fine. I had no way of know-

ing that I would be struggling with cancer for the next 3 decades.

Facing Recurrent Cancer After my daughter Kimberly was born, I had thoracic surgery to remove the mass in my chest and 33 rounds of radiation to my mediastinum, which put me in remission for 4 years. Two weeks before I was scheduled to see my on-

well, which I’ve always regretted. I had my transplant in January 1992 and was cancer-free for 18 years. Then, in the fall of 2010, I began feeling lethargic, I was having trouble breathing, and my voice grew hoarse. I knew something was seriously wrong. I made an appointment with my primary care physician, who found a small mass on the back of my tongue. A biopsy de-

I know sometimes the world can be a depressing place. But having cancer has taught me how precious life is and the importance of making a contribution to the happiness of others. —Lori Piggott

cologist for my final checkup, I noticed a mass behind my left ear, which was later diagnosed as Burkitt’s lymphoma, possibly the result of all the radiation therapy to my chest and lower face. I had surgery to remove the mass and was prescribed a regimen of five chemotherapies, but despite the aggressive treatment, the cancer progressed rapidly. My only chance to halt the cancer, said my oncologist, was an autologous bone marrow transplant. There were seven of us on the transplant unit, but I was so sick from the induction therapy, I didn’t get to know any of them very

termined that it was diffuse large B-cell lymphoma. My oncologist treated me with four cycles of rituximab (Rituxan), and I’m currently in remission.

Coping With the Aftermath of Cancer My history with cancer has extended over so many years, and for a while I struggled with severe panic attacks. People think once you’re through with treatment, the terror of having cancer is over and it’s time to move on. But that’s not how it works, especially when you have recurrent disease. I have been with

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

my oncologist and medical team for so long, we are on a first-name basis, and their constant kindness and continual support have helped me overcome any lingering fear of what might lie ahead. Despite all that I’ve endured, I know how fortunate I am, and I’m grateful for every day. Soon after my bone marrow transplant I learned that I was the only one of the seven of us on the transplant unit to survive the treatment.

Legacy of Courage Having cancer has given me the gift of courage, which I have passed down to my children, now 31, 29, and 27. Because I have been ill for most of their lives, I’ve instilled in my children the importance of finding happiness in whatever they choose to do and the confidence to pursue their dream. So profound was cancer on their lives, Kimberly became a cytotechnologist studying cancer cells, and my older daughter Beverly is a cancer researcher who recently received a Damon Runyon Cancer Fellowship Award. Perhaps Beverly’s research will result in breakthroughs that protect other mothers, fathers, and children from this dreaded and unforgiving disease. I know sometimes the world can be a depressing place, but having cancer has taught me how precious life is and the importance of making a contribution to the happiness of others. n Lori Piggott lives in Brodhead, Wisconsin.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

The ASCO Post | SEPTEMBER 1, 2014

PAGE 86

Journal Spotlight Oncology Practice continued from page 1

Chase Cancer Center, looked specifically at whether and how much the use of the two agents, both epidermal growth factor receptor (EGFR) inhibitors, declined after each event. The first

was ASCO’s Annual Meeting in June 2008, where the evidence was presented. The following February, ASCO issued a Provisional Clinical Opinion recommending that the drugs be used only in patients with wild-type KRAS, and in August 2009, the FDA changed

Drivers of Cancer Care ■■ New medical evidence is the fundamental driver of practice change, but other factors may influence how long it takes clinical practice to reflect new findings. ■■ Public presentation of new data, issuance of professional guidelines, and an FDA label change each had a significant impact on prescriptions for antiEGFR agents in colorectal cancer. ■■ Other factors may also be involved, such as reimbursement policy and quality assurance activities.

the drugs’ labels to reflect the new evidence.

Significant Changes Using a commercial insurance claims database, the authors found that at the time of the ASCO presentation, 59.4% of colorectal cancer patients had received one of the antiEGFR agents as part of second-line therapy, or beyond. That dropped to 46.2% following the publication of the Provisional Clinical Opinion by ASCO and to 35.2% at the time of the FDA label change. Eight months after the FDA action, only 16.2% of patients received the drugs. The greatest decline occurred after the label change, but the decrease in use was

statistically significant at all points. “These results suggest the attentiveness of the oncologic community to clinical presentations at national meetings and ASCO guidance,” the authors wrote. “It is also evidence that oncologists change their practice promptly in the face of highly publicized data, even years after a drug’s original approval.” n

Disclosure: Dr. Dotan reported no potential conflicts of interest. For full disclosures of all study authors, visit jop.ascopubs.org.

Reference 1. Dotan E, Li T, Hall MJ, et al: Oncologists’ response to new data regarding the use of epidermal growth factor receptor inhibitors in colorectal cancer. J Oncol Pract. July 22, 2014 (early release online).

EXPERT POINT OF VIEW

nformation on the drivers of cancer care is important in helping to deliver higher-quality and potentially less costly cancer treatments, noted Richard L. Schilsky, MD, ASCO’s Chief Medical Officer, in a commentary accompanying the study by D otan et al.1 Moreover, practice change can be a complex process, and there is probably more to the story than the three important factors pointed out by the investigators, he wrote.

More to the Story While new medical evidence is fundamental to practice change, it may take a year or two for policy to recalibrate, Dr. Schilsky said in an interview with The ASCO Post. And during that time, there is uncertainty, which makes life complicated for many parties—clinicians, pharmaceutical companies, laboratories, insurers, and others. The reimbursement policies of different insurers, for instance, may begin to change following new data. That almost certainly was the case with KRAS testing and the use of cetuximab (Erbitux) and panitumumab (Vectibix), Dr. Schilsky wrote. For instance, Aetna announced a

policy change in April 2009, and a local Medicare carrier in Florida announced a change in February 2009—both in line with the ASCO guidance. Rates of change may also depend on the clinical context. In this case,

U.S. Food and Drug Administration– approved test became available. Other potential drivers of practice change, Dr. Schilsky wrote, are quality assessment and improvement activities, including changes in re-

Whether driven primarily by guideline revisions, regulatory actions, or changes in reimbursement policies, changes in clinical practice result primarily from the generation of new medical evidence through well-designed research studies and from the commitment of every oncologist to deliver the highest quality care to his or her patients. —Richard L. Schilsky, MD

one factor could have been how quickly KRAS tests became available. After the ASCO presentation, many laboratories began to develop their own tests, but it was a year before a

quirements for provider licensing or certification. Also, public reporting of physician reimbursement or transfers of value from pharmaceutical companies to physicians, such as required by

the Physician Payments Sunshine Act, may contribute. “The effect may be subtle,” he said, “but there is increased awareness that some interactions of clinicians with pharmaceutical companies are now subject to public reporting. These kinds of things can affect behavior.”

Fundamental Drivers Regardless of which factors play a role, the fundamental drivers remain the same. “Whether driven primarily by guideline revisions, regulatory actions, or changes in reimbursement policies,” Dr. Schilsky wrote, “changes in clinical practice result primarily from the generation of new medical evidence through well-designed research studies and from the commitment of every oncologist to deliver the highest quality care to his or her patients.” n

Disclosure: Dr. Schilsky is Chief Medical Officer of ASCO.

Reference 1. Schilsky RL: Drivers of change in cancer care. J Oncol Pract. July 22, 2014 (early release online).

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 1, 2014

PAGE 88

In the News Breast Cancer

Survival Benefit of Contralateral Prophylactic Mastectomy Less Than 1% at 20 Years, but Numbers of Procedures Have Increased By Charlotte Bath

or women with stage I and II breast cancer without BRCA mutations, the absolute 20-year survival benefit from contralateral prophylactic mastectomy was less than 1%, regardless of age, estrogen receptor status, and cancer stage, according to a decision analysis study using a Markov model to simulate survival outcomes with or without the procedure. The study, published in the Journal of the National Cancer Institute,1 also noted that the 10-year cumulative risk of contralateral breast cancer is about 4% to 5% but may be even lower for women diagnosed with breast cancer today. These figures are at odds with the estimated risks of contralateral breast cancer and expected benefits of contralateral prophylactic mastectomy reported by patients. Todd M. Tuttle, MD, MS, Chief of the Division of Surgical Oncology at the University of Minnesota in Minneapolis and Medical Director of the University of Minnesota Breast Center, and one of three study authors, told The ASCO Post “A few years ago, we conducted a prospective study in our institution of women with unilateral breast cancer who didn’t have a BRCA mutation. We asked them to estimate their 10-year risk of getting a contralateral breast cancer. The mean perceived risk was over 30%, which is about the same as what it is for a BRCA mutation.” Dr. Tuttle also cited another survey study of women under 40 diagnosed with breast cancer, published in 2013.2 “They also substantially overestimated their risk of developing a contralateral breast cancer,” he noted. “In that study, a large proportion of women said the reason that they chose to have a [contralateral prophylactic mastectomy] was to improve their survival; it was one of the most common reasons women cited for having a contralateral prophylactic mastectomy. However, our data clearly show that the vast majority of women will not have a meaningful survival benefit from this operation.”

Complex Modelling, High Sensitivity Asked if the finding of an overall survival benefit of less than 1% surprised him and his coauthors, Dr. Tuttle replied, “No, it actually didn’t. We had previously performed crude estimations, and this is the number that kept coming up. But this study is a much more rigorous analy-

sis, with sensitivity analysis and complex modeling.” He added that the Markov model “is a well accepted methodology when a randomized clinical trial cannot be performed. We used the highest quality of resources that were available.” The model simulates the long-term prognosis of hypothetical cohorts of women with newly diagnosed unilateral breast cancer according to two scenarios: (1) contralateral prophylactic mastectomy (ie, double mastectomy) and (2) no contralateral mastectomy (assuming that women undergo either lumpectomy with radiation therapy or unilateral mastectomy), the authors explained in the JNCI article. “We projected the benefit of

a contralateral prophylactic mastectomy vs those who have not, the patients who undergo the procedure have better survival rates, primarily because women who undergo contralateral prophylactic mastectomy are younger, healthier, and often have better access to health-care insurance, Dr. Tuttle noted.

Stage and Age Differences Contralateral prophylactic mastectomy was more beneficial among women with stage I than those with stage II cancer, according to the model. Predicted life expectancy gains from contralateral prophylactic mastectomy “ranged from 0.13 to 0.59 years for women with stage

Our data clearly show that the vast majority of women will not have a meaningful survival benefit from this operation. —Todd M. Tuttle, MD, MS

[contralateral prophylactic mastectomy] for cohorts of women defined by age at breast cancer diagnosis (40, 50, or 60 years), stage of primary breast cancer (I, II), and estrogen receptor status (positive, negative).” Stage-specific breast cancer mortality rates were derived from relative survival curves reported in the Surveillance, Epidemiology, and End Results (SEER) data. Probabilities for developing contralateral breast cancer, dying from contralteral and primary breast cancer, and age-specific mortality rates were estimated from published studies. Those studies included meta-analyses of large numbers of randomized clinical trials, sometimes spanning 10 to 15 years, Dr. Tuttle noted. Explaining the use of the model, the researchers contended that prospective randomized trials of contralateral prophylactic mastectomy vs no contralateral prophylactic mastectomy are not feasible, and “retrospective studies evaluating a potential survival benefit with [contralateral prophylactic mastectomy] are limited by short follow-up, potential selection bias, and lack of important clinical information.” In retrospective studies comparing the outcomes of women who have had

I breast cancer and 0.08 to 0.29 years for those with stage II breast cancer. Absolute 20-year survival differences ranged from 0.56% to 0.94% for women with stage I breast cancer and 0.36% to 0.61% for women with stage II breast cancer,” the results showed. “We focused on stage I and II disease because as the stage goes up, your chances of dying from your known cancer go markedly up as well. So if you have a stage III breast cancer, there is going to be no benefit at all, because almost all the survival risk is due to the known cancer,” Dr. Tuttle explained. Contralateral prophylactic mastectomy was also more beneficial among women with estrogen receptor–negative breast cancer and younger women. For example, a 60-year old woman would gain less than 2 months life expectancy from contralateral prophylactic mastectomy, while a 40-yearold woman would gain as much as 7 months, according to the model. Dr. Tuttle said that older women frequently opt for contralateral prophylactic mastectomy, but not as often as younger women. “Young age is consistently associated with having a [contralateral prophylactic mastectomy].”

Overall Exaggerated Risk Women with BRCA mutations were excluded from the study. Women who do not have BRCA mutations have a lower risk of breast cancer and “don’t have contralateral prophylactic mastectomies as frequently as those women who do have a BRCA mutation,” Dr. Tuttle said, but the rate has been rising. “Numerous studies in the United States have shown that the rates of [contralateral prophylactic mastectomy] use among all women, but also including women who don’t have BRCA mutations, is markedly increased,” he added. Those studies include one that Dr. Tuttle coauthored in 2007 that found the use of contralateral prophylactic mastectomy had doubled in a 6-year period.3 “In the United States, there is an overall exaggerated risk for breast cancer,” Dr. Tuttle said. “For example, women who do not have breast cancer substantially overestimate their chances of getting breast cancer. Women who have early breast cancer, or ductal carcinoma in situ, substantially overestimate their risk of getting a recurrence or dying from that cancer. And, as we found, women who have cancer in one breast substantially overestimate the risk of getting cancer in the opposite breast.” The reason for the exaggerated risk is unclear, he said. It could be due to the prevalence of breast cancer themes in movies and on television, or races and other fundraising events, “or maybe the unintended consequence of increased breast cancer awareness.” n Disclosure: Dr. Tuttle reported no potential conflicts of interest.

References 1. Portschy PR, Kuntz KM, Tuttle TM: Survival outcomes after contralateral prophylactic mastectomy: A decision analysis. J Natl Cancer Inst 106(8):dju160, 2014. 2. Rosenberg SM, Tracy MS, Meyer ME, et al: Perceptions, knowledge, and satisfaction with contralateral prophylactic mastectomy among young women with breast cancer: A cross-sectional survey. Ann Intern Med 159:373-381, 2013. 3. Tuttle TM, Haberman EB, Grund EH, et al: Increasing use of contralateral prophylactic mastectomy for breast cancer patients: A trend toward more aggressive surgical treatment. J Clin Oncol 25:5203-5209, 2007.

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In the News

Expect Questions and Perhaps Unrealistic Expectations By Charlotte Bath

recent study reporting the absolute 20-year survival benefit from contralateral prophylactic mastectomy was less than 1% for women with stage I and II breast cancer without BRCA mutations runs counter to common perceptions about the risk of contralateral breast cancer among these women and the benefits of contralateral prophylactic mastectomy.1 (Earlier studies about perceptions of contralateral breast cancer and contralateral prophylactic mastectomy are referenced in the current study.) The less than 1% survival benefit was found among all subgroups studied—by age, estrogen receptor status, and cancer stage—although contralateral prophylactic mastectomy was more beneficial among younger women, those with stage I disease, and those with estrogen receptor–negative breast cancer, according to the report, published in the Journal of the National Cancer Institute.1 The stated aim of the study was “to provide projected long-term survival information by using a stimulated Markov model for physicians and their patients when discussing breast cancer risk-reduction strategies.” In an interview with The ASCO Post, study coauthor Todd M. Tuttle, MD, MS, noted that those risk-reduction strategies could include standard follow-up and tamoxifen or an aro-

matase inhibitor. “There is a growing body of research looking at alternative ways to reduce risk as well by diet and exercise,” he added, although “there are not really strong data on that yet.” Dr. Tuttle is Chief of the Division of Surgical Oncology at the University of Minnesota in Minneapolis and Medical Director of the University of Minnesota Breast Center.

More and Better Information The article concludes that the “survival estimates derived from our model may be useful for physicians and breast cancer patients to arrive at evidence-

Dr. Tuttle. In that opinion article, titled “The Wrong Approach to Breast Cancer,” New York Times Magazine contributing writer Peggy Orenstein discussed the study and personal experiences with breast cancer, writing, “Treatment decisions are ultimately up to the individual. But physicians can frame options and educate patients in a way that incorporates psychology as well as statistics. Beyond that, doctors are not obliged to provide treatment that is not truly necessary.” 2 The study report noted that “the use of accurate and easily understood decision aids may reverse some of the

Treatment decisions are ultimately up to the individual. But physicians can frame options and educate patients in a way that incorporates psychology as well as statistics. —Todd M. Tuttle, MD, MS

based informed decisions regarding [contralateral prophylactic mastectomy].” While the study’s impact cannot yet be gauged, Dr. Tuttle said, “What I hope it does is at least provides women with better information.” Information about the study appeared in reports in both the medical and popular press, including a New York Times Sunday Review opinion article that included comments from

mastectomy trends recently observed in the United States.” Still in the development phase and intended to be used in addition to patient-physician discussions, those decision aids could include online tools to provide women with information on what they can expect from risk of recurrence, risk of death, risk of complications, and side effects from having these different procedures, Dr. Tuttle explained.

Other Potential Benefits The JNCI authors acknowledged that survival “is only one potential benefit of a cancer risk-reduction strategy; effects on cancer-related anxiety, cosmesis, and self-image are also important in decision-making processes. For some women, the negative impact of contralateral prophylactic mastectomy on quality of life may outweigh a potential survival benefit. For others who are very anxious about [contralateral breast cancer], [contralateral prophylactic mastectomy] may result in a psychological benefit even if survival benefits are minimal.” An accompanying editorial points out, “The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering [contralateral prophylactic mastectomy].”3 n References 1. Portschy PR, Kuntz KM, Tuttle TM: Survival outcomes after contralateral prophylactic mastectomy: A decision analysis. J Natl Cancer Inst 106(8):dju160, 2014. 2. Orenstein P: The wrong approach to breast cancer. New York Times, July 26, 2014. 3. Pauker SG, Alseiari M: How big is big enough? Thinking about contralateral prophylactic mastectomy. J Natl Cancer Inst 106(8):dju175, 2014.

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The ASCO Post | SEPTEMBER 1, 2014

PAGE 90

Awards

Royal Society Presents 2014 Royal Medal to Tony Hunter, PhD, FRS, Salk Professor

ony Hunter, PhD, FRS, has been awarded the 2014 Royal Medal for Biological Sciences by the Royal Society, an international fellowship of scientists based in the United Kingdom. The award recognizes Dr.

Tony Hunter, PhD, FRS

Hunter, Director of Salk Institute Cancer Center in San Diego, for his contributions to the understanding of cellular signaling transduction. Dr. Hunter discovered a master “switch” for this cell growth signaling that ultimately led to the development of a number of new cancer drugs. Dr. Hunter is also a Professor in the Molecular and Cell Biology Laboratory at the Salk Institute.

Research Changed Cancer Treatment Landscape “Tony Hunter’s discoveries have changed the landscape for the treatment of cancer and other related diseases and underscores the importance of basic science,” said William Brody, MD, PhD, President of the Salk Institute. “All of us at the Salk Institute are thrilled that the Royal Society is recognizing Dr. Hunter’s groundbreaking discoveries with the award of the Royal Medal.” Each year, the Royal Society, which was founded in 1660 and is the oldest scientific academy in continuous existence, awards three Royal Medals, also referred to as the “Queen’s Medals,” for the most important contributions in the physical, biological, and applied sciences. The medal will be presented at the Society’s Anniversary Day meeting on December 1, 2014. “I am delighted to have been selected to receive the 2014 Royal Medal of the Royal Society of London, and I am extremely honored to join the scientific luminaries who

make up the list of past biological sciences medal winners,” says Dr. Hunter, who is also an American Cancer Society Professor and the holder of Salk’s Renato Dulbecco Chair.

Dr. Hunter, a Fellow of the Royal Society (FRS) and a member of the National Academy of Sciences studies how mutations in genes that control growth lead to the unchecked

proliferation of cancer cells. In 1979, his lab uncovered an entirely new mechanism of protein regulation in cells by discovering that the addition of a phosphate group to

ASCOPost.com | SEPTEMBER 1, 2014

PAGE 91

Awards

the amino acid tyrosine in proteins affects how cells multiply. This seminal discovery of a cellular “master switch” opened the door to the study of the dozens of proteins that act as enzymes to add the phosphate to tyrosine—known as tyrosine kinases—and their important role in cancer and other human diseases. This

knowledge has resulted in the development of new cancer treatments, such as imatinib for leukemia. Dr. Hunter received his PhD from the University of Cambridge, England, and completed his postdoctoral fellowship at The Salk Institute and University of Cambridge. Other recipients of this year’s

Royal Medals are Professor Howard Morris, FRS, and Professor Terence Tao, FRS. Professor Morris was awarded the 2014 Royal Medal for his pioneering work in biomolecular mass spectrometry including strategy and instrument design and for outstanding entrepreneurship in biopharmaceutical characteriza-

When you and your patient face the challenge of advanced medullary thyroid cancer (MTC),

Lead the way

with

FDA-approved in April 2011 as the ﬁrst medication for advanced MTC.1 CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH • CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA • Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration • Monitor electrolytes periodically • Avoid drugs known to prolong the QT interval • Only prescribers and pharmacies certiﬁed with the restricted distribution program are able to prescribe and dispense CAPRELSA To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certiﬁcation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program. Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Lead Forward

tion. Professor Terence Tao, FRS, was awarded the 2014 Royal Medal for his many deep and varied contributions to mathematics, including harmonic analysis, prime number theory, partial differential equations, combinatorics, computer science, statistics, representation theory, and much more. n

The ASCO Post | SEPTEMBER 1, 2014

PAGE 92

News Breast Cancer

Postmenopausal Breast Cancer Risk Decreases Rapidly After Starting Regular Physical Activity compared with women who exercised less during those 4 years, according to data published recently in Cancer Epidemiology, Biomarkers & Prevention.1 “Twelve MET-h [metabolic equiva-

lent task-hours] per week corresponds to walking 4 hours per week or cycling or engaging in other sports 2 hours per week, and it is consistent with the World Cancer Research Fund recom-

mendations of walking at least 30 minutes daily,” said Agnès Fournier, PhD, a Researcher in the Centre for Research in Epidemiology and Population Health at the Institut Gustave Roussy in Ville-

In the treatment of advanced medullary thyroid cancer (MTC),

CAPRELSA Signiﬁcantly Prolonged Progression-Free Survival (PFS)* vs Placebo in the ZETA Study2 65% Relative Reduction in Risk of Progression2 HR=0.35 (95% CI: 0.24, 0.53) P<.0001

1.0

Median PFS not reached Progression-free survival

ostmenopausal women who in the past 4 years had undertaken regular physical activity equivalent to at least 4 hours of walking per week had a lower risk for invasive breast cancer

(95% CI: 22.6 months, non-estimable)

0.75

Results from a phase 3, international, randomized, double-blind, placebocontrolled trial in adult patients (N=331) with unresectable locally advanced or metastatic MTC. At disease progression, patients had the option to receive open-label CAPRELSA.2,3

0.50 2

16.4 months median PFS (95% CI: 8.3, 19.7)

0.25

CAPRELSA 300 mg

Placebo

59/231

41/100

Events/Patients

0.0 0

Months Number at Risk CAPRELSA 300 mg

231

173

145

118

Placebo

100

Risk of Progression

Overall Survival (OS)

Subgroup analysis showed similar PFS results for2: • Symptomatic patients HR=0.31 (95% Cl: 0.19, 0.53) • Patients who had progressed within 6 months prior to ZETA study enrollment HR=0.41 (95% Cl: 0.25, 0.66)

• First OS analysis: at the time of the primary analysis of PFS, 15% of patients had died. There was no significant difference in OS between the 2 treatment groups2 • Further OS analysis will take place when ≥50% of patients have died3

Additional Important Safety Information for CAPRELSA (contd) • Do not use in patients with congenital long QT syndrome • CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA • Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction • Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose

• Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above • Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions • Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation

ASCOPost.com | SEPTEMBER 1, 2014

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News

juif, France. “So, our study shows that it is not necessary to engage in vigorous or very frequent activities; even walking 30 minutes per day is beneficial.”

Rapid Impact on Risk Postmenopausal women who in the previous 4 years had undertaken 12 or more MET-h of physical activity each

Agnès Fournier, PhD

week had a 10% decreased risk of invasive breast cancer compared with women who were less active. Women who undertook this level of physical activity between 5 and 9 years earlier but were less active in the 4 years prior to the final data collection did not have a decreased risk for invasive breast cancer. “Physical activity is thought to de-

Additional Important Safety Information for CAPRELSA • Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed • Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event • Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage • Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA • Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose • Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA treated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly • Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA

• Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS • Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval • Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis • CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established • CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA • The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/ colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%) • CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS) For more information, contact the CPAS Program at 1-800-367-4999 or visit www.CAPRELSACPAS.com Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages. * PFS is deﬁned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment. 3 Centralized, independent blinded review of the imaging data was used in the assessment of PFS. 2 References: 1. FDA Web site. US Department of Health and Human Services, Food and Drug Administration. Notable FY 2011 approvals. http://www.fda.gov/AboutFDA/Reports ManualsForms/Reports/ucm276413.htm. Accessed March 27, 2014. 2. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

2977331

4/14

www.LeadWithCAPRELSA.com

crease a woman’s risk for breast cancer after menopause,” said Fournier. “However, it was not clear how rapidly this association is observed after regular physical activity is begun or for how long it lasts after regular exercise stops. “Our study answers these questions,” Fournier continued. “We found that reccontinued on page 94

The ASCO Post | SEPTEMBER 1, 2014

PAGE 94

News Breast Cancer Risk continued from page 93

reational physical activity, even of modest intensity, seemed to have a rapid impact on breast cancer risk. However, the decreased breast cancer risk we found associated with physical activity was attenuated when activity stopped. As a result, postmenopausal women who exercise

should be encouraged to continue and those who do not exercise should consider starting because their risk of breast cancer may decrease rapidly.” Fournier and colleagues analyzed data obtained from biennial questionnaires completed by 59,308 postmenopausal women who were enrolled in E3N, the French component of the Eu-

ropean Prospective Investigation Into Cancer and Nutrition (EPIC) study. The mean duration of follow-up was 8.5 years, during which time, 2,155 of the women were diagnosed with a first primary invasive breast cancer. n

Disclosure: Dr. Fournier reported no potential conflicts of interest. This study was supported by funds from Institut National du

CAPRELSA® (vandetanib) Tablets for Oral Use BRIEF SUMMARY. Before prescribing, please see full Prescribing Information. WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA [see Warnings and Precautions]. INDICATIONS AND USAGE CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA. DOSAGE AND ADMINISTRATION The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can also be administered through nasogastric or gastrostomy tubes. Dosage Adjustment For adverse reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities. Interrupt CAPRELSA for the following: • Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns to less than 450 ms. • CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1. For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade 1 severity, if continued treatment is warranted. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions]. For patients with renal impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings and Precautions and Use in Specific Populations]. For patients with hepatic impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment [see Use in Specific Populations]. CONTRAINDICATIONS Do not use in patients with congenital long QT syndrome [see Boxed Warning]. WARNINGS AND PRECAUTIONS QT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2) in full Prescribing Information]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to prolong the QT interval [see Warnings and Precautions and Drug Interactions]. If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration]. Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see Dosage and Administration]. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation. Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms. Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed. Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event. Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage.

Cancer, the Fondation de France, and the Institut de Recherche en Santé Publique. The E3N cohort is financially supported by the Institut National du Cancer, the Mutuelle Générale de l’Education Nationale, the Institut de Cancérologie Gustave Roussy, and the Institut National de la Santé et de la Recherche Médicale.

Reference 1. Fournier A, et al: Cancer Epidemiol Biomarkers. August 11, 2014 (early release online).

Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA. Diarrhea Diarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration [see Warnings and Precautions]. Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration]. Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebotreated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 - 4 weeks and 8 - 12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly. Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA [see Dosage and Administration]. Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS. Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information]. Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and Administration, Use in Speciﬁc Populations and Clinical Pharmacology (12.3) in full Prescribing Information ]. Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration]. Embryofetal Toxicity Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day and had adverse effects on female fertility, embryofetal development, and postnatal development of pups. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they must use effective contraception during CAPRELSA treatment and for at least four months following the last dose of CAPRELSA [see Use in Speciﬁc Populations]. CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: • QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions] • Skin Reactions and Stevens-Johnson Syndrome [see Warnings and Precautions] • Interstitial Lung Disease [see Warnings and Precautions] • Ischemic Cerebrovascular Events [see Warnings and Precautions] • Hemorrhage [see Warnings and Precautions] • Heart Failure [see Warnings and Precautions] • Diarrhea [see Warnings and Precautions] • Hypothyroidism [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] • Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions] • Embryofetal Toxicity [see Warnings and Precautions] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%).

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Announcements Thoracic Oncology

NIH Announces Launch of Precision Medicine Trials in Early-Stage Lung Cancer

he National Institutes of Health (NIH) recently announced the launch of the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST. The purpose of the trial, which has three components, is to identify patients with

early-stage lung cancer whose tumors harbor certain uncommon genetic mutations and evaluate whether drug treatments targeted against those mutations can lead to improved survival. The three component trials of ALCHEMIST are:

• screening component (A151216), coordinated by the Alliance for Clinical Trials in Oncology; Principal Investigators: Pasi A. Jänne, MD, PhD, and Geoffrey Oxnard, MD, DanaFarber Cancer Institute, Boston. www.cancer.gov/clinicaltrials/

CAPRELSA® (vandetanib) Tablets Table 1 – Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥5% (All Grades)1] System Organ Class Preferred Term

CAPRELSA 300 mg N=231

Placebo N=99

All Grades (%)

Grade 3-4 (%)

All Grades (%)

Grade 3-4 (%)

Diarrhea/Colitis

Nausea

Abdominal Pain2

Vomiting

Dyspepsia

Dry Mouth

Gastrointestinal Disorders

Skin and Cutaneous Disorders Rash3

Dermatitis Acneiform/Acne

Dry Skin

Photosensitivity Reaction

Pruritus

Nail abnormalities4

Alopecia

N/A

Headache

Dysgeusia

Decreased Appetite

Hypocalcemia

Vascular Disorders Hypertension/Hypertensive Crisis/Accelerated Hypertension Nervous System Disorders

General Disorders Fatigue5 Infections Upper Respiratory Tract Infections6 Metabolic and Nutritional Disorders

Investigations ECG QT Prolonged7 Eye Disorders Corneal Abnormalities8

Blurred Vision

Renal Disorders Proteinuria Psychiatric Disorders Depression Endocrine Disorders Hypothyroidism Musculoskeletal Disorders Muscle Spasms 1. 2. 3. 4. 5. 6. 7. 8.

CTCAE version 3 was used to grade adverse events. Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort. Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema. Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection. Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group. Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and tracheitis. 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction. Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits, acquired corneal dystrophy.

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). Blurred vision was more common in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination, including slit lamp examination, in patients who report visual changes. Class effects CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibition of VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSA treated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% in patients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study.

Table 2 – Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1] Laboratory Abnormalities CAPRELSA 300 mg Placebo N = 231 N = 99 All Grades Grade 3-4 All Grades Grade 3-4 (%) (%) (%) (%) Chemistries Hypocalcemia 57 6 25 3 ALT Increased 51 2 19 0 Hypoglycemia 24 0 7 1 Creatinine Increased 16 0 1 0 Hypomagnesemia 7 <1 2 0 Hematologic Neutropenia 10 <1 5 2 Thrombocytopenia 9 0 3 0 1.

CTCAE version 3 was used to grade laboratory abnormalities.

No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study. DRUG INTERACTIONS Effect of CYP3A4 Inducers on CAPRELSA Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use of known strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John’s Wort because it can decrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effect of CAPRELSA on OCT2 Transporter CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transporter type 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that are transported by OCT2 [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effect of CAPRELSA on Digoxin CAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities when administering CAPRELSA with digoxin [see Clinical Pharmacology (12.3) in full Prescribing Information]. Drugs that Prolong the QT Interval Avoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. Risk Summary Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to those expected at the recommended human dose of 300 mg/day. If CAPRELSA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal data When vandetanib was administered to female rats prior to mating and through the first week of pregnancy at a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos. During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in postimplantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times the human exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embryofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study. Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax in patients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicating delayed fetal development. In a rat pre- and post-natal development study, at doses producing mild maternal toxicity (1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CAPRELSA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established. Geriatric Use The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently compared to younger patients. Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 8), moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. [see Dosage and Administration and Warnings and Precautions]. Females and Males of Reproductive Potential Contraception Females of reproductive potential should avoid pregnancy. Use effective contraception during treatment and up to 4 months after the last dose of CAPRELSA. Infertility There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate that vandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1) in full Prescribing Information]. OVERDOSAGE In the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adverse reactions may not resolve quickly. Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 CAPRELSA is a registered trademark of the AstraZeneca group of companies © AstraZeneca 2014. All Rights Reserved. 3/14 2975903 5/14

NCT02194738 • EGFR treatment component (A081105), coordinated by the Alliance for Clinical Trials in Oncology; Principal Investigator: Ramaswamy Govindan, MD, Washington University, St. Louis. www.cancer.gov/clinicaltrials/ NCT02193282 • ALK treatment component (E4512), coordinated by ECOG-ACRIN; Principal Investigator: David E. Gerber, MD, University of Texas Southwestern Medical Center at Dallas. www.cancer.gov/clinicaltrials/ NCT02201992

Study Objectives “We believe that the findings from ALCHEMIST will not only help answer an important question about the addition of targeted therapies in earlierstage disease but will also help us in understanding the prevalence and natural history of these genomic changes in earlier-stage lung cancer. We also hope to gain a better understanding regarding the genetic changes in the tumor at the time of recurrence,” said Shakun Malik, MD, Head of Thoracic Cancer Therapeutics in the Clinical Investigations Branch of the National Cancer Institute (NCI). In the ALCHEMIST screening trial, surgically removed tissue will be tested in a central laboratory for certain genetic changes in two genes, ALK and EGFR. Participants with tumors found to harbor EGFR mutations or rearrangement of the ALK gene will then be referred to one of two randomized, placebo-controlled ALCHEMIST treatment trials. These studies will evaluate the value of adding therapy with erlotinib (Tarceva) (targeted against EGFR) and crizotinib (Xalkori) (targeted against ALK), in the postoperative setting.

Support for the Trial ALCHEMIST is supported by the NCI, with coordination of the component trials by the Alliance for Clinical Trials in Oncology and the ECOG-ACRIN Cancer Research Group. All of the NCIsupported National Clinical Trials Network (NCTN) groups collaborated in the development of ALCHEMIST and are participating in the component trials. ALCHEMIST is the second precision medicine clinical trial to launch as part of the new NCTN. The first trial, Lung-MAP, for patients with advanced squamous cell lung cancer, was launched in June 2014. n

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2014-2015 Oncology Meetings September American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Cancer Medicine and Hematology 2014 September 14-19 • Boston, Massachusetts For more information: www.hmscme.com/cancermedicine 18th Annual Meeting: Collaborative Group of the Americas on Inherited Colorectal Cancer September 15-16 • New Orleans, Louisiana For more information: www.clevelandclinicmeded.com/live/ courses/cga/default.asp Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org

European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home. aspx

2nd International Conference on Hematology & Blood Disorders September 29–October 1 • Linthicum, Maryland For more information: omicsgroup.com/hematology-blooddisorders-conference-2014/index.php

2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org

Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx

American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

Atlanta Lung Cancer Symposium October 18 • Atlanta, Georgia For more information: www.phillipsgilmore.com/alcs2014

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

October

14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety.org.uk/index. cfm?task=meetings&meetingid=37

NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/ meetings/hematological/

2014-2015

11th Meeting of the European Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php 2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/breastcancer/ pages/index.aspx

11th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO) October 23-24 • Arlington, Virginia For more information: www.isgio.org

ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org continued on page 98

MULTIPLE MYELOMA

NEVER

GIVES UP.

BUT NEITHER

DO WE. There is no cure for multiple myeloma. That’s why we’ve dedicated ourselves to three guiding principles: a relentless commitment to scientific advances, a persistent focus on patient needs, and a progressive approach to collaboration. Celgene has put these beliefs into practice for more than 15 years. And we’re not done yet.

02/13

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2014-2015 Oncology Meetings continued from page 96

Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org

CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org

UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org

Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306

24th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists December 5-7 • Vienna, Austria For more information: iasgo2014.org

19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014: Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

2014-2015

11th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congressesmeetings/items/5th-ichno

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org

The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/

Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/32nd-Annual-MiamiBreast-Cancer-Conference

March 13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com/lung-cancercongress-europe/index.asp Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

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The ASCO Post | SEPTEMBER 1, 2014

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Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY BET Bromodomain Inhibition Highly Active in CastrationResistant Prostate Cancer Progression to castration-resistant prostate cancer after androgen ablation therapy is primarily due to deregulated androgen receptor signaling. Treatment with agents that target such signaling, such as abiraterone (Zytiga) and enzalutamide (Xtandi), has been successful. However, durable response is infrequently achieved, likely reflecting development of acquired resistance. BRD4 is a member of the BET family of bromodomain-containing proteins that influence transcription by binding to acetylated histones. Recently, selective small-molecule inhibitors (JQ1 and I-BET762) that target the amino-terminal bromodomains of BRD4 have been found to exert antiproliferative effects in several cancers. In a study reported in Nature, Asangani and colleagues showed that androgen receptor signaling–competent human castration-resistant prostate cancer cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. JQ1 was shown to inhibit the physical interaction of BRD4 with the Nterminal domain of the androgen receptor and, like enzalutamide, disrupt androgen receptor recruitment to target gene loci. Unlike enzalutamide, JQ1 was found to function downstream of the androgen receptor and to more effectively inhibit both BRD4 localization to receptor tar-

get loci and androgen receptor–mediated gene transcription, with effects including inhibition of TMPRSS2-ERG gene fusion and its oncogenic activity. BET bromodomain inhibition was found to be more effective in reducing tumor growth than direct androgen receptor inhibition in castration-resistant prostate cancer xenograft mouse models. The investigators concluded, “Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.” Asangani IA, et al: Nature 510:278282, 2014.

IMMUNOTHERAPY Fusion Protein Improves Dendritic Cell Penetration, Raising Prospect of Efficient Cancer Vaccine Immunotherapy with dendritic cells in combination with cytotoxic chemotherapy may eliminate minimal disease burden by generating cytotoxic T lymphocytes (CTLs). Improving the cytosolic bioavailability of tumor-specific antigens to improve access to HLA class I molecules would result in better generation of cytotoxic T lymphocytes. Numerous cell-penetrating domains (CPDs) are known to carry linked heterologous antigens through the plasma membrane into the intracellular compartment. In a study reported in JAMA Surgery, Batchu and colleagues assessed whether

fusing melanoma antigen family A,3 (MAGE-A3), a tumor-specific cancertestis antigen, with a cell-penetrating domain would increase the cytosolic bioavailability of MAGE-A3. MAGE-3 was amplified by polymerase chain reaction and cloned in frame with a cell-penetrating domain (YARKARRQARR) at the amino-terminal end and hexahistidine at the carboxy-terminal end to generate CPD–MAGE-A3. Western blot analysis with MAGE-A3 antibodies recognized both MAGE-A3 and CPD–MAGE-A3 proteins, whereas analysis with cell-penetrating domain antibodies recognized only CPD–MAGEA3. Purified CPD–MAGE-A3 exhibited improved dendritic cell membrane penetration vs MAGE-A3 alone. The finding on flow cytometry of high expression of unique dendritic cell markers (CD80, CD83, CD86, and HLA-DR) on dendritic cells was consistent with a mature dendritic cell phenotype, indicating that pulsing with CPD–MAGE-A3 did not alter the repertoire of cell-surface antigens required for T-cell activation. The investigators concluded, “We have demonstrated for the first time, to our knowledge, that cloning and purification of MAGE-A3 with CPD enhances its cytosolic bioavailability in [dendritic cells] without altering cell-surface antigens, potentially making it a more potent therapeutic cancer vaccine compared with existing MAGE-A3 protein and peptide vaccines.” Batchu RB, et al: JAMA Surg 149:451457, 2014.

NOVEL MECHANISMS Dysregulated Cell-Cycle Progression and Akt Hyperactivation in Cancer

Akt plays important roles in cell proliferation, survival, and metabolism. Akt hyperactivation contributes to tumorigenesis and is associated with poor prognosis and resistance to chemotherapy and radiotherapy. It is known that activation of Akt results from phosphorylation at S473 and T308, but it is unclear whether other mechanisms are involved in full Akt activation. It is also unclear whether Akt hyperactivation is associated with dysregulated cell-cycle progression, which is also involved in tumorigenesis. In a study reported in Nature, Liu and colleagues found that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. They showed that

phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclindependent kinase 2 (Cdk2)/cyclin A or mTORC2 promoted Akt activation by facilitating or functionally compensating for S473 phosphorylation. Deletion of the cyclin A2 allele in the mouse olfactory bulb resulted in reduced S477/T479 phosphorylation and increased apoptosis. Cellular apoptosis in mouse embryonic stem cells induced by cyclin A2 deletion was partly inhibited by S477D/T479EAkt1, supporting a physiologic role for cyclin A2 in controlling Akt activation. The investigators concluded, “Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.” Liu P, et al: Nature 508:541-545, 2014.

Small Molecule Induces Catastrophic Vacuolization and Death of Glioblastoma Cells In a study reported in Cell, Kitambi and colleagues screened patient-derived glioblastoma cells to identify targetable cellular processes gained by these cells that are not necessarily involved in malignancy. They found that a quinine derivative (NSC13316) selectively compromised viability of glioblastoma cells. Structure-activity relationships of the derivative were identified and exploited to produce analogs (vacquinols) with increased potency. The vacquinols were shown to induce death of glioblastoma cells via membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture. Short hairpin RNA screening identified the MAP kinase MKK4 as a critical signaling node, with the kinase being required for vaquinol-induced vacuolization. In a glioblastoma multiforme animal model, vacquinol-1 had good pharmacokinetics and brain exposure and was associated with reduced disease progression and prolonged survival. The investigators concluded, “These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.” Kitambi SS, et al: Cell 157:313-328, 2014.

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Lab Notes

15-PGDH Expression in Normal Mucosa May Be Biomarker for Aspirin Prevention of Colorectal Cancer Aspirin use reduces the risk of colorectal cancer at least in part via inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2) pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide; 15-PGDH, HPGD) is a metabolic antagonist of PTGS2 and is downregulated in colorectal cancer. In a study reported in Science Translational Medicine, Fink and colleagues investigated whether the effect of aspirin in reducing risk of colorectal cancer is antagonized by low 15-PGDH expression in normal colon mucosa. The study involved analysis of data on aspirin use collected every 2 years and occurrence of colorectal cancer among 127,865 participants in the Nurses’ Health Study and the Health Professionals Follow-Up Study. A total of 270 colorectal cancer cases in which 15-PGDH expression could be assessed were identified. Compared with nonuse, regular aspirin use was associated with lower risk of development of colorectal cancer in normal colonic mucosa with high 15-PGDH expression (multivariate hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.34– 0.71) but not in normal colonic mucosa with low 15-PGDH expression (multivariate HR = 0.90, 95% CI = 0.63–1.27, P = .018 for heterogeneity). The investigators concluded, “Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.” Fink SP, et al: Sci Transl Med 6:233re2, 2014.

TARGETED THERAPY Spleen Tyrosine Kinase Inhibition Has Promise in High-Risk Precursor B-Cell ALL In a study reported in Science Translational Medicine, Perova and colleagues found that pre–B-cell receptor–independent spleen tyrosine kinase signaling was necessary for leukemic Bcell survival and proliferation in a mouse model. Investigation of samples from

subtypes, including high-risk subtypes. Treatment of immunodeficient mice with one of the inhibitors reduced disease burden in high-risk B-cell ALL xenografts BLEED:8.375” of leukemia and decreased dissemination into the spleen, liver,TRIM:7.875” kidney, and central SAFETY:7” nervous system. The investigators concluded, “[Spleen tyrosine kinase] activation sustains the

growth of multiple [high-risk] B-ALL subtypes, suggesting that [spleen tyrosine kinase] inhibitors may improve outcomes for [high-risk] and relapsed B-ALL.” n Perova T, et al: Sci Transl Med 6:236ra62, 2014. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Now enrolling for alectinib

NCT 02075840 BO28984

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Randomize 1:1

BIOMARKERS

pediatric and adult B-cell acute lymphoblastic leukemia (ALL) showed that spleen tyrosine kinase and downstream targets were phosphorylated independently of pre–B-cell receptor expression or genetic subtype. Studies with two small-molecule spleen tyrosine kinase inhibitors showed reduced growth in vitro of B-cell ALL

Patients (N=286) • Advanced, recurrent, or metastatic ALK-positive NSCLC

Primary Endpoint:

Alectinib1

Crizotinib

Secondary Endpoints:

• Progression-free survival (PFS), investigator-assessed,

• Objective response rate, investigator-assessed,

by RECIST 1.1

using RECIST 1.1 • Time to CNS progression, IRC-assessed, using

RECIST 1.1 • PFS, IRC-assessed, using RECIST 1.1 • Duration of response • Overall survival • Safety: incidence of adverse events • AUC of alectinib • Patient-reported outcomes

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from

• ECOG performance status of 0-2 • No prior systemic therapy for advanced, recurrent, or

metastatic disease • Measurable disease by RECIST 1.1

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com. 1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

The ASCO Post | SEPTEMBER 1, 2014

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Perspective The Year Ahead continued from page 1

patients to realize the goal of personalized medicine. I believe the best clinical results are achieved for each patient when the patient’s personal values and goals are met. That is really what quality of care is all about: achieving outcomes that matter to patients. I plan to focus on several areas this year, but they all center on strengthening our Society and supporting members in their daily work. One of the goals I would like to achieve this year is to use our accumulating knowledge base in the application of more effective patient-centered care to achieve the goals the patient desires. Another important priority of mine is to meet and exceed the needs of our membership to ensure that ASCO remains a leader in the oncology community. I have been traveling in the United States, Asia, and Europe to meet with domestic and international members (who now make up 30% of ASCO membership) as well as our sister professional societies, to learn about their needs and concerns. I’m finding that the problems confronting them are not that different from practice to practice or country to country and that we all share common goals and values. Overly bureaucratic health-care systems, unaffordable cancer care, and the challenges of financing medical education and ongoing professional development are issues every ASCO member is confronting. Although many of the solutions will be different depending on the local resources and political realities of each country, many will be the same and we can learn from each other.

Membership Diversity Domestically, I am concentrating on the diversity between our members at academic centers and in community practices to understand the challenges they face. Although their career goals are somewhat different—academic oncologists are generally more focused on discovering new therapies for cancer, whereas community oncologists tend to be more focused on learning how to apply those discoveries in the clinic—they are really based on one principle: to generate new knowledge

and apply that knowledge to improve patient care. Recently, we have seen a dramatic shift in the size and number of many community practices as smaller practices merge with another practice, an academic medical center, or a community hospital, or have to shutter their doors completely. This is a particularly troubling trend since these practices see more than one-third of new patients and play a critical role in the nation’s cancer care system. ASCO is dedicated to supporting the viability of community practices and finding solutions to help them remain solvent. This issue will be a main focus of mine this year.

Harnessing Big Data After several years of development, in 2015, ASCO through its subsidiary, the ASCO Institute for Quality, will launch its rapid learning health informatics system called CancerLinQ™. ASCO is developing CancerLinQ to monitor, coordinate, and improve the quality of

We anticipate that CancerLinQ will provide insights into the design of new models of cancer care delivery that are sustainable and that address societal objectives, provide supportive mechanisms to sustain a thriving community practice base, and allow the voice of the physician to be resonant, while speeding progress in the development and delivery of better treatment options for patients.

High-Value Cancer Care The drive for health-care reform in the United States has led ASCO to examine the complex concept of value in cancer care. The rising prices of cancer drugs are creating a difficult situation for patients and oncologists, and ASCO is investigating the integration of cost of care into evidence-based medicine, policy, and research. We know our members have a difficult enough task dealing with medically complex cancer patients. To have to discuss with patients not only the scientific evidence that shows which treatments

The initiatives we are undertaking to study new models of providing high-quality, high-value cancer care will hold us in good stead during these challenging times and enable us to continue to be at the forefront of innovation. —Peter P. Yu, MD, FASCO

care provided to cancer patients through the collection, aggregation, and analysis of data extracted from electronic health records of patients from participating oncology practices. The system will revolutionize how we care for people with cancer—improving quality and value and accelerating research. The initial launch of CancerLinQ will take place in a small group of 12 or more “vanguard practices,” which will vary from small community practices to major academic cancer centers to capture the diversity of different models of care delivery. The initial version of CancerLinQ will be followed by rapid releases with expanding functionality into the larger oncology ecosystem.

are most likely to improve survival and enhance quality of life, but also issues regarding cost of treatment and the impact it may have on their financial security, raises the demands on already limited time available for patient interaction. But these are the factors that define high-quality oncology care. Ultimately, what is of value to one patient may not be the same for another, and we have to take that factor into account when attempting to define value. We are not proposing that the determination of value is the same for all patients, but we believe that we need to start having this conversation with our patients. Currently, ASCO’s Value in Cancer Care Task Force is developing a value

algorithm to help define and assess the value of cancer treatment options. Once the prototype is completed, we will share it with our members and others in the oncology community and get their input.

Palliative Care Endeavors Providing our patients with optimal oncology care and improving their quality of life at every stage of their disease and survivorship is of such critical importance to ASCO, the Society is launching a Palliative Care in Oncology Symposium this fall. The scientific meeting will be held October 24–25, 2014, in Boston, and will focus on innovative strategies in the management of treatment- and disease-related symptoms and models of integrated health-care delivery during every stage of disease. Together with the Academy of Hospice and Palliative Care Medicine, ASCO is working on defining the palliative care skill set every oncologist needs to be familiar with to manage patients’ symptoms. Another initiative is a virtual learning collaborative that brings together 25 community and academic oncology practices from around the country to design, execute, present, and evaluate quality improvement projects with the goal of optimizing palliative care delivery. The program, which began earlier this year, will be in place for 2 years.

Common Ground and Diversity All of the goals I have outlined here relate to one overarching focus of my presidential term, and that is to address the needs of all our members—domestic and international, in private and academic practices—and to look for common ground and common solutions to the issues confronting all of us. That said, it is our members’ diversity that makes our Society strong and will define our place in the global effort to improve the lives of patients with cancer. The initiatives we are undertaking to study new models of providing high-quality, high-value cancer care will hold us in good stead during these challenging times and enable us to continue to be at the forefront of innovation. n

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In the Literature

Emerging Clinical Data on Cancer Management RISK FACTORS Prolonged TV Viewing, Other Sedentary Behaviors Linked to Increased Risk of Particular Cancers “Prolonged TV viewing and time spent in other sedentary pursuits is associated with increased risks of certain types of cancer,” concluded a meta-analysis of data from 43 observational studies including more than 4 million people and 68,936 cancer cases. A positive association with overall sedentary behavior was found for colon, endometrial, and lung cancer. “The primary finding from our metaanalysis is that prolonged TV viewing and time spent in other sedentary pursuits is associated with increased risks of colon and endometrial cancer. Each 2-hour per day increase in sedentary time was related to a statistically significant 8% increase in colon cancer risk and 10% increase in endometrial cancer risk,” Daniela Schmid, PhD, MSc, and Michael F. Leitzmann, MD, DrPH, Department of Epidemiology and Preventive Medicine, University of Regensburg, Germany, wrote in the Journal of the National Cancer Institute. “Sedentary behavior was unrelated to cancers of the breast, rectum, ovaries, prostate, stomach, esophagus, testes, renal cell, and non-Hodgkin lymphoma.” The authors noted that sedentary behavior is emerging as an independent risk factor for chronic disease and mortality. Television viewing was singled out because it “is accompanied by increased consumption of unhealthy foods, such as sugar-sweetened beverages, sweets, and fast food and it is related to enhanced smoking initiation,” the investigators stated. “We performed a comprehensive electronic literature search in Cochrane, EMBASE, Medline, and SciSearch databases through February 2014 for published articles investigating sedentary behavior in relation to cancer incidence. Because randomized controlled trials are difficult to perform on this topic, we focused on observational studies that met uniform inclusion criteria,” the researchers explained. Data in the studies had been obtained with self-administered questionnaires and interviews. “Comparing the highest vs lowest levels of sedentary time, the relative risks (RRs) for colon cancer were 1.54 (95% confidence interval [CI] = 1.19 to 1.98) for TV viewing time, 1.24 (95% CI =

1.09 to 1.41) for occupational sitting time, and 1.24 (95% CI = 1.03 to 1.50) for total sitting time. For endometrial cancer, the relative risks were 1.66 (95% CI = 1.21 to 2.28) for TV viewing time and 1.32 (95% CI = 1.08 to 1.61) for

total sitting time. A positive association with overall sedentary behavior was also noted for lung cancer (RR = 1.21; 95% CI = 1.03 to 1.43),” the authors wrote. Among the biologic mechanisms that “may mediate the observed posi-

TELL YOUR ADVANCED PRACTICE COLLEAGUES TO

tive association between sedentary behavior and cancer,” the investigators listed decreased energy expenditure accompanied by weight gain and obesity, and vitamin D deficiency. The authors continued on page 104

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In the Literature Emerging Clinical Data continued from page 103

pointed out that while sedentary behavior was strongly associated with colon cancer and endometrial cancer, “tumors that are considered obesity-related,” sedentary behavior was not associated with breast cancer and renal cell cancer, “even though obesity is positively associated with those malignancies. This suggests that sedentary behavior and obesity mediate risk for certain cancers (eg, colorectal cancer and endometrial cancer) through shared mechanisms, whereas other cancers (eg, breast cancer and renal cell cancer) show distinct obesity-specific pathways.” The authors called for stronger individual and public health efforts to reduce time spent on sedentary behavior. “Given the strength of the data, the dose–response relation, and the lack of heterogeneity among studies, these data support a causal relation between sedentary behavior and both colon and endometrial cancers. For other cancers that are related to obesity (breast, kidney), the association for sitting may operate through obesity-specific pathways,” noted an accompanying editorial by Lin Yang and Graham A. Colditz, MD, DrPH, of the Siteman Cancer Center and Department of Surgery, Washington University School of Medicine, St. Louis. “Cancer prevention requires a sufficient evidence base, political will to fund programs to address the prevention potential, and a social strategy or plan by which we apply our knowledge to initiate or improve programs,” the editorialists continued. They mentioned several possible interventions including worksite modifications to reduce sedentary time and “replacing sedentary time in transport with active commuting.” Schmid D, Leitzmann MF: J Natl Cancer Inst 106(7):dju098, 2014. Yang L, Colditz GA: J Natl Cancer Inst 106(7):dju135, 2014.

COLORECTAL CANCER Patient, Tumor Characteristics Associated With BRAF and KRAS Mutations KRAS and BRAF V600E mutations were nearly mutually exclusive and associated with specific patient and tumor characteristics, such as age and smoking status, according to an analysis of data from the N0147 phase III trial for stage III colon cancer. Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair status,

Wilson I. Gonsalves, MD, of the Mayo Clinic, and colleagues explained in the Journal of the National Cancer Institute. That information was merged with clinical characteristics collected at the time of randomization, and patient characteristics, including activity level, smoking, alcohol intake, and family history of colorectal cancer, obtained from the 2,326 (93%) of the 3,397 enrolled patients who completed questionnaires. “Specifically, age of 70 years or older, smoking, high-grade histology, and [defective mismatch repair] status were associated with a lower incidence of mutant KRAS tumors but a higher incidence of BRAF [V600E]-mutated tumors. Both mutations tend to [occur in rightsided tumors] and were nearly mutually exclusive, but BRAF [V600E]-mutated tumors are more common in females, non-Hispanic white patients, those having four or more positive lymph nodes, stage T4 disease, and those with a history of gastrointestinal conditions. Finally, within KRAS mutant tumors, those with a KRAS Gly13Asp mutation tend to be associated with [defective mismatch repair] status and high-grade histology,” the researchers reported. “The presence of a KRAS mutation is predictive for resistance to anti-[epidermal growth factor receptor (EGFR)] monoclonal antibodies in advanced colon cancer,” the authors noted, although “it has been suggested that patients whose tumors harbor a KRAS Gly13Asp mutation may benefit from anti-EGFR [monoclonal antibody] therapy. BRAF activating mutations, specifically V600E, occur in less than 10% of patients with sporadic colon cancer and are a strong negative prognostic marker; however, their predictive value for efficacy of anti-EGFR [monoclonal antibody] treatment is less certain.” In the current study, there were 783 tumors (35%) that had KRAS mutations, “of which 191 (24%) were KRAS Gly13Asp, whereas 310 (14%) tumors had a BRAF [V600E] mutation. Of 2,231 tumors analyzed for [mismatch repair] status, 279 (13%) were characterized as [defective mismatch repair],” according to the study report. “KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations [excluding those with KRAS Gly13Asp mutation] were less likely to have [defective mismatch repair] (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001),” the investigators stated. “Tumors with BRAF [V600E] mutations

were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men.” The authors noted that further studies are warranted to explain the association between the mutations and the cited epidemiologic and clinicopathologic characteristics. Gonsalves WI, et al: J Natl Cancer Inst 106(7):dju106, 2014.

SKIN CANCER Simple Bedside Assessment of Pain and Itch Is Valuable Tool for the Evaluation of Suspicious Skin Lesions A prospective, clinicopathologic study involving 268 patients with biopsy-proven basal cell carcinoma, squamous cell carcinoma, malignant melanoma, or melanoma in situ “revealed that pain is associated with histologic features that involve deeper dermal processes in [squamous cell carcinoma] lesions, such as ulceration and depth of invasion, whereas itch is linked with the more superficial [basal cell carcinoma] lesions.” The study by Gil Yosipovitch, MD, of the Department of Dermatology and Temple Itch Center, Temple University School of Medicine, Philadelphia, and colleagues was published in JAMA Dermatology. The authors concluded, “These findings support the theory that itch emanates from the upper layers of the skin, whereas pain is associated with deeper processes.” The investigators also stated that the study “highlights the importance of a simple bedside evaluation for the presence and intensity of pain and itch as an easily implementable tool for physicians to use when evaluating suspicious skin lesions.” Drawn from the patient population presenting to the Department of Dermatology surgical unit at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, from July 1, 2010, through March 31, 2011, the study participants represented 339 histologically confirmed cutaneous neoplasms: 166 basal cell carcinomas, 146 squamous cell carcinomas, and 27 melanomas. The participants completed questionnaires assessing itch and pain intensity of their skin tumors at the time of excision. Histopathologic analysis for each neoplasm included assessment of the amount and type of inflammation, ulceration, perineural invasion, and depth of invasion. Across all types of skin cancers,

itch was prevalent in 36.9% and pain in 28.2%. “The prevalence of itch was greatest in [squamous cell carcinoma] (46.6%), followed by [basal cell carcinoma] (31.9%) and melanoma (14.8%). Pain prevalence was also greatest in [squamous cell carcinoma] (42.5%), again followed by [basal cell carcinoma] (19.9%) and melanoma (3.7%). The prevalence of itch and pain was significantly greater in [squamous cell carcinomas] (P = .002) and [basal cell carcinomas] (P < .001) compared with melanoma,” the researchers reported. Grouping all skin cancers together, the mean depth of invasion was highest in the most painful lesions and lowest in the painless lesions. “Pain intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P < .001), presence of neutrophils in the inflammatory infiltrate (predominantly mononuclear vs mixed or neutrophilic; P = .003), presence of eosinophils (present vs absent; P = .007), ulceration (yes vs no; P = .003), perineural invasion (yes vs no; P < .001), depth of invasion (P = .001), and largest diameter length of skin lesion (P < .003), the researchers reported. “Itch intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P = .001) and the presence of eosinophils (present vs absent; P = .02),” they added. The authors acknowledged that the relatively small sample size of melanoma cases “does not allow us to draw firm conclusions about the association between pain and itch and histopathologic features of melanoma. However, it is clear that melanomas have a significantly decreased prevalence of pain and itch compared with nonmelanoma skin cancer, a finding confirmed by a similar study that examined itch and tenderness in patients with melanoma,” the investigators noted. Yosipovitch G, et al: JAMA Dermatol. July 23, 2014 (early release online).

LYMPHOMA First Prospective Study of Rare Lymphoma Shows Promising but Inconclusive Results With DA-EPOCH-R Presenting “the first prospective study” of mediastinal gray zone lymphoma, researchers from the National Cancer Institute reported that DA-EPOCHR (infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (Rituxan) and filgrastim (Neupo-

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In the Literature

gen) in untreated mediastinal gray zone lymphoma produced event-free survival of 62% and overall survival of 74% at 59 months median follow-up. “DA-EPOCH-R alone produced durable remissions in most patients indicating it is an effective treatment for these relatively resistant lymphomas,” the authors wrote. While the results of the trial, which involved 24 patients, were considered promising, “we cannot rigorously determine if DA-EPOCH-R is optimal treatment for [mediastinal gray zone lymphoma] given the limited number of cases and absent a randomized study design,” Wyndham H. Wilson, MD, PhD, and colleagues wrote in Blood. Mediastinal gray zone lymphoma is extremely rare, the investigators noted, and has pathologic features intermediate between the more common types of mediastinal B-cell lymphomas, nodular sclerosis Hodgkin lymphoma and primary mediastinal B-cell lymphoma. “The indeterminate pathobiology of [mediastinal gray zone lymphoma] has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized,” the researchers wrote. Study participants had a median age of 33 years (range, 14–59) years and 46% had mediastinal masses ≥ 10 cm. “All patients had histological and/or phenotypic features intermediate between [primary mediastinal B-cell lymphoma] and [nodular sclerosis Hodgkin lymphoma]. Usually, the tumors have a predominant morphology, which was either [primary mediastinal B-cell lymphoma]like in 33% (8/24), or more frequently Hodgkin-like in 63% (15/24) of cases, and one case was classified as composite [nodular sclerosis Hodgkin lymphoma] and [primary mediastinal B-cell lymphoma],” the researchers noted. “All patients responded with 19 complete and 5 partial remissions,” the investigators reported. Nine patients were diagnosed with active disease at a median of 3 months (range, 1–6) after completing therapy. Based on positron-emission tomography/computed tomography evaluation showing disease limited to the mediastinal area, all nine patients received involved-field salvage radiotherapy “and four are in continuous remission at 3, 73, 91, and 128 months,” according to the study report. “The occurrence of treatment failure in one third of [mediastinal gray zone lymphoma] patients and the curative potential of salvage radiotherapy makes early identification of treatment failure important,” the authors noted. Indicators of worse outcome include low ab-

solute lymphocyte count, the presence of tumor-associated dendritic/macrophage cells, and CD15 expression on the malignant cells. Results of the study were compared to a cohort of patients with primary mediastinal B-cell lymphoma prospectively treated with DA-EPOCH-R. “Patient eligibility was identical for both groups

except patients with [primary mediastinal B-cell lymphoma] were required to have a mediastinal mass at least 5 cm. Treatment and follow-up were identical in both groups,” the investigators stated. “Compared with [primary mediastinal B-cell lymphoma], [mediastinal gray zone lymphoma] patients were more likely to be male, express CD15, have

lower expression of CD20 and to have a worse outcome.” The trial was registered at ClinicalTrials.Gov (NCT00001337).n Wilson WH, et al: Blood. July 14, 2014 (early release online). In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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The ASCO Post | SEPTEMBER 1, 2014

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In Memorium

Jesse L. Steinfeld, MD, Past Surgeon General, ASCO President, Dies at 87 By Ronald Piana

he 1964 Surgeon General’s Report on Smoking and Health started a culture change in the way Americans viewed tobacco and their health, and has saved countless million of lives. But the 1964 Report remained scientifically ambiguous on certain vital issues, such as the effect smoking had on the unborn child. This was a crucial issue, as Big Tobacco had targeted America’s women as a growing source of new smokers, playing down harms associated with smoking while pregnant. In 1971, then Surgeon General Jesse L. Steinfeld, MD, took Big Tobacco to task, stating, “Let me suggest that certain purveyors of cigarettes stop making remarks about how some young mothers in childbirth might welcome smaller babies. The mother who smokes is subjecting the unborn child to the adverse effects of tobacco, and as a result we are losing babies and possibly handicapping babies.” Dr. Steinfeld died on August 5, 2014, at the age of 87.

Education and Early Career The son of Jewish immigrants from Hungary, Dr. Steinfeld was born on January 6, 1927, in the Pittsburgh suburb of West Aliquippa, deep in coal country. When he was 5 years old, his father, a lifelong smoker, died of lung cancer. Boys in his social class were routine-

ly placed in vocational tracks that often led to the coal mines. However, Dr. Steinfeld persuaded his counselor to put him on an academic track instead; he graduated high school with honors at age 16 and received his bachelor’s degree 19 months later from the University of Pittsburgh in 1945. Dr. Steinfeld earned his MD in 1949 from Western Reserve University, now called Case Western Reserve University, in Cleveland. He then did his internship at Cedars of Lebanon Hospital in Los Angeles and his residencies at the Veterans Administration Hospital in Long Beach, California, and at the University of California, where he studied oncology. In 1954, Dr. Steinfeld took a position at the National Cancer Institute (NCI), serving as Director of the Radioisotope Laboratory until 1958. In 1959, he returned to California, where he joined the faculty of the University of Southern California School of Medicine, serving as Assistant Professor of Medicine, rising to Associate Professor in 1963, and full professorship in 1967. During this period, most of his research focused on cancer. Dr. Steinfeld returned to the NCI in 1968, serving as Associate Director for Programs. Later that same year, he was appointed Deputy Assistant Secretary for Health and Scientific Affairs, and

on December 18, 1969, he became the U.S. Surgeon General. During his tenure

Dr. Steinfeld’s antismoking passion led him into uncharted waters. Citing numer-

It is high time to ban smoking from all public places…. It is time we interpret the Bill of Rights for the nonsmoker as well as the smoker. —Jesse L. Steinfeld, MD, in 1971

as Surgeon General, Dr. Steinfeld also served as ASCO’s seventh President, from 1970 to 1971.

Antismoking Passion For various political reasons prior to his appointment, the Surgeon General’s position had been watered down, operating without a clear line of authority. But that changed with Dr. Steinfeld, who embraced the role of public-figure activist. His antitobacco stance was bold and unequivocal, leading him to become Big Tobacco’s worst enemy. Remarkably, his two predecessors had been smokers. Dr. Steinfeld removed all the ashtrays and placed no-smoking signs in his offices, an unheard of move against the status quo in that era.

ous studies showing that women were less likely than men to quit smoking, he spearheaded a campaign to reduce the number of female smokers. He spoke liberally without mincing words about how Big Tobacco cleverly marketed cigarettes to women, even pregnant women, despite the deleterious effects on the fetus. He was also at an unpopular vanguard, warning against the dangers of secondhand smoke. Many of his ideas about banning smoking on airplanes, trains, restaurants, the workplace, and other public places would take hold decades later as antismoking activists lobbied for and achieved smoke-free zones. But at the time, they were considered radical. Not surprisingly, Big Tobacco atcontinued on page 107

Pioneer in Fight Against Tobacco, Emanuel Farber, MD, PhD, Dies at 85 By Ronald Piana

n December 11, 1969, a soft-spoken pathologist wearing outsized spectacles answered a long and complex series of questions by the legal team representing Liggett & Myers Tobacco Company, the maker of Chesterfield cigarettes. The tobacco lawyers contended that one Leslie Thayer—a lifelong smoker of Chesterfields—had died of lung cancer due to “misuse” of their product. The expert witness, Emanuel Farber, MD, PhD, dismantled that contention, demonstrating that years of smoking Chesterfield cigarettes had caused Leslie Thayer’s death of lung cancer. Dr. Farber’s groundbreaking research in carcinogenesis was instrumental in the paradigm shift in American attitudes toward smoking. Dr. Farber died on August 3, 2014, at the age of 95.

Early Life Dr. Emmanuel Farber was born in Toronto in 1918. His lifelong interest

Emanuel Farber, MD, PhD

in science blossomed during his early schooling, leading him to the Faculty of Medicine, University of Toronto, in 1936, where he received his MD degree in 1942. Having completed his residency training in pathology at the Hamilton General Hospital in Ontario, Canada, Dr. Farber served in the Royal Canadian Army Medical Corps. After his military service, Dr. Farber entered the University of California Graduate School, Berkeley, obtaining his doctorate in biochemistry in 1949.

Dr. Farber developed an early interest in liver disease that can be traced to a 1950 fellowship awarded by the American Cancer Society. There he worked with Hans Popper, MD, who was the driving force behind the founding of the American Association for the Study of Liver Diseases. During this exciting period of study, Dr. Farber wrote several papers dealing with early theories on the etiology of liver diseases.

Pathologist, Biochemist, and Educator Although Dr. Farber was a renowned pathologist and biochemist, he was also an educator. When he was elected as an honorary member of the Society of Toxicologic Pathologists, his colleague Felix A. de la Iglesia, MD [now Chief Enterprise Officer of the Michigan Technology & Research Institute at Wayne State University School of Medicine, Ann Arbor, Michigan] wrote, “Those who are fortunate enough to work

near or under Dr. Farber’s guidance enjoy the feeling of continuing mental probing, the intense research intellectual exercise, and the amazing flow of energy that emanates from his personality.” He began his academic teaching career as an instructor in pathology at Tulane University in New Orleans, serving as Associate Professor from 1950 to 1959. He later became the American Cancer Society Research Professor of Pathology and Biochemistry from 1959 to 1961. After leaving the American Cancer Society, Dr. Farber became Professor and Chair of the Pathology Department and Professor in the Biochemistry Department at the University of Pittsburg School of Medicine, serving from 1961 to 1970. From 1970 through 1975, Dr. Farber was at the Fels Research Institute in Philadelphia, where he was appointed as Director. continued on page 107

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In Memorium Jesse L. Steinfeld, MD continued from page 106

tacked him. In 1972, the President of R.J. Reynolds wrote to Elliot Richardson, the Secretary of Health, Education, and Welfare: “The results of public misinformation are evident. Public transportation, for example, is beset with no-smoking policies on the basis of the Surgeon General’s arbitrary campaign to ban all smoking.”

Undaunted Zeal Dr. Steinfeld remained undaunted in his zeal for public health. Besides his nonstop vigorous antismoking campaign, he also spoke out about what he regarded as a negative influence on children—violence on television. His call for networks to impose certain types of self-censorship or to at least give parental warnings about

Emanuel Farber, MD, PhD continued from page 106

In 1975, Dr. Farber returned to his native city of Toronto, to serve as Chairman of the Department of Pathology at the University of Toronto. Later, Dr. de la Iglesia, would write, “Dr. Farber’s academic career and research achievements

violent programs drew heavy criticism, which also attracted the ire of the Nixon administration. His superiors ordered him not to testify before Congress on the television violence issue, but true to form, Dr. Steinfeld testified without clearing his remarks first. This latest move against the industry created a firestorm. When Nixon was reelected in 1972, he asked certain members of his administration to submit letters of resignation. Dr. Steinfeld’s letter, which needed to be rewritten several times to dilute its power, was finally accepted. Following his forced resignation, Dr. Steinfeld spent a year at the Mayo Clinic and 2 years at the University of California, Irvine. From 1976 to 1983, Dr. Steinfeld served as Dean at the Medical College of Virginia School of Medicine. He became

President of the Medical College of Georgia in 1983. Health-related issues led to his retirement in 1987, but he remained a strong public advocate for nonsmoker’s rights. In 1971, Dr. Steinfeld publically stated before Congress, “It is high time to ban smoking from all public places…. It is

Early in Dr. Farber’s career, he was the recipient of the Parke-Davis Award in Experimental Pathology, a prize given to an investigator under age 40 who has shown a promising career in pathology. The Parke-Davis Award would be the first of many bestowed on Dr. Farber. In 1984, he was made a Fellow of

ogy confirmed that chemical carcinogens are capable of binding to nucleic acids, in turn generating specific DNA adducts. These early findings led to the observation that chemical carcinogenesis is a sequential process. Dr. Farber later substantiated this theory by showing that cancer could be induced through a series of step-by-step chemical treatments in the liver. Dr. Farber served on the Surgeon General’s first Advisory Committee on Smoking and Health from 1961 to 1964. The committee was responsible for issuing the landmark 1964 Surgeon General’s Report, which has now done more to prevent tobacco-related disease than any other public health document, and is credited with saving tens of millions of lives. Moreover, Dr. Farber promoted the concept that to understand carcinogenesis, one must also understand the cellular, genetic, metabolic, and molecular changes that are occurring during the process. This conviction, along with Dr. Farber’s energy and enthusiasm in exploring the nature of cancer, has inspired the guid-

[H]e represents a guiding example of a life devoted to serving his fellow man and scientific colleagues with unmatched qualities of integrity, humbleness, deep reasoning, and an exquisite no-nonsense … approach to science. —Felix A. de la Iglesia, MD

are the proof that pathologists must seek with interdisciplinary knowledge and profound biochemical insight into the biological processes they study through the microscope. At an early age, Dr. Farber devoted himself to this discipline; thus, his leading role in developing experimental and biochemical pathology.”

the Royal Society of Canada, an award that recognizes outstanding Canadians.

Legacy Work Dr. Farber’s work in illuminating the public health disaster associated with smoking was his legacy work. His groundbreaking studies in experimental pathol-

time we interpret the Bill of Rights for the nonsmoker as well as the smoker.” Lest we forget, our public health has greatly improved because of courageous physicians like Dr. Steinfeld. He is survived by three daughters, two grandchildren, and his wife of more than 61 years, the former Gen M. Stokes. n

Jesse L. Steinfeld, MD, and The War on Cancer

n “Stories on the History of Cancer,” available on ASCO’s Cancer .Progress.Net, past ASCO presidents and other oncology luminaries discuss the founding of ASCO, the early days of cancer treatment, and the notable changes that have occurred since then—both in the care of people with cancer and in our understanding of the disease. In one such interview, Dr. Jesse Steinfeld recalls the excitement surrounding the 1971 National Cancer Act. To view Dr. Steinfeld’s interview, visit http://cancerprogress .net/story/war-cancer. n

 In Memoriam

Jesse L. Steinfeld, MD January 6, 1927 – August 5, 2014

Emanuel Farber, MD, PhD October 19, 1918 – August 3, 2014 

ance for cancer researchers worldwide. In addition to his academic and research contributions, Dr. Farber was a very active member of the American Association for Cancer Research (AACR), serving as Vice President from 1971 to 1972 and President from 1972 to 1973. He was a member of the AACR Board of Directors and served as Associate Editor of Cancer Research; he was elected as an inaugural Fellow of the AACR Academy in 2013.

Unmatched Tenacity As news of Dr. Farber’s death became public, colleagues uniformly remembered him as researcher of unmatched tenacity and devotion to scientific exploration. A remark by Dr. de la Iglesia in 1985 captures the essence of the scientific communities that Dr. Farber touched: “For us he represents a guiding example of a life devoted to serving his fellow man and scientific colleagues with unmatched qualities of integrity, humbleness, deep reasoning, and an exquisite no-nonsense … approach to science.” n

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