TAP Vol 3 Issue 16 by Harborside Press LLC

Dacomitinib in Advanced NSCLC

| Cost of Care

| Genetics of Breast Cancer

VOLUME 3, ISSUE 16

NOVEMBER 1, 2012

Editor-in-Chief, James O. Armitage, MD

35th ESMO Congress

Combination of BRAF and MEK Inhibitors Paves Way for Phase III Studies in BRAF-mutated Metastatic Melanoma

Ignoring Level 1 Evidence in Invasive Bladder Cancer: Is Ignorance Bliss?

By Alice Goodman

By Derek Raghavan, MD, PhD

wo late-breaking studies presented at the 2012 European Society for Medical Oncology (ESMO) Congress highlight the promising potential of combining dual BRAF and MEK inhibitors for the treatment of BRAF-mutated Georgina Long, MD metastatic melanoma. A phase II study showed that combining full doses of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved outcomes. A phase Ib study demonstrated noteworthy preliminary responses for the combination of the BRAF inhibitor vemurafenib (Zelboraf) plus the investigational MEK inhibitor GDC-0973.

Dabrafenib plus Trametinib The phase II study was presented by Georgina Long, MD, of Westmead Hospital and the Melanoma Institute of Australia in Sydney.1 In that trial, the combination of full-dose dabrafenib plus full-dose tra metinib achieved superior progression-free survival, overall response rate, and duration of response in See Page 75 patients with V600 BRAF mutation–positive metastatic melanoma vs full-dose dabrafenib plus half-dose trametinib vs dabrafenib monotherapy. Simultaneously with the ESMO presentation, the findings were published online in The New England Journal of Medicine.2 Dabrafenib and trametinib are under development by GlaxoSmithKline. continued on page 8

A Day in the Life

Challenging Times: A Day in the Life of a Community Oncologist ommunity oncologists man the front line of cancer care, treating upward of 85% of our nation’s patients. Over the past 2 decades, regulatory and economic changes have left many practices in a state of flux and uncertainty, some struggling to keep their doors open. To shed light on the community practice experience, K.M. Steve Lo, MD, shared a day in his life, and offered observations about today’s challenging environment.

’ve been part of the uro-oncology community for more than 30 years and have been proud to be involved in a good number of wellpowered, enthusiastically subscribed randomized clinical trials. These have dated back to a time before randomization was necessarily the fashion. I have had the pleasure of helping to design or simply participating in randomized studies that proved: (a) a survival benefit from MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) compared to cisplatin for metastatic bladder cancer, (b)�� GCT (gemcitabine, cisplatin, paclitaxel) doesn’t offer a major benefit over GC (gemcitabine, cisplatin) for metastatic bladder cancer, (c) continuous androgen blockade is superior to intermittent androgen blockade for metastatic prostate cancer if surcontinued on page 15

Dr. Raghavan is President, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.

By K.M. Steve Lo, MD, as told to Ronald Piana

ASCOPost.com

MORE IN THIS ISSUE The Practice

rather dramatic changes that have affected our oncology services, in both positive and negative ways.

—K.M. Steve Lo, MD

Oncology Meetings Coverage 35th ESMO Congress 3, 9, 28, 30 NCCN Hematologic Malignancies Congress 10 2012 Breast Cancer Symposium 21 2012 AACR Annual Meeting 35 Best of ASCO® ’12 50 FDA Update 2 Direct from ASCO 41 Pain in Oncology Outpatients 69

Changing Times This is my 20th year in private practice, and over the past 3 to 4 years I’ve seen rather dramatic continued on page 44

November is Lung Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | NOVEMBER 1, 2012

PAGE 10

NCCN Hematologic Malignancies Congress

Challenges Persist in Treatment of Elderly Patients with CLL, but Novel Agents Hold Promise for Future Strategies By Alice Goodman

hronic lymphocytic leukemia (CLL) is mainly a disease of the elderly, and the lack of a standard regimen for elderly patients has been a major challenge. The myelosuppressive regimens used to treat younger patients are not well tolerated by the elderly. However, some newer approaches currently under investigation and on the horizon appear to be promising. In particular, small-molecule inhibitors have had encouraging results in early clinical trials.

“FCR is for elderly patients at high risk. I use it if I think the CLL will kill them. When I start FCR in elderly patients, I reduce the dose of fludarabine and cyclophosphamide from the get-go and anticipate myelosuppression and dose reductions in order to get six cycles of treatment,” he told listeners. Even with FCR, Dr. Wierda said, survival is shorter in older patients, for whom median progression-free survival is about 3 years, compared with more than 6 years in younger patients.

Other Current Options

William G. Wierda, MD, PhD

“The whole CLL community is excited about the newer strategies,” said William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston. Dr. Wierda discussed real-world management of challenges in older patients with CLL at the recent NCCN 7th Annual Congress on Hematologic Malignancies.1 Median age at diagnosis of CLL is 72 years, yet the median age in most clinical trials is in the early 60s, Dr. Wierda said. “The evolution of treatments [for CLL] has been based on studies of younger patients who can tolerate myelosuppressive agents.”

FCR Regimen Current treatments for previously untreated CLL include chemoimmunotherapy, alemtuzumab (Campath), and bendamustine (Treanda). A regimen pioneered at MD Anderson Cancer Center, FCR (fludarabine, cyclophosphamide, rituximab [Rituxan]), is preferred for younger patients but is used very cautiously with reduced chemotherapy doses in high-risk elderly patients, Dr. Wierda said. Unfavorable prognostic factors associated with high-risk CLL include advanced age, increased beta2-microglobulin, 11qand 17p- deletions by fluorescence in situ hybridization (FISH), unmutated VH status, and leukemia expression of CD38 or ZAP-70.

Rituximab monotherapy is a reasonable option in elderly patients. “It does not compromise response to subsequent chemotherapy if needed,” he stated. Lenalidomide (Revlimid) is active and well tolerated as front-line therapy and salvage therapy in elderly CLL patients. Myelosuppression is the doselimiting toxicity. “I think patients need at least 5 mg/d of lenalidomide to achieve a response, so I try to get them to at least that daily continuous dose, and I may use growth factor support,” he continued. Moving forward, the combination of rituximab plus lenalidomide is being studied in elderly CLL patients for firstline therapy, and thus far, results are encouraging. “If a patient is doing well on lenalidomide, continue therapy,” he recommended. “If you stop, they are likely to lose their response.”

Bendamustine has activity as monotherapy in CLL, but Dr. Wierda was not enthusiastic about this option. “In my opinion, bendamustine is better in combination with rituximab, but it is not clear whether [the combination] is better tolerated than any other chemoimmunotherapy regimen. Further study is needed to characterize tolerability in the elderly,” he commented.

Novel Small-molecule Inhibitors “It is an interesting and exciting time for CLL. The newer agents [ie, Bruton’s tyrosine kinase, PI3K, and Bcl-2 inhibitors] are entering clinical trials and will change the face of CLL. We may be moving away from chemotherapy for these patients,” Dr.Wierda stated. Bruton’s tyrosine kinase inhibitor interferes with intracellular signaling downstream of the B-cell receptor and causes B-cell leukemia to undergo apoptosis. Ibrutinib (formerly PCT-32765), an oral Bruton’s tyrosine kinase inhibitor, is now in clinical trials. Studies thus far show a high frequency of durable response in treatment-naive patients over age 65, he said. The drug is well tolerated with no significant myelosuppression, making it particularly suitable for elderly patients. The most frequent adverse events have been grade 1 or 2 diarrhea and nausea.2 “Ibrutinib affects interaction between CLL cells and the microenviron-

Older Patients with Chronic Lymphocytic Leukemia ■■ No standard regimen is recommended for elderly patients with CLL, as

current regimens have evolved based on studies of patients < 65 years old.

■■ FCR (fludarabine, cyclophosphamide, rituximab) can be used in high-risk elderly patients, usually with reduced doses.

■■ Lenalidomide is an option in older patients with CLL, perhaps in combination with rituximab.

■■ Small-molecule inhibitors appear promising for elderly CLL patients. Experience thus far suggests that elderly patients do not do well on fludarabine vs chlorambucil (Leukeran), and that alemtuzumab does not improve survival, irrespective of age. Rituximabcontaining regimens improve outcomes over fludarabine alone, regardless of age. “I would argue that there is no standard regimen for elderly patients. Lenalidomide is an option, and FCR is an option for aggressive disease,” Dr. Wierda suggested.

ment. With this drug, we see early redistribution of leukemia cells, and efflux of leukemia cells results in reduction of lymph node size,” he said. “Because of this phenomenon, the criteria for response to this drug have been modified to include the lymph node response and not to consider a transient increase in leukemia count as disease progression. We have seen responses with ibrutinib in all high-risk categories, including advanced age and 17p deletion, and the

response improves over time. This drug is impressive, and there is much excitement about it. Refer patients to clinical trials,” he advised.

Newer Agents CAL-101 (now called GS1101) is another new oral small-molecule inhibitor that selectively acts on PI3K. The drug is active as monotherapy and in combination therapy for CLL.3 It is being studied as front-line therapy in combination with rituximab in previously untreated elderly patients with CLL. ABT-199, another oral small-molecule inhibitor, is selectively targeted to Bcl-2. It is being studied in phase I trials. In the first cohort of patients, the drug achieved rapid reduction of CLL burden, with normalization of lymphocyte count at 6 weeks in 79% of patients, as well as reduction in See Page 75 nodal size. The only toxicity to emerge thus far requiring dose reduction was tumor lysis syndrome.4 This trial is continuing to enroll patients. “ABT-199 is active in high-risk patients, including those with 17p deletions and those who are fludarabinerefractory,” Dr. Wierda noted.

■

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

References 1. Wierda W: Challenges in managing elderly patients with CLL. NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012. 2. O’Brien S, Furman R, Coutre S, et al: The Bruton’s tyrosine kinase inhibitor ibrutinib is highly active and tolerable in relapsed or refractory (R/R) and treatment naïve (TN) CLL patients: Updated results of a phase Ib/II study. European Hematology Association 2012. Abstract 542. Presented June 14-17, 2012. 3. Sharman J, de Vos S, Leonard JP, et al: A phase I study of the selective phosphatidylinositol 3-kinase delta (PI3K) inhibitor, CAL-101 (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed CLL. Blood 118(21):1787, Abstract 642, 2011. 4. Roberts A, Davids M, Mahadevan D, et al: Selective inhibition of BCL-2 is active against CLL: First clinical experience with the BH3-mimetic ABT-199. European Hematology Association 2012. Abstract 546. Presented June 14-17, 2012.

NOW

APPRO ED For Patients With Advanced HR+ BC AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

Important Safety Information

There have been reports of non-infectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR® (everolimus), some with fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared to patients <65 years of age. Oral ulceration is the most frequently occurring adverse event and occurred at an incidence ranging from 44% to 86% of AFINITOR-treated patients across the clinical trials experience. Most of these events were Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 4%-8% of patients. Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported; monitoring of laboratory tests is recommended. The use of live vaccines and close contact with those who have received live vaccines should be avoided. AFINITOR can cause fetal harm when administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Please see Brief Summary of Prescribing Information on adjacent pages. For more information, please visit www.AFINITOR.com.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

7/12

AFB-1039129

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] . Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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 be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

T:14”

B:14.25”

S:13”

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 AFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years. A prospective, open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34). AFINITOR has not been studied in patients with SEGA < 3 years of age. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITORtreated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-132 July 2012

The ASCO Post | NOVEMBER 1, 2012

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Journal Spotlight

Phase II Study Suggests Advantage of Irreversible Pan-HER Inhibition in Advanced NSCLC By Matthew Stenger

acomitinib is a new tyrosine kinase inhibitor that forms irreversible covalent bonds with the ATP domain of each of the three kinaseactive members of the HER family— EGFR/HER1, HER2, and HER4. Agents such as erlotinib (Tarceva) and gefitinib (Iressa), which are of proven benefit in advanced non–small cell lung cancer (NSCLC), are reversible tyrosine kinase inhibitors that selectively target EGFR/ HER1 through competitive binding at the tyrosine kinase domain. In precliniSee Page 75 cal studies, dacomitinib showed greater HER kinase inhibition and antitumor activity than these agents in sensitive and resistant cell lines and in NSCLC xenograft models. A randomized phase II trial recently reported by Ramalingam and colleagues in Journal of Clinical Oncology suggests that dacomitinib may have greater activity than erlotinib in advanced NSCLC.1 The trial is the first to directly compare an irreversible panHER tyrosine kinase inhibitor with a reversible EGFR-selective tyrosine kinase inhibitor.

Baseline Imbalances In the phase II study, 188 patients with advanced NSCLC who had progressed after one or two chemotherapy regimens for advanced disease and

that may have contributed to differences in study outcomes. A higher proportion of dacomitinib-treated patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 vs 0, 1 (20% vs 3%) and had received two prior chemotherapy regimens (40% vs 29%). Further, there were some imbalances in mutation distribution, notably a greater proportion of KRAS wild-type (any EGFR mutation status) tumors in the erlotinib group and a greater proportion of EGFR mutant tumors (against which EGFR inhibitors have greater activity) in the dacomitinib group. Overall, KRAS mutational status in the dacomitinib group was wild-type in 61%, mutant in 18%, and unknown in 21%, and that status in the erlotinib group was 68%, 15%, and 17%, respectively. EGFR mutational status in the dacomitinib group was wild-type in 62%, mutant in 20%, and unknown in 18%, and that in the erlotinib group was 69%, 12%, and 19%, respectively.

Progression-free Survival Improvements Overall, median progression-free survival—the primary outcome measure—was significantly prolonged in the dacomitinib group (2.86 vs 1.91 months), with a hazard ratio [HR] of 0.66 (95% confidence interval [CI] = 0.47–0.91, P �� = .012) based on a stratified log-rank test with EGFR mutation status, KRAS mutation status, and

Dacomitinib in Non–Small Cell Lung Cancer ■■ Dacomitinib improved progression-free survival in the overall population of patients with NSCLC, and in KRAS wild-type/EGFR any status and KRAS wild-type/EGFR wild-type subgroups.

■■ Findings raise questions of whether pan-HER inhibition may be of

particular benefit in patients with KRAS wild-type/EGFR any status tumors.

■■ Dacomitinib was associated with greater frequencies of tyrosine kinase

inhibitor–type adverse events, drug-related discontinuation of treatment, and dose reduction.

had received no prior EGFR-targeted therapies received dacomitinib at 45 mg (n = 94) or erlotinib at 150 mg (n = 94) once daily. Although treatment groups were well balanced for most baseline characteristics, there were some imbalances

ECOG performance status as stratification factors. The unadjusted hazard ratio in the total population was 0.66 (P = .009). The improvement in progressionfree survival with dacomitinib was observed across most clinical and molec-

Dacomitinib: Better in Whom? Better in What? By Tony Mok, MD Professor, Department of Clinical Oncology The Chinese University of Hong Kong

rug development is a highly competitive business. A new drug must be proven to be better than the standard one before it can be registered for public use. Starting with preclinical data, there should be evidence of lower 50% inhibitory concentrations in selective cell lines or a broader spectrum of molecular targeting. Then the early clinical studies must demonstrate more favorable pharmacokinetics or higher efficacy and possibly a better toxicity profile. The Tony Mok, MD ultimate evidence will likely be superiority over the standard treatment in a randomized phase III comparative study. But in the current era of molecular targeted therapy, we must also address the questions of “better in whom?” and “better in what?” Development of dacomitinib is a classic example of this quandary. The pan-HER inhibition and irreversible covalent bonds would make this drug a more potent EGFR inhibitor. Preclinical studies on multiple cell lines and xenograft models have helped to establish its potency, based on which Ramalingam et al led a randomized phase II study comparing dacomitinib with erlotinib (Tarceva) as second-line therapy in an unselected population. Median progression-free survival favored dacomitinib (2.86 vs 1.91 months) with a hazard ratio of 0.66. These results set the path for a phase III study. However, the questions remain—“better in whom and better in what?”

Interpreting the Data Interpretation of the overall findings in this unselected population is difficult because the incidence of EGFR mutation was not balanced between the two arms. Furthermore, one out of five patients had unknown EGFR mutation status. The standard formula used for sample size estimation was based on assumption of a homogeneous population. But when the study population is a heterogeneous mix of patients with and without EGFR mutation, the accuracy of such an estimate is doubtful, especially when the impact of an EGFR tyrosine kinase inhibitor is dramatically different between the two groups. Without an absolute certainty of equality in the incidence of EGFR mutation between the two study arms, any marginal difference must be interpreted with caution. The authors did find that the KRAS wild-type subgroup had a greater benefit from dacomitinib (median progression-free survival, 3.71 vs 1.91 months). However, the absence of KRAS mutation doesn’t imply the presence of EGFR mutation. The median progression-free survival of the KRAS wild-type/EGFR wild-type group was 2.2 months. Thus, it would take some imagination to state that the drug may significantly benefit patients without EGFR mutation.

Key Question The real question should be: “Is dacomitinib better than first-generation EGFR tyrosine kinase inhibitors in patients with activating EGFR mutations?” Another irreversible EGFR tyrosine kinase inhibitor, afatinib, is being compared with gefitinib (Iressa) in patients with EGFR mutations in the LUX-Lung 7 trial. The primary endpoint is progression-free survival. This is exactly what is required to confirm the efficacy of dacomitinib: It needs to be shown to be better in a biomarker-selected subgroup and better in duration of disease control.

■

Disclosure: Dr. Mok is a consultant and speaker for AstraZeneca, Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, Merck Serono, Taiho, BeiGene, and Eisai.

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Journal Spotlight

ular subgroups. In patients with KRAS wild-type/EGFR any status tumors, median progression-free survival durations were 3.71 months with dacomitinib and 1.91 months with erlotinib (HR = 0.55, 95% CI = 0.35–0.85, P = .006). In those with KRAS wild-type/ EGFR wild-type tumors, median progression-free survival durations were 2.21 months and 1.84 months, respectively (HR = 0.61, 95% CI = 0.37–0.99, P = .043). Progression-free survival hazard ratios for dacomitinib vs erlotinib in molecular subgroup comparisons were 0.99 (95% CI = 0.45–2.17) in the KRAS mutant subgroup, 0.70 (95% CI = 0.47–1.05) in the EGFR wild-type subgroup, and 0.46 (95% CI = 0.18–1.18) in the EGFR mutant subgroup. The objective response rate was higher with dacomitinib (17.0%, including one complete response, vs = .011), as were clinical ben5.3%, P �� efit rate (response plus stable disease ≥ 24 weeks, 29.8% vs 14.9%, P = .014) and median duration of response (16.56 months, range = 3.15–23.95+ months, vs 9.23 months, range = 5.69–16.58 months). An analysis of median overall survival (performed after 80% of patients had died) showed a nonsignificant increase with dacomitinib (9.53 vs 7.44 months, HR = 0.80, 95% CI = 0.56-

1.13, P = .205) on a stratified log-rank test with EGFR mutation status, KRAS mutation status, and ECOG performance status as stratification factors. The greater apparent activity of dacomitinib was accompanied by higher rates of adverse events expected with EGFR tyrosine kinase inhibitors (eg, diarrhea and skin effects), although most such adverse events were of grade 1 or 2. The most common adverse events of any grade with dacomitinib were diarrhea (73% vs 48% with erlotinib), acneiform dermatitis (65% vs 57%), and stomatitis (29% vs 11%). The most common grade 3 adverse events with dacomitinib were diarrhea (12% vs 4%) and acneiform dermatitis (11% vs 6%). One dacomitinib patient had four grade 4 adverse events, consisting of anemia, increased ALT, increased AST, and increased blood creatinine, which were considered to be drug-related. One erlotinib patient had a drug-related grade 4 adverse event (pneumonia). Adverse events requiring treatment withdrawal and dose reductions were more common in the dacomitinib group. Among 7 dacomitinibtreated patients (7.5%) discontinuing treatment due to adverse events, 5 had grade 1 to 3 dermatologic

toxicity (4 during the first month of treatment), 1 had grade 2 diarrhea, and 1 had grade 3 dehydration. Two erlotinib recipients (2.1%) discontinued treatment due to adverse events (grade 2 nausea and grade 2 malaise). Treatment-related dose reductions occurred in 40.9% of the dacomitinib group (1 reduction in 31.2%, 2 reductions in 7.5%, and 3 reductions in 2.2%) and 17% of the erlotinib group (1 reduction in all patients). As related by the investigators, although the progression-free survival improvement with dacomitinib in the total population may have been affected by between-group baseline imbalances, the superiority of dacomitinib is strongly suggested by the significance of the between-group difference on the stratified log-rank test coupled with the significant unadjusted hazard ratio for the overall population. Further, dacomitinib’s relative benefit is indicated by the fact that subgroup results were consistently distributed around the overall hazard ratio. Additional benefit of dacomitinib was observed in the subset analysis of patients with KRAS wild-type/EGFR wild-type tumors, suggesting that the benefit of dacomitinib was not solely driven by the disproportionate number of patients with mutant EGFR in the dacomitinib group.

Bladder Cancer

Wallace and I reported did not show a survival benefit. We figured that the early survival data from our phase II studies might simply have reflected the impact of CT scanning with associated stage migration. Soon thereafter, multicenter working parties conceived two important randomized trials, testing the survival benefit of either neoad-

trial showed only a 5% hike in survival, which was less than the desired 10% in the initial design. As a result, we recorded it as a “negative” study in the interim report.1 However, it was clear that the MVAC trial showed an increment in median survival of 3 years and an absolute survival increment of 7%.2 The most recent (final) report of the CMV

continued from page 1

vival is the key endpoint, and (d)�� bleomycin confers a survival benefit when added to vinblastine/cisplatin for patients with advanced testis cancer, among others. I have even sunk to the depths of meta-analysis, a poor man’s randomization surrogate, to show the modest benefits of maintaining combined androgen blockade compared to monotherapy in advanced prostate cancer. Thus, my portfolio of approaches used in clinical practice is heavily dominated by evidence-based strategies, at least for first-line therapy. This is why something that I see increasingly in the management of invasive bladder cancer puzzles me.

Neoadjuvant Data In the early 1980s, Dr. Mark Soloway and I, working independently, demonstrated anticancer efficacy of neoadjuvant single-agent cisplatin for patients with invasive bladder cancer, but a randomized trial that Dr. David

More Adverse Events

Until someone shows (for the first time) that there really is an overall survival benefit from the use of adjuvant chemotherapy after cystectomy [for invasive bladder cancer], our only proven approach is the use of neoadjuvant treatment with MVAC or CMV. — Derek Raghavan, MD, PhD

juvant MVAC before cystectomy or CMV (cisplatin, methotrexate, vinblastine) before either cystectomy or radiotherapy for invasive, clinically nonmetastatic bladder cancer. Both studies showed a survival benefit, although the first report of the CMV

trial confirmed the impact of neoadjuvant combination chemotherapy with a reduction in hazard ratio of 16% and an overall survival benefit of 7%.3 As if that wasn’t enough, our meta-analysis of all of the published data reached the same conclusion.4

As stated by the authors, “[The] results raise the possibility that patients with KRAS wild-type/EGFR any status NSCLC may particularly benefit from dacomitinib…. Given the degree of benefit reported here for patients with KRAS wild-type/EGFR any status or KRAS wild-type/EGFR wild-type tumors, and the uncertainty surrounding KRAS as a predictor of response in NSCLC, there is clearly a need for prospective studies of the role of KRAS in tumor response to panHER inhibition.” The phase III ARCHER 1009 trial is underway to compare dacomitinib and erlotinib as second- or third-line therapy in advanced NSCLC. The trial includes the coprimary endpoints of progression-free survival in all patients and in patients with KRAS wild-type/ EGFR any status tumors to permit evaluation of dacomitinib in an unselected population and to assess the relationship between KRAS molecular status and treatment outcome.

■

Reference 1. Ramalingam SS, Blackhall F, Krzakowski M, et al: Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 30:3337-3344, 2012.

Despite this wealth of level�� 1�� evidence to confirm the survival benefits of neoadjuvant CMV or MVAC chemotherapy prior to surgery or radiotherapy, four surveys over the past 10 years have shown that less than 25% of patients are treated according to this strategy.5-8 One could reasonably discount the first two reports as they reflected time periods when the mature randomized data had not yet been published, but the two more recent studies show little improvement.

Puzzling Practice So why is potentially lifesaving treatment withheld? Most of my colleagues in the world of urology seem pretty up to date with the literature. Perhaps they think they can avoid chemotherapy by doing a radical cystectomy first and applying adjuvant chemotherapy for particularly tough tumors. That really can’t be the explanation because no well-powered, randomized trial has ever shown an overall survival benefit for that stratcontinued on page 18

In Advanced Renal Cell Carcinoma (RCC)...

INDICATION VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY 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,” 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.

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). 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: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). 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 Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic 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 thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic events were reported

in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) 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. 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 one week), and frequently thereafter. Treat increased blood pressure promptly with standard antihypertensive 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 7% (19/290) of patients treated with VOTRIENT in the

Move Forward With VOTRIENT In a Phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC of clear cell or predominant clear cell histology1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options

Once-daily oral dosing1

VOTRIENT: Adverse events profile included1:

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (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 • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In RCC, initial dose reduction should be 400 mg; additional dose decrease or increase should be in 200-mg steps based on individual tolerability • Dose modifications, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced

randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, and fetal harm • Most common adverse events (>20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting • See below and accompanying Brief Summary for additional Important Safety Information, including warnings and precautions

• Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • 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. Avoid grapefruit and grapefruit juice.

• 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.

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.

• 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.

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.

• 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. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages. References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed June 1, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

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. • Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

VOTRIENT.com

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Bladder Cancer continued from page 15

egy. The closest to a positive result came from the Stanford group, which showed an improved disease-free interval, but the Data and Safety Monitoring Committee closed the study at that point, and no overall survival benefit was shown.

The European Organisation for Research and Treatment of Cancer (EORTC) attempted to answer this important question, but the study closed prematurely because of lack of accrual. Our team at the University of Southern California, under the leadership of Dr. Don Skinner and Dr. Richard Cote, and in collabora-

tion with the Southwest Oncology Group (SWOG), assessed the utility of p53 mutation as a predictor of outcome in a trial that compared adjuvant MVAC to observation after radical cystectomy for patients with p53-mutant urothelial cancer.9 While the study had some problems of execution, and fewer events than

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 renal cell carcinoma (RCC). 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 RCC, the initial dose reduction should be 400 mg, and additional dose 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. 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. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. 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 RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. 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% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. 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 (7.3)]. 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 RCC trials

anticipated in design, it was quite clear that there was no difference in outcome for p53-positive and p53-negative cases. More importantly, there was no difference in survival between the two treatment groups—thus, nothing to support the routine use of adjuvant MVAC in this contemporary study.

of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy studies. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo 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 overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. 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: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. 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 Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic 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 thrombotic 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 including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 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. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: 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)]. 5.10 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. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis

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Proven Approach Patients with bladder cancer are generally very much inclined to take the advice of their clinicians and, as such, are rather different from some other groups of patients with urologic malignancy. Urologists, the gatekeepers of bladder cancer, have a huge influence on their patients with this disease,

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with respect to both the choice of primary therapy and the role of adjunctive treatments, and even regarding therapies at the time of relapse. Until someone shows (for the first time) that there really is an overall survival benefit from the use of adjuvant chemotherapy after cystectomy, our only proven approach

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)]. 5.13 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. 5.14 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. 5.15 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 wellcontrolled 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)].

Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4

% % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). 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.

remember that in an underpowered study comparing two treatments, a nonsignificant P value may simply reflect the fact that the sample size is too small to show the existence of a true difference in survival; it doesn’t necessarily mean that the outcomes are the same. continued on page 20

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290)

Parameters

Placebo (N=145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose 41 <1 0 33 1 0 increased Total bilirubin 36 3 <1 10 1 <1 increased Phosphorus 34 4 0 11 0 0 decreased Sodium 31 4 1 24 4 0 decreased Magnesium 26 <1 1 14 0 0 decreased Glucose 17 0 <1 3 0 0 decreased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. 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. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 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. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 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. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. 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. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies 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]. 7.3 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.

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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 thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

is the use of neoadjuvant treatment with MVAC or CMV. While gemcitabine/cisplatin has been shown to be approximately equivalent to MVAC in patients with metastatic disease, that similarity has never been confirmed in a well-powered randomized trial for the neo-adjuvant or adjuvant setting. One must

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Bladder Cancer continued from page 19

So now what? I guess I will go and write a paper on this topic for a urology journal. Let’s hope, for our patients’ sake, that somebody reads it.

■

Disclosure: Dr. Raghavan is on the President’s Advisory Board of Sanofi Aventis and is an occasional consultant for Gerson Lehrman.

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References 1. Hall R, Sylvester R, Raghavan D, et al, for International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. Lancet 354:533-540, 1999. 2. Grossman HB, Natale RB, Tangen

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 least once every 4 weeks for the first 4 months of treatment or 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 GlaxoSmithKline.

results of the BA06 30894 Trial. J Clin Oncol 29:2171-2177, 2011. 4. Advanced Bladder Cancer Metaanalysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 361:1927-1934, 2003. 5. David KA, Milowsky MI, Ritchey J, et al: Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: A report from the National Cancer Data Base. J Urol 178:451454, 2007. 6. Miles BJW, Fairey AS, Eliasziw M, et al: Referral and treatment rates of neoadjuvant chemotherapy in muscleinvasive bladder cancer before and after publication of a clinical practice guideline. Can Urol Assoc J 4:263-267, 2010. 7. Porter MP, Kerrigan MC, Donato BM, et al: Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol 29:252-258, 2011. 8. Raj GV, Karavadia S, Schlomer B, et al: Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer. Cancer 117:276-282, 2011. 9. Stadler W, Lerner SP, Groshen S, et al: A phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on P53 status. J Clin Oncol 29:3443-3449, 2011.

The ASCO Post

B:15” T:13” S:12”

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)]. 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 preand post-implantation 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 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 with rats. Body weight loss and morbidity were observed at these doses. 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 ≥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. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. 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 studies 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 subjects 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.

CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003. 3. Griffiths G, Hall R, Sylvester R, et al, for International Collaboration of Trialists: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term

@ASCOPost

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2012 Breast Cancer Symposium Will mTOR Inhibitors Change the Treatment of Endocrine-sensitive HER2-negative Breast Cancer? By Caroline Helwick

or the treatment of endocrinesensitive metastatic breast cancer, the combination of an mTOR inhibitor and an endocrine agent represents a promising new option. At the 2012 Breast Cancer Symposium, the 18-month update of BOLERO-2, which tested therapy with everolimus (Afinitor) plus exemestane, confirmed a more than doubling in progressionfree survival, with a 62% reduction in risk.1 Exploratory analyses also suggested that everolimus has positive effects on bone markers and prevents disease progression in the bone.2 With FDA approval of this combination for patients whose disease progresses on letrozole or anastrozole, the regimen is gaining traction in the clinic. The optimal use of everolimus, however, is an evolving scenario, and the next generation of trials seeks to answer several important questions. “The everolimus approval is likely to be only the beginning in a new phase of outcome improvements for estrogen receptor–positive, HER2negative disease based on PI3-kinase pathway inhibition in combination with endocrine agents,” predicted Matthew J. Ellis, MB, PhD, of Washington University, St. Louis.

Why the Excitement? In a lecture about mTOR inhibition, William Gradishar, MD, of Northwestern University Feinberg School of Medicine, Chicago, said, “We know that mTOR is a critical node in an important signaling pathway in most cancers.”

studies, the combination of everolimus plus letrozole suppressed tumor cell proliferation more potently than letrozole alone. Early hints of clinical activity culminated in the promising results of BOLERO-2, in which progression-free survival was 7.8 months with everolimus/exemestane vs 3.2 months with exemestane alone in the 18-month update; by central review, the difference was 11.0 months vs 4.1 months, respectively (P < .0001 for both).

We know that mTOR is a critical node in an important signaling pathway in most cancers. — William Gradishar, MD

Long-term Estrogen Deprivation “The interesting thing is that the same was not seen with temsirolimus (Torisel) in a large randomized trial,” he added. The phase III trial included 1,112 patients with metastatic breast cancer who had not received prior hormonal therapy for metastasis.3 Progression-free survival was approximately 9 months in each arm, and the study was closed due to futility. “It may be that the absence of an activated pathway in the largely endocrine-untreated population may be

mTOR Inhibitors in Metastatic Breast Cancer ■■ The promising results of BOLERO-2 have triggered great interest in

determining how best to pair mTOR inhibitors with endocrine agents.

■■ Everolimus (and possibly other mTOR inhibitors) may overcome endocrine resistance in hormone-sensitive patients who become refractory to endocrine treatments.

■■ The best partner for everolimus is unknown; while exemestane plus

everolimus doubled progression-free survival in BOLERO, tamoxifen plus everolimus improved overall survival in the smaller TAMRAD trial.

In breast cancer, the currently available mTOR inhibitors appear to enhance endocrine responsiveness where endocrine resistance has taken hold. In both preclinical and phase II clinical

finding that PI3K/Akt/mTOR intracellular signaling can be activated during long-term estrogen deprivation.4 “This is a situation that may be replicated in a treated estrogen receptor–positive breast cancer that develops acquired resistance to long-term aromatase inhibitor treatment,” he suggested. “This supports the idea that priming the survival pathway may be important in order to derive an effect from an mTOR inhibitor.” In other words, mTOR inhibitors

responsible for the lack of benefit with the combination,” Dr. Gradishar said. This, he added, is in keeping with a preclinical discovery made a decade ago in Dr. Mitch Dowsett’s laboratory: the

may work best in combination with an endocrine agent among patients who develop resistance to endocrine agents. This was implied in the B OLERO-2 trial, as well as in a smaller phase II French study, TAMRAD, which demonstrated greater clinical benefit with everolimus plus tamoxifen (61%) vs tamoxifen alone (42%).5 An exploratory analysis demonstrated benefits in terms of time to progression and overall survival. The effect in TAMRAD was greater among patients with secondary hormone resistance, in whom progression-free survival was 17.4 months with the combination vs 5.0 months with tamoxifen alone (HR = 0.38), than among those with primary hormone resistance (HR = 0.74). While this suggests patients with hormone-sensitive disease may derive greater benefit, BOLERO-2 actually showed no difference between this subset (86% of the population) and those with primary resistance (16%), said Hope S. Rugo, MD, of the University of California, San Francisco. Dr. Rugo argued that the TAMRAD subsets were likely too small to be reliable; therefore, one cannot conclude that patients with primary endocrine resistance do not benefit.

Hope S. Rugo, MD

Best Partner for Everolimus? Considering the negative findings for temsirolimus plus exemestane, can one conclude that everolimus is a superior mTOR inhbitor? Probably not, according to Dr. Gradishar. The two mTOR inhibitors do have pharmacokinetic differences, but the discrepancy in outcome is more likely related to the difference in the trial populations. While temsirolimus was given to endocrine therapy-naive patients, everolimus was given to patients with prior exposure to endocrine agents in the metastatic setting. This likely activates the survival pathways and creates a setting where mTOR inhibition is apt to have an impact, the researchers said. It is also possible that the disappointing results with temsirolimus were due to an inadequate dose or schedule, Dr. Rugo added, or to the possible dilution of benefit in the 55% of patients without previous exposure to adjuvant hormone therapy (and presumably reduced activation of resistance pathways). According to Dr. Ellis, even better outcomes might be achieved if everolimus were not paired with exemestane, but with a stronger agent. “Exemestane is a very weak endocrine agent in the setting of nonsteroid aromatase inhibiSee Page 75 tor resistance,” Dr. Ellis pointed out. “Tamoxifen is actually more active in this setting.” Notably, an exploratory analysis of TAMRAD showed an overall survival benefit with everolimus plus tamoxifen. In the most recent analysis, median overall survival was 32.9 months with tamoxifen alone but had not yet continued on page 22

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2012 Breast Cancer Symposium mTOR Inhibtors continued from page 21

been reached with the combination, representing a 55% reduction in risk (P = .007), he emphasized. “Exemestane plus tamoxifen achieved a survival effect in a relatively small study,” Dr. Ellis noted. “Perhaps we would have seen an even greater effect in BOLERO-2 if a more effective endocrine agent had been chosen. Everolimus should probably be tested in combination with potentially more active endocrine agents, such as tamoxifen, high-dose toremifene (Fareston), fulvestrant (Faslodex), or the fulvestrant/aromatase inhibitor combination, with exemestane/everolimus as the control arm.”

Who Should Receive Everolimus? Meanwhile, BOLERO-2 is having an impact on clinical practice. “With the new data, and the recently updated guidelines, we have a variety of choices for postmenopausal patients, and everolimus plus exemestane is a reasonable consideration for wom-

en who fit the eligibility profile of BOLERO-2,” Dr. Gradishar said. “But while there is a role for this combination, we do not have sufficient data to say that we should be using this in every endocrine-responsive patient or in the first-line setting.” Dr. Rugo added that the expected benefit of this regimen should be weighed against the potential risks in an individual patient. “If well tolerated, a more than doubling of progression-free survival certainly seems to be worthwhile.” She urged caution in patients with primary hormone resistance, but said there are no convincing data that these patients should be excluded.6

Future Trials In the first-line setting, the phase II BOLERO-4 trial will evaluate the addition of everolimus to letrozole. e who have had disease progression on an aromatase inhibitor, BOLERO-6 will compare everolimus with and without exemestane vs capecitabine (Xeloda), while the phase II PrECOG study will evaluate fulvestrant plus everolimus. The

Southwest Oncology Group (SWOG) 2107 trial will move everolimus into the adjuvant setting, evaluating 5 years of endocrine therapy with and without everolimus in high-risk patients. Clinical trials of eight dual mTOR inhibitors (primarily mTOR/PI3K inhibitors) are underway, and six panmTOR inhibitors are in development. “We are awaiting trials that will inform us not only about efficacy with these combinations but also toxicity,” Dr. Gradishar said.

■

Disclosure: Dr. Ellis has served in a consulting or advisory role for GlaxoSmithKline, Novartis, and Pfizer, and has received honoraria or research funding from AstraZeneca, Merck, and Novartis. Dr. Gradishar has served in a consulting or advisory role for Novartis. Dr. Rugo receives research funding through the University of California from Novartis, Pfizer, and Merck.

References 1. Arena FP, Noguchi S. Pritchard KI, et al: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2012 Breast Cancer Symposium. Abstract 99. Presented September 13, 2012. 2. Hart LL, Baselga J, Rugo HS, et al:

Effects of everolimus on disease progression in bone and bone markers in patients with bone metastases. 2012 Breast Cancer Symposium. Abstract 102. Presented September 14, 2012. 3. Chow LWC, Sun Y, Jassem J, et al: Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 100(suppl 1):Abstract 6091, 2006. 4. Martin LA, Farmer I, Johnston SR, et al: Enhanced estrogen receptor alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 278:3045830468, 2003. 5. Bachelot T, Bourgier C, Cropet C, et al: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone-receptor-positive, HER2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30:2718-2724, 2012. 6. Rugo HS, Keck S: Reversing hormone resistance: Have we found the golden key? J Clin Oncol 30:2707-2709, 2012.

Dealing with the Toxicity of Everolimus/Exemestane By Caroline Helwick

hile packing a punch in terms of clinical benefit, everolimus plus exemestane can also be a tough pill to swallow for many patients. The management of the potential toxicities associated with this new regimen was addressed at the 2012 Breast Cancer Symposium by Matthew J. Ellis, MB, PhD, of Washington University in St. Louis. In a poster presentation at the meeting, BOLERO-2 investigators detailed the side-effect profile of the regimen.1 Grade 3/4 adverse events Matthew J. Ellis, MB, PhD (irrespective of relationship to study drug) were observed in 53% of patients receiving the combination vs 28% of the control arm. The major complaints were stomatitis (59%, all grades; 8%, grade 3), fatigue (37%, all grades; 4%, grade 3), diarrhea (34%, all grades; 2%, grade 3), and rash (39%, all grades; 1%, grade 3). “Personally, I have been using everolimus for a while, and I have seen every side effect listed on the poster. Many of them have the potential to significantly impact quality of life,” Dr. Ellis noted. “To use everolimus, you must follow your patients weekly, at least for the first 4 to 6 weeks. You must watch for and actively manage side effects in order to keep patients on the drug and realize the benefits of this regimen.”

Specific Reactions Stomatitis, which is usually of low grade, typically arises less than 1 month after treatment initiation. A prophylactic treatment approach and early recognition is important to minimize its impact. Patient education and precautionary measures may reduce the incidence. Patients should be told to report their first signs of mouth discomfort. “Clearly, when the patient’s symptoms are moderate to severe, you need to temporarily dose-reduce,” he said. “This side effect often requires considerable

holding of the dose and the use of a steroid mouth wash. If from the outset you encourage good dental hygiene and mouth rinses (avoiding those that contain peroxide or alcohol), and provide topical corticosteroids, you can reasonably control most patients.” Noninfectious pneumonitis occurs in 16% of patients (all grades), characterized by a nonmalignant infiltration of the lungs that may be immunologically mediated. “I have noticed that quite a lot of patients have subclinical ‘fluffy’ infiltrates at 3 to 6 months. This can look alarming, but patients may be reasonably asymptomatic,” he said. For radiographic findings only, no dose adjustments are required. In the presence of mild symptoms, infection should be ruled out; patients can be treated with corticosteroids and dose interruptions if necessary. “For patients with any suggestion of shortness of breath, I measure oxygenation with pulse oximetry after they have walked up and down the corridor for 5 minutes,” he added. Serious pneumonitis occurs only in 3% of patients but can be life-threatening, he cautioned. Dr. Ellis noted that hyperglycemia and rash, while considered part of the toxicity profile, are not particularly a problem, in his experience. He added that older patients can tolerate treatment almost as well as younger patients, according to an analysis by age.2 “It is reasonable to use the drug in older patients, but with caution,” he said.

■

Disclosure: Dr. Ellis has served in a consulting or advisory role for GlaxoSmithKline, Novartis, and Pfizer, and has received honoraria or research funding from AstraZeneca, Merck, and Novartis.

References 1. Perez AT: Safety of everolimus in estrogen receptor–positive advanced breast cancer. 2010 Breast Cancer Symposium. Abstract 103. Presented September 14, 2012. 2. Rugo HS, Burris HA, Gnant M, et al: Safety of everolimus for women over age 65 with advanced breast cancer: 12.5-month follow-up of BOLERO-2. 2012 Breast Cancer Symposium. Abstract 104. Presented September 14, 2012.

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Lab Notes

Ongoing Molecular Research in the Science of Oncology BIOMARKERS Noninvasive Measurement of Interstitial Fluid Pressure as Marker of Tumor Aggressiveness Increased interstitial fluid pressure in tumors can cause metastatic dissemination and treatment resistance. Study of interstitial fluid pressure has been challenging due to a lack of noninvasive imaging strategies. In a recent study, Hompland and colleagues from the Institute of Cancer Research at the Norwegian Radium Hospital in Oslo showed that interstitial fluid pressure can be measured by a noninvasive strategy using gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) as a contrast agent for dynamic contrast-enhanced MRI (DCE-MRI). In mouse xenograft models of several types of human cancers, velocity of outward flow of a rim of Gd-DTPA high signal intensity in the tumor periphery was significantly correlated with interstitial fluid pressure. The primary tumors of mice with metastasis had higher DCE-MRI Gd-DTPA– measured fluid flow velocity and interstitial fluid pressure than the primary tumors of mice without metastasis. These findings were confirmed in studies in patients with cervical cancer: DCE-MRI fluid flow velocity was significantly higher (P < .00001) in those with pelvic lymph node metastases compared with those without lymph node involvement. The authors noted, “Together, these findings establish that GdDTPA-based DCE-MRI can noninvasively visualize tumor [interstitial fluid pressure], and they reveal the potential for v0 [fluid flow velocity] determined by this method to serve as a novel general biomarker of tumor aggressiveness.” Hompland T, et al: Cancer Res 72:48994908, 2012.

GENE PROFILING Whole-blood RNA Expression Profiles as Prognostic Models for Castration-resistant Prostate Cancer Survival among patients with castration-resistant prostate cancer is highly variable, and there is a scarcity

of prognostic markers that could be used to stratify patients in clinical trials, improve treatment, and accelerate drug development. Two recent studies reported in Lancet Oncology have shown that whole-blood RNA pro-

filing can sort patients with prostate cancer into distinct risk groups. Bleed:7.875” Six-gene Signature

Trim:7.625” In one study, Ross and colleagues Live:7” from Dana-Farber Cancer Institute,

Harvard Medical School, and GeneNews in Boston, Statistical Innovations in Belmont, Massachusetts, and Mount Sinai School of Medicine, Memorial-Sloan Kettering Cancer continued on page 24

NOW AVAILABLE ZALTRAP®, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatincontaining regimen. IMPORTANT SAFETY INFORMATION FOR ZALTRAP WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation. Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. WARNINGS AND PRECAUTIONS • Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events — Monitor patients for signs and symptoms of bleeding — Do not initiate ZALTRAP in patients with severe hemorrhage — Discontinue ZALTRAP in patients who develop severe hemorrhage Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Visit www.ZALTRAP.com to learn more. For more information about ZALTRAP, call 1-855-ZALTRAP (1-855-925-8727).

FPO

The ASCO Post | NOVEMBER 1, 2012

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Lab Notes

Ongoing Molecular Research continued from page 23

Center (MSKCC), and Weill Cornell Medical College in New York, investigated a whole-blood RNA transcript-based model as a prognostic biomarker in castration-resistant prostate cancer. Peripheral blood was prospectively collected from 62 men

with castration-resistant prostate cancer on various treatment regimens at the Dana-Farber Cancer Institute (August 2006–June 2008, training set) and from 140 patients with castration-resistant prostate cancer at MSKCC (August 2006–February 2009, validation set). Both of the cohorts were hetero-

geneous with respect to patient characteristics and treatment exposures. A panel of 168 inflammation-related and prostate cancer–related genes was assessed with optimized quantitative reverse transcriptase polymerase Bleed:7.875” chain reaction testing to determine Trim:7.625” potential associations with survival. Live:7” A six-gene model (ABL2, SE-

MA4D, ITGAL, C1QA, TIMP1, and CDKN1A) distinguished a lowrisk group of patients with median survival of more than 34.9 months (median survival not reached) and a high-risk group with a median survival of 7.8 months (P < .0001). The prognostic utility of the model was validated in the independent cohort,

NOW AVAILABLE

IMPORTANT SAFETY INFORMATION FOR ZALTRAP® (cont’d) • GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP — Monitor patients for signs and symptoms of GI perforation — Discontinue ZALTRAP in patients who experience GI perforation • Discontinue ZALTRAP in patients with compromised wound healing — Suspend ZALTRAP for at least 4 weeks prior to elective surgery — Do not initiate/resume ZALTRAP until at least 4 weeks after surgery and surgical wound is fully healed • Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Discontinue ZALTRAP therapy in patients who develop ﬁstula • An increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP — Monitor blood pressure every two weeks or more frequently and treat with appropriate anti-hypertensive therapy during treatment with ZALTRAP — Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles — Discontinue ZALTRAP in patients with hypertensive crisis • Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. Discontinue ZALTRAP in patients who experience an ATE • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP — Suspend ZALTRAP when proteinuria ×2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg — Discontinue ZALTRAP if nephrotic syndrome or TMA develops • A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP — Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ×1.5 x 109/L • Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI — The incidence of diarrhea is increased in patients ×65 years of age. Monitor closely • Discontinue ZALTRAP in patients who develop reversible posterior leukoencephalopathy syndrome

ADVERSE REACTIONS • The most common adverse reactions (all grades, ×20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache • The most common Grade 3-4 adverse reactions (×5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia • Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection • In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNING. In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 sanoﬁ-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

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although the difference in survival was less dramatic than in the training cohort (9.2 vs 18.5 months [hazard ratio = 2.3, 95% confidence interval = 1.39–3.70]), potentially reflecting model overfitting. In the validation cohort, the model had greater prognostic power than a five-variable clinicopathologic model (P = .0067).

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion

Nine-gene Signature In another study, Olmos and colleagues from Royal Marsden NHS Foundation Trust and Institute of Cancer Research in Sutton and London, Spanish National Cancer Bleed:7.875” Research Centre in Madrid, Sidney Trim:7.625” Kimmel Center for Prostate and UroLive:7” logic Cancers, MSKCC, and Weill

Rx Only

Brief Summary of Prescribing Information WARNING:

HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

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Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/ hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)]. 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)]. 5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information]. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen and in none of the patients treated with placebo/ FOLFIRI regimen. Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)]. 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)]. 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)]. 5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/ FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)]. 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC,

In a test set cohort consisting of 64 patients with metastatic castrationresistant disease and 30 patients on watchful waiting from Royal Marsden Hospital NHS Foundation Trust and Beatson West of Scotland Cancer Centre, profiling sorted patients into four molecular subgroups, with

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1 INDICATIONS AND USAGE ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity. 2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)]. • For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)]. For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information. 2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag. 2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus.

Cornell College of Medicine in New York, Beatson West of Scotland Cancer Centre and University of Glasgow in Glasgow, and Johns Hopkins University in Baltimore, used wholeblood mRNA expression arrays to identify patients with metastatic castration-resistant prostate cancer with poorer outcome.

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Ongoing Molecular Research continued from page 25

one of these groups containing only patients with metastatic castrationresistant disease. Patients with castration-resistant prostate cancer in this subgroup had significantly poorer overall survival compared with patients with castration-resistant dis-

ease in other subgroups (10.7 vs 25.6 months, P < .0001). A nine-gene signature (TERF2IP, TMCC2, GABARAPL2, SNCA, RIOK3, TFDP1, SLC4A1, HMBS, and STOM) classified patients into this subgroup with a very low percentage of misclassification (1.2%). In the validation set cohort consist-

ing of 70 patents with progressive metastatic castration-resistant disease from MSKCC, the nine-gene signature was significantly associated with worse overall survival (9.2 vs 21.6 months, P = .001). The signature was Bleed:7.875” an independent prognostic factor on Trim:7.625” multivariable analysis in both the test Live:7” and validation cohorts.

proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Obtain a 24-hour urine collection in patients with a UPCR greater than 1. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)]. 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/ FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Conﬁrm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)] 6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reﬂect the rates actually observed in clinical practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1). The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

Expert Commentary These findings with two distinct gene signatures suggest that wholeblood gene profiling can identify higher- and lower-risk patients with castration-resistant prostate cancer. As stated by Dr. Karina Sørensen in an editorial accompanying the two studies, “The biological relevance of

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modiﬁcation in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1. Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI ZALTRAP/FOLFIRI (N=605) (N=611) Primary System Organ Class All grades Grades All grades Grades Preferred Term (%) 3–4 3–4 Infections and infestations Urinary Tract Infection 6% 0.8% 9% 0.8% Blood and lymphatic system disorders Leukopenia 72% 12% 78% 16% Neutropenia 57% 30% 67% 37% Thrombocytopenia 35% 2% 48% 3% Metabolism and nutrition disorders Decreased Appetite 24% 2% 32% 3% Dehydration 3% 1% 9% 4% Nervous system disorders Headache 9% 0.3% 22% 2% Vascular disorders Hypertension 11% 1.5% 41% 19% Respiratory, thoracic and mediastinal disorders Epistaxis 7% 0 28% 0.2% Dysphonia 3% 0 25% 0.5% Dyspnea 9% 0.8% 12% 0.8% Oropharyngeal Pain 3% 0 8% 0.2% Rhinorrhea 2% 0 6% 0 Gastrointestinal disorders Diarrhea 57% 8% 69% 19% Stomatitis 33% 5% 50% 13% Abdominal Pain 24% 2% 27% 4% Abdominal Pain Upper 8% 1% 11% 1% Hemorrhoids 2% 0 6% 0 Rectal Hemorrhage 2% 0.5% 5% 0.7% Proctalgia 2% 0.3% 5% 0.3% Skin and subcutaneous tissue disorders Palmar-Plantar 4% 0.5% 11% 3% Erythrodysesthesia Syndrome Skin Hyperpigmentation 3% 0 8% 0 Renal and urinary disorders Proteinuria* 41% 1% 62% 8% Serum creatinine increased 19% 0.5% 23% 0 General disorders and administration site conditions Fatigue 39% 8% 48% 13% Asthenia 13% 3% 18% 5% Investigations AST increased 54% 2% 62% 3% ALT increased 39% 2% 50% 3% Weight decreased 14% 0.8% 32% 3% Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients

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these prognostic signatures, which are the first of their kind, is largely unknown. Whole-blood expression profiles presumably reflect changes in peripheral blood mononuclear cells, because [circulating tumor cells] are extremely rare. The [nine-gene] signature correlated with increased immature erythroid cells and decreased

lymphoid immune response, while the six-gene signature associated with impaired immunity of the myeloid lineage. The signatures represent molecular snapshots of distinct host immune functions, relevant for patient Bleed:7.875” survival. However, further investigaTrim:7.625” tion into the underlying biological mechanismsLive:7” is needed … [and] fu-

Ross RW, et al: Lancet Oncol. October 8, 2012 (early release online). Olmos D, et al: Lancet Oncol. October 8, 2012 (early release online). Sørensen KD: Lancet Oncol. October 8, 2012 (early release online).

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. 10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-AUG12

Revised: August 2012

Genome-wide Analysis Reveals Molecular Pathway Aberrations in Uterine Serous Cancer The molecular pathogenesis of uterine serous carcinoma, the most aggressive form of uterine cancer, remains largely undefined. Kuhn and colleagues from Johns Hopkins Medical Institutions recently identified prominent genetic alterations in uterine serous carcinoma using whole-exome sequencing. Somatic mutations identified by whole-exome sequencing in 10 uterine serous carcinomas and normal blood or tissue sample were verified by Sanger sequencing, with the most frequent alterations being validated See Page 75 in 66 additional uterine serous carcinomas and 9 serous endometrial intraepithelial carcinomas isolated by laser capture microdissection. Gene copy number was also characterized using single-nucleotide polymorphism (SNP) arrays in 23 uterine serous carcinomas, including 10 that were assessed by whole-exome sequencing.

Specific Mutations

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Frequent somatic mutations found among the 76 uterine serous carcinomas included those in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%). All nine serous carcinomas with an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status. DNA copy number analysis showed frequent genomic amplification of the CCNE1 locus (which encodes cyclin E, a known substrate of FBXW7) and deletion of the FBXW7 locus. Of 23 uterine serous carcinomas analyzed by SNP array, 7 tumors with FBXW7 mutations (4 with point mutations and 3 with hemizygous deletions) did not have CCNE1 amplification and 13 had either a molecular alteration in FBXW7 or CCNE1 amplification; nearly half of these carcinomas (48%) had PIK3CA mutation or PIK3CA amplification. As concluded by the investigators, “Molecular genetic aberrations involving the p53, cyclin E–FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.”

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treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose. 8.3 Nursing Mothers It is not known whether ZALTRAP 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 ZALTRAP, 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 effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age. 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment. 8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information].

ture studies should clarify if any of the 15 signature genes are functionally relevant, or are surrogate markers for other processes.”

■

Kuhn E, et al: J Natl Cancer Inst 104:15031513, 2012 Lab Notes is compiled and written by Matthew Stenger.

The ASCO Post | NOVEMBER 1, 2012

PAGE 28

35th ESMO Congress Thoracic Oncology

Role of Crizotinib in Previously Treated ALK-positive Advanced NSCLC By Alice Goodman

n yet another success story for personalized medicine, a targeted therapy extended survival in patients whose cancers expressed the target. Crizotinib (Xalkori), the first-in-class ALK inhibitor, extended progression-free survival and improved response rates compared with single-agent chemotherapy in patients with advanced, previously treated, ALK-positive, non–small cell lung cancer (NSCLC). Compared with chemotherapy, patients in the crizotinib arm had significantly greater improvements in lung cancer symptoms and quality of life as well. These findings of the phase III PROFILE 1007 trial were reported at the Presidential Symposium during the 2012 ESMO Congress in Vienna.1

Alice Shaw, MD

Rearrangements or translocations in the ALK gene occur in about 5 % of lung cancers, which translates to about 50,000 cases per year, explained lead author Alice Shaw, MD, Massachusetts General Hospital, Boston. Clinical features associated with ALK abnormalities include younger age (average, ~50 years), no smoking history, and adenocarcinoma histology. “These results establish crizotinib as the standard of care for patients with advanced previously treated ALK-positive NSCLC,” Dr. Shaw told listeners at an ESMO press conference.

Head-to-head Study PROFILE 1007 is the first head-tohead study comparing crizotinib with standard chemotherapy in NSCLC. The global study, conducted at 105 sites in 21 countries, randomly assigned

347 patients with ALK-positive, stage IIIB or IV NSCLC to crizotinib at 250 mg twice daily, pemetrexed (Alimta) at 500 mg/m2, or docetaxel at 75 mg/ m2 on a 21-day cycle. All patients had received one prior chemotherapy. The primary endpoint was progression-free survival assessed by independent radiologic review. Median progression-free survival was 7.7 months with crizotinib vs 3 months with chemotherapy, representing a 51% reduction in risk of progression for the ALK inhibitor (P < .0001). Comparing crizotinib with pemetrexed and docetaxel separately, median progression-free survival was 7.7 months with crizotinib vs 4.2 months with pemetrexed (P = .0004 compared with crizotinib) vs 2.6 months with docetaxel (P < .0001). Crizotinib tripled the overall response rate compared with chemotherapy: 65.3% vs 19.3%, respectively (P < .0001). An interim analysis showed no difference in overall survival between the two arms, but Dr. Shaw said the data are immature and that the majority of patients in the chemotherapy arms crossed over to crizotinib. “This makes determining overall survival very challenging,” she stated.

Adverse Events Toxicities of crizotinib were mild and manageable. Most grade 3 or 4 toxicities with crizotinib were observed in fewer than 5% of patients, with the exception of elevated transaminases (16%), pulmonary embolism (5%), and neutropenia (13%). Time to deterioration in lung cancer symptoms was significantly delayed with crizotinib (5.6 months with crizotinib vs 1.4 months with chemo<�� .0001). Also, patient-retherapy, P �� ported quality of life was significantly improved with crizotinib (P < .0001). Median progression-free survival was less than 8 months, and it is expected that resistance to crizotinib will develop, Dr. Shaw explained. Investigational drugs that also target ALK are in early-phase trials; these include LDK378, AP26113,

Crizotinib in Non–Small Cell Lung Cancer ■■ The first-in-class ALK-targeted agent crizotinib extends progression-free survival compared with single-agent chemotherapy.

■■ Improved quality of life was reported by patients in the crizotinib group compared with chemotherapy recipients.

European Database

n a separate presentation at the 2012 ESMO Congress, Fiona Blackhall, MD, Manchester University and Christie Hospital NHS Foundation Trust, Manchester, UK, reported findings from the European Thoracic Oncology Platform (ETOP) Lungscape Project.1 This is the first large European dataset to evaluate the presence and outcome of ALK positivity in patients with stage I to III resected lung carcinoma using immunohistochemistry (IHC) and fluorescence in situ hybridization Fiona Blackhall, MD (FISH) testing as confirmation. Thus far, about 1,099 patient cases have been enrolled in the database. Of these, 69 (6.3%) were ALK-positive by IHC. A high level of concordance was seen between ALK IHC-positive and FISH-positive cases, with 90.5% sensitivity and 97.7% specificity for FISH positivity in ALK IHC3+ cases. Positive IHC and FISH results also appear to provide prognostic information in patients with stage I to III surgically resected carcinoma, Dr. Blackhall said.

■

Disclosure: Dr. Blackhall has received honoraria from Pfizer for speaker and advisory board roles.

Reference 1. Blackhall FH, Peters S, Kerr KM, et al: Prevalence and clinical outcomes for patients with ALK gene rearrangement in Europe. 2012 ESMO Congress. Abstract 1670. Presented September 29, 2012.

and heat shock protein 90 inhibitors. Crizotinib was granted accelerated approval from the FDA in August 2011, for locally advanced or metastatic ALK-positive NSCLC.

Remaining Questions At the ESMO press conference, Fortunato Ciardello , MD, Seconda Università di Napoli in Naples, Italy, said, “This shows that a selective specific inhibitor of a molecular target makes a big difference in treatment outcome. We need to define the underlying genetics and then select therapy accordingly.” Formal discussant of the PROFILE 1007 presentation, Jean Charles Soria, MD, Institut Gustave Roussy, Paris, congratulated the investigators on this “amazing” phase III randomized trial showing extended progression-free survival and improved quality of life. He also cited some remaining questions: “How should we implement this in daily practice? Now that we have a biomarker, who should pay for it, what is the optimal technique, optimal sample, and tissue availability?” Dr. Soria continued. He added that EGFR and ALK testing should not be done separately. Rather, patients should be tested for different molecular abnormalities. In France, 24,000 patients have been tested for EGFR and only 4,000 for ALK, he noted.

Practice Variations In the United States, National Comprehensive Cancer Network (NCCN) guidelines for NSCLC call for ALK and EGFR testing, and this is done at major comprehensive cancer centers. It is less clear whether community oncologists are routinely testing for EGFR and ALK, Dr. Shaw said at the press conference. Dr. Soria was critical about the slowness of the European approval process, noting that crizotinib has been approved in the United States for more than 1 year but is not yet approved in Europe. “There is a different attitude between FDA and EMA [European Medicines Agency]. The EMA needs to establish risk vs benefit. It took 5 months for the FDA to approve crizotinib and it took 14 months for EMA to call for more data,” he stated. On average, there is an 8-month lag between approval in the United States and Europe, he added.

■

Disclosure: Dr. Soria has received honoraria from Pfizer. Drs. Shaw and Ciardello reported no potential conflicts of interest.

Reference 1. Shaw AT, Kim DW, Nakagawa K, et al: Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive nonsmall cell lung cancer (PROFILE 1007). 2012 ESMO Congress. Abstract LBA1. Presented September 30, 2012.

Resistance or intolerance to CML therapy may occur. In some cases, repeatedly. Even today, with a number of available options for treating resistant/intolerant chronic phase chronic myeloid leukemia (CP-CML), a gap in therapy exists. One post-imatinib study found 42% of patients discontinued dasatinib as a second-line therapy by 6 years due to disease progression and/or study drug toxicity.1 Another post-imatinib study found 47% of patients discontinued nilotinib by 4 years due to disease progression and/or drug-related adverse events. 2 Itâ&#x20AC;&#x2122;s clear that for these patients, unmet medical needs persist.

Visit CMLResponseProject.com to learn more. References: 1. Rea D, Vellenga E, Junghanss C, et al. Six-year follow-up of patients with imatinib-resistant or imatinib-intolerant chronic-phase chronic myeloid leukemia (CP-CML) receiving dasatinib. Poster presented at: 17th EHA Annual Congress; June 14-17, 2012; Amsterdam, The Netherlands. 2. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. ÂŠ2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5347112

The ASCO Post | NOVEMBER 1, 2012

PAGE 30

35th ESMO Congress Genitourinary Oncology

Pazopanib Noninferior to Sunitinib as Front-line Therapy for Metastatic Renal Cell Carcinoma By Alice Goodman

azopanib (Votrient) is poised to become another option for firstline therapy of metastatic renal cell carcinoma based on results of the phase III COMPARZ trial reported at the 2012 ESMO Congress in Vienna.1 The study met its primary endpoint by demonstrating that pazopanib was nonSee Page 75 inferior to sunitinib (Sutent), a standard front-line therapy in this setting. Both drugs have different side-effect profiles, which could become the basis for opting for one over the other, depending on physician and patient preference.

panib would be his preference for firstline treatment. “In my view, this trial tips the scale from sunitinib, the reference standard, to pazopanib, based on better tolerance,” he stated. COMPARZ, the largest trial to date in metastatic renal cell carcinoma, randomly assigned 1,110 patients with the disease to either pazopanib or sunitinib. Baseline demographic and disease characteristics were well balanced between the two arms. Median age was 61years, about 72% were male, and 83% had prior nephrectomy. The study included all risk groups; the majority were considered intermediate risk, and about 12% were poor risk.

Pazopanib vs Sunitinib in Renal Cell Carcinoma ■■ Pazopanib was found to be noninferior to sunitinib in previously untreated metastatic renal cell carcinoma.

■■ The drugs have different side-effect profiles, and quality-of-life data suggest patients prefer pazopanib to sunitinib.

■■ Side-effect profiles should be discussed with patients to individualize therapy.

Largest Trial to Date

Key Findings

“COMPARZ showed that the efficacy of the two drugs is the same. The differentiated safety profile of pazopanib shows a lower incidence of hand-foot syndrome, fatigue, stomatitis, and mucositis. More liver function abnormalities were observed with pazopanib,” stated lead author Robert Motzer, MD, Memorial Sloan-Kettering Cancer Center, New York. Dr. Motzer said that

Based on independent review of scans by blinded radiologists, median progression-free survival was 8.4 months with pazopanib vs 9.5 months with sunitinib, a nonsignificant difference for noninferiority. The hazard ratio of 1.047 was within the acceptable boundary of claiming noninferiority, Dr. Motzer explained. Liver enzyme elevations and hair color changes were more frequently reported in the pazopanib group. Patients treated with sunitinib had higher rates of fatigue, hand foot syndrome, taste alteration, and thrombocytopenia. Dr. Motzer said that in his experience, fatigue and hand-foot syndrome are the most troublesome side effects for patients on sunitinib, and this is reflected in the quality-of-life analysis, where patients showed greater satisfaction with pazopanib therapy, with less fatigue and fewer physical symptoms compared with sunitinib. These results mirror a smaller patient preference study called PISCES, which showed 70% of patients preferred pazopanib and 22% preferred sunitinib. PISCES

Robert Motzer, MD

the quality-of-life analysis in this study suggested that the side-effect profiles translated to quality-of-life benefit. He noted that treatment for kidney cancer should be individualized. Based on side-effect profiles, pazo-

EXPERT POINT OF VIEW

“O

ver the past few years, we have gone from famine to feast.… We now have sorafenib [Nexavar] and sunitinib [Sutent], temsirolimus [Torisel], and everolimus [Afinitor], and interferon plus bevacizumab [Avastin] for treatment of metastatic renal cell carcinoma. If these drugs [in COMPARZ] are similarly effective, the drug that is ‘kinder’ to the patient becomes important,” stated Tim Eisen, MD, University of Cambridge, UK, in his formal discussion of the COMPARZ data. Tim Eisen, MD Dr. Eisen said that the data were pretty convincing about these drugs being similarly effective. “From this trial, I would accept they are of similar benefit to the patient,” he said. “But the quality-oflife data are less convincing.” The design of the trial to assess quality of life was problematic, in Dr. Eisen’s view, because assessments were made at time points that favored pazopanib but during the nadir of quality of life for sunitinib. (Patients were treated continuously with pazopanib but had weeks on and weeks off with sunitinib. Assessments were made at 28 days.) “Luckily we have the PISCES trial, which showed a clear difference in patient preference between these two drugs,” he stated.

Toward an Optimal Outcome “Pazopanib is equipotent [to sunitinib], and the drug can now be considered a first-line standard of care alongside sunitinib. Most patients would tolerate pazopanib better. However, doctors should be mindful of performing liver function tests. We would like to predict who will get these problems,” Dr. Eisen concluded. Both drugs carry a black box warning for severe hepatotoxicity and liver failure. Weighing in on this discussion after the ESMO meeting, Robert Figlin, MD, Samuel Oschil CanRobert Figlin, MD cer Institute at Cedars-Sinai Medical Center, Los Angeles, said that noninferiority designs and patient preference designs are not the ideal way to establish the superior safety and efficacy of one drug over another. “Rather than saying one drug is better than another, physicians will have the opportunity to modulate side effects to obtain the optimal clinical outcome,” Dr. Figlin noted.

■

Disclosure: Drs. Eisen and Figlin reported no potential conflicts of interest.

was reported at ASCO 2012.2 Both COMPARZ and PISCES were funded by GlaxoSmithKline. Dr. Motzer emphasized that both sunitinib and pazopanib are highly effective and are options in the first-line setting for metastatic renal cell carcinoma, in addition to bevacizumab (Avastin) plus interferon.

■

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

References 1. Motzer RJ, Hutson TE, Reeves J, et

al: Randomized open-label phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): Results of the COMPARZ trial. 2012 ESMO Congress. Abstract LBA8. Presented October 1, 2012. 2. Escudier B, et al: Patient preference between pazopanib (Paz) and sunitinib: Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. 2012 ASCO Annual Meeting. Abstract CRA4502. Presented June 2, 2012.

To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. September 2011. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

AVA0000400601

Printed in USA.

(11/11)

www.avastin.com

T:10.25" S:9.5"

AVASTIN ® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004

compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control))

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None.

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6%

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. 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. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of 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 data below reflect exposure to Avastin in 4198 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment,

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).] Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were signficantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL+ + Placebo (n = 396) 74%

Arm 2 IFL+ + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1– 4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

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5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

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ASCOPost.com | NOVEMBER 1, 2012 AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3). Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the

In the Clinic

Vismodegib: Novel Agent for Treating Advanced Basal Cell Carcinoma 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.

Indication In January 2012, vismodegib (Erivedge) was approved for treatment of adult patients with metastatic basal cell carcinoma who are not candidates for radiation therapy and adult patients with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery or radiation.1 Approval was based on findings in a single-arm trial in which 96 patients with confirmed locally advanced basal cell carcinoma (n = 63) or metastatic basal cell carcinoma (n = 33) received oral vismodegib at 150 mg once daily.2 Patients had a meSee Page 75 dian age of 62 years, 61% were male, and 97% had an ECOG performance status of 0 or 1. Among metastatic basal cell carcinoma patients, 97% had received prior treatment, including surgery (97%), radiation (58%), and systemic therapies (30%). Among those with locally advanced basal cell carcinoma, 94% had received prior treatment, including surgery (89%), radiation

Vismodegib in Basal Cell Carcinoma ■■ Vismodegib (Erivedge)

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

is approved for treating metastatic basal cell carcinoma in adults who are not candidates for radiotherapy, and locally advanced basal cell carcinoma in those who are not candidates for surgery or radiation as well as in those with a postsurgical recurrence.

■■ Vismodegib is given at 150

mg once daily until disease progression or unacceptable toxicity.

(27%), and systemic or topical treatments (11%). Objective response rates assessed by an independent review facility were 30.3% in patients with metastatic basal cell carcinoma and 42.9% in those with locally advanced basal cell carcinoma. All responses in patients with metastatic basal cell carcinoma were partial responses. Among patients with locally advanced disease, complete response occurred in 20.6% and partial response occurred in 22.2%. Median duration of response was 7.6 months in both groups.

OF NOTE Vismodegib is an inhibitor of the hedgehog signaling pathway, which can contain mutations that result in constitutive signaling and unrestrained proliferation of basal cells.

How It Works Vismodegib is an inhibitor of the hedgehog signaling pathway, a key regulator of developmental cell growth and differentiation that controls epithelial and mesenchymal interactions in many tissues during embryogenesis.3 The hedgehog pathway is inactive in adult tissues. However, most basal cell tumors have mutations in the pathway that can result in constitutive signaling and unrestrained proliferation of basal cells of the skin.

How It Is Given Vismodegib is dosed at 150 mg once daily until disease progression or unacceptable toxicity. It can be taken with or without food.

Safety Profile Safety data from 138 patients receiving vismodegib monotherapy for basal cell carcinoma in clinical trials indicate that the most common adverse events are muscle spasms (72%), alopecia (64%), dysgeusia (55%), weight loss (45%), fatigue (40%), nausea (30%), diarrhea (29%), decreased appetite (25%), constipation (21%), arthralgias (16%), vomiting (14%), and ageusia (11%).2 A total of 3 of 10 premenopausal women developed amencontinued on page 34

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6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. 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. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

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The ASCO Post | NOVEMBER 1, 2012

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In the Clinic

Vismodegib

OF NOTE

continued from page 33

orrhea. Grade�� 3 adverse events occurring in more than 1% of patients were weight loss (7%), fatigue (5%, plus grade 4 in 1 patient), muscle spasms (4%), and decreased appetite (2%). Vismodegib carries a boxed warning for embryo/fetal death and severe

The vismodegib label includes a boxed warning for embryo/fetal death and severe birth defects. birth defects. Practitioners should verify pregnancy status prior to initiation of vismodegib, counsel pregnant

women on the potential risks to the embryo/fetus, and advise nonpregnant women to use highly effective contraception during treatment and for up to 7 months after the last dose. To avoid exposing an embryo or fetus to vismodegib that may be contained in semen, male patients should use condoms with spermicide during

ROS1 TESTING NOW AVAILABLE

Decode each patient’s tumor – individualize cancer treatment. DNA mutations. Gene copy number variations and rearrangements. RNA and Protein expression.

treatment with the drug and for 2 months after the last dose. Practitioners are encouraged to report to Genentech any cases of vismodegib exposure during pregnancy (direct exposure in female patients or via seminal fluid from male patients) and to advise pregnant women to participate in the Erivedge pregnancy pharmacovigilance program to collect information on pregnancy outcomes.

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References 1. U.S. Food and Drug Administration: Vismodegib. Available at http://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289571.htm. Accessed September 28, 2012. 2. ERIVEDGETM (vismodegib) capsules prescribing information. Genentech, Inc, January 2012. Available at http:// www.accessdata.fda.gov/drugsatfda_ docs/label/2012/203388lbl.pdf. Accessed September 28, 2012. 3. Von Hoff DD, LoRusso PM, Rudin CM, et al: Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361:1164-1172, 2009.

REPORT ADVERSE EVENTS

Caris Target Now® examines them all to illuminate a clearer path through your patients’ treatment options.

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 http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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The use of the Caris Target Now service, the use or interpretation of any information provided as part of such service, and/or the selection of any drug agents is solely at and within the discretion of the treating physician’s independent medical judgment. The Caris Target Now services are performed by Caris Life Sciences, a CLIA-certified laboratory operating under the U.S. Clinical Laboratory Amendment Act of 1988 and in compliance with all relevant U.S. state and federal regulations. None of the Caris Target Now services have been reviewed by the United States Food and Drug Administration. Persons depicted are models and used for illustrative purposes only. ©2012 Caris Life Sciences and affiliates. All rights reserved.

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PAGE 35

2012 AACR Annual Meeting AACR’s Cancer Progress Report 2012 Highlights Advances, Challenges, Opportunities By Margot J. Fromer

he American Association for Cancer Research (AACR) recently released its Cancer Progress Report for 2012,1 providing a snapshot of the major advances in cancer research, and highlighting the great need for continued funding for the field.

Margaret Foti, PhD, MD (hc)

“It is a new day for cancer research and cancer patients,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “The inspiring stories of courage that are narrated in this report should serve as a catalyst for strengthening our nation’s resolve to eradicate cancer as a major threat to American lives.” Nevertheless, the report points out, about 577,000 Americans will die of the disease this year. Since cancer is largely a disease of aging, the number of cancer deaths will likely increase dramatically in the future. That said, the NIH budget has remained essentially flat for the past decade, but because of biomedical inflation the agency has effectively lost 20% of its ability to fund lifesaving research within its current budget parameters. Moreover, a budget mechanism called sequestration will likely be put into effect on January 2, 2013. This means that the NCI and NIH will be forced to absorb an actual 8% cut in funding.

Impact of Sequestration Sequestration is an economic maneuver arising from the GrammRudman-Hollings Deficit Reduction Act of 1985. It is designed to reform Congressional voting procedures to See Page 75 make the size of the federal budget a matter of choice rather than the outcome of a somewhat arbitrary appropriations process. That

is, if the various appropriations bills that Congress passes provide for total government spending in excess of previously delineated budget limits—and if Congress cannot agree to decrease that total—then automatic spending cutbacks are triggered. Sequestration is based on the monetary difference between the budget cap and the amount appropriated but not yet handed over to agencies. In theory, every agency has the same percentage of its appropriation withheld, but in practice, some large agencies and programs have been exempted (for example, Defense and Social Security). The number of exempted programs has increased, so other agencies have ever-bigger bites taken out of their appropriations, virtually crippling some of their programs, including those of the NIH and NCI. Cancer will soon be the leading cause of American deaths, said the AACR report, and without major new advances to prevent and treat it, the economic burden will be staggering.

Treatment Advances The report highlighted numerous treatment advances. For instance, in the past year, the FDA approved eight new cancer drugs and four new uses for three already approved. These agents are generally more effective and less toxic. However, progress varies from one type of cancer to another, which points to the need for continued research, especially in the genetic underpinnings of the disease and the repurposing of proven treatments for different cancers. The AACR authors also acknowledged the advances to date in our understanding of biologic, genetic, and molecular processes that drive the growth and spread of cancer. “We have never been better positioned to capitalize on our hard-won understanding of cancer. Unfortunately, continued progress is in jeopardy as investments have steadily declined since 2003,” the report noted.

Prevention and Early Detection “Advances in cancer prevention and early detection have resulted in some of the greatest reductions in

EXPERT POINT OF VIEW

he ASCO Post asked AACR President Frank McCormick, PhD, Director, UCSF Helen Diller Family Comprehensive Cancer Center, about the ongoing problem of health-care disparities among minorities and other subpopulations. First, can the Patient Protection and Affordable Care Act lessen these disparities? He noted that the most immediate effect of the legislation is expanded coverage for the un- and underinsured. Minorities are disproportionately represented in Frank McCormick, PhD these ranks, especially those with preexisting conditions. For cancer specifically, lack of health insurance lowers screening rates. In addition, Dr. McCormick pointed out: The Affordable Care Act will expand community health centers, which tend to be located in underserved areas and which specialize in marginalized populations. “However, when certain groups are more susceptible to cancer or respond differently to treatment, there needs to be a greater focus on the underlying science.” The law also created the Patient-Centered Outcomes Research Institute to identify priorities and provide funding for research on outcome differences in subpopulations such as racial and ethnic minorities. The Affordable Care Act requires plans to ensure that all patients have access to clinical trials, which is of critical import in oncology. The provision aims to remove the economic barriers to trial enrollment. In addition, AACR advocates for a provision in the law that prohibits health insurers from denying coverage of routine costs associated with trial participation and from discriminating against patients in trials. The Affordable Care Act established the Prevention and Public Health Fund, which addresses problems such as poor nutrition, smoking, and the environment.

Reducing Disparities The ASCO Post also asked Dr. McCormick about strategies that AACR envisions to lessen the disparities. He said that the basic approach is through research to understand the biologic underpinnings that cause disparities. For instance, the organization’s annual Conference on the Science of Cancer Health Disparities stimulates development of new research that results in science-based policy changes. “In fact, AACR will host a congressional briefing during the lame duck session to summarize conference results in order to focus greater attention on ways to address disparities,” he noted. AACR has submitted comments to the Centers for Medicare & Medicaid Services on the kinds of information that should be collected for electronic health records, including demographic data and family history. These data enable retrospective study of the differential rates of cancer incidence, mortality, and treatment response in subpopulations. “The more such data we have, the better researchers can elucidate causal or confounding factors and tailor interventions accordingly,” said Dr. McCormick.

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

cancer mortality,” said the authors. These have been achieved by translating scientific discoveries into action by means of public health initiatives in education and policy, as well as personalized care.

The report also noted points of intervention when certain cancers can be stopped in their tracks. However, two out of every three cancer deaths in the United States still will continued on page 37

CURRENTLY ENROLLING for RELAPSED or REFRACTORY MULTIPLE MYELOMA

A Multicenter, Single-arm, Open-label Treatment Use Program For Pomalidomide in Combination With Low-dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma Primary Objective To provide patients with relapsed or refractory multiple myeloma access to pomalidomide while the medication is not commercially available

Key Eligibility Criteria* • ≥18 years or older • Confirmed, measurable, relapsed or refractory multiple myeloma • Received ≥4 antimyeloma regimens (induction bone marrow transplant with or without maintenance therapy is considered 1 regimen)

N=350

Study Treatment† • Oral pomalidomide 4 mg on Days 1-21 of 28-day cycle • Oral dexamethasone 40 mg weekly on Days 1, 8, 15, and 22 of 28-day cycle

*Additional criteria apply. †

Patients may continue on study treatment until documented disease progression, discontinuation of study treatment for any reason, or pomalidomide becomes commercially available.

Investigational use of pomalidomide.

For more information, e-mail thepexiusstudy@celgene.com, visit www.thepexiusstudy.com, or scan the QR code to the left.

ASCOPost.com | NOVEMBER 1, 2012

PAGE 37

2012 AACR Annual Meeting Cancer Progress Report

Cancer Health Disparities

continued from page 35

As it has in the past, AACR noted the significantly higher incidence of certain cancers in certain populations, as well as poorer treatment outcomes (see sidebar). These populations include racial and ethnic minorities, low-income people, and the elderly. The causes of these disparities are many, complex, and poorly understood, but they include unequal access to care, varying behavioral, environmental, and genetic risk factors, lack of inclusion in some clinical trials, and social and cultural biases that affect the relationship between patients and providers. Lack of health insurance is a major factor in health-care disparities. Overall, 14% of Americans are uninsured,

be due to preventable causes. Therefore, public health measures must be implemented to reduce exposure to cancer-causing agents, infectious causes of cancer must be prevented or treated, and population-based screening and public education need to be stepped up, the authors continued. Moreover, since most tumors are a result of genetic changes and since we are learning more about the timing, sequence, and frequency of these changes, we now have unique opportunities for earlier identification of aberrations and, thus, new prospects for early intervention.

American Association for Cancer Research Mourns the Loss of Senator Arlen Specter

Source: NIH

Influential Supporter of Cancer Research

Arlen Specter

he American Association for Cancer Research (AACR) mourns the loss of Arlen Specter, who represented Pennsylvania in the U.S. Senate from 1981 to 2011. With his passing, the cancer research and biomedical science community lost one of its greatest supporters and promoters. During his five terms and 30 years in the U.S. Senate, Senator Specter served as a tireless champion in the fight against cancer and was the driving force behind strengthening America’s leadership in securing sustained funding for cancer research and biomedical science. Margaret Foti, PhD, MD (hc), AACR’s Chief Executive Officer noted that “for years, Senator Specter was one of the most ardent advocates for increased spending for the National Institutes of Health, which has resulted in countless lives being saved. All of us are indebted to him for his vision and his extraordinary legacy.”

During his tenure in the Senate, Senator Specter served on the House Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies, which is the subcommittee responsible for allocating funding for the NIH. He served as chairman for 10 of those years, during which time he asserted his status as one of the most influential supporters of cancer and biomedical research. Senator Specter was the driving force in accomplishing the 5-year doubling of the NIH budget, which was completed in 2003. In addition, his courageous support of an amendment to the American Recovery and Reinvestment Act in 2008 led to an additional $10.4 billion to support the work of the NIH, including the National Cancer Institute. “Senator Specter brought a powerful and personal voice to the fight against this terrible disease. His personal strength in battling cancer while carrying on his critical duties in the U.S. Senate was a tribute to his courage and dedication to biomedical research in this country,” Dr. Foti added. “His unwavering support has truly made a difference in the lives of millions of cancer survivors, patients, and their families across the nation.”

■

whereas 37% of Latinos and 20% of blacks are uninsured. When insurance coverage is not the problem, there are fewer providers and facilities to meet the needs of minorities and other underserved populations. Further, even when care is available, social and cultural factors often inhibit patients from taking advantage of it.

Continued Progress Congressional support is the critical ingredient to further cancer research. AACR urges Congress to work in a constructive, bipartisan fashion to prevent sequestration. In addition, Congress should designate NIH-NCI as a top national priority by providing annual budget increases at least comparable to the

biomedical inflation rate. The report noted that if the proposed sequestration cuts are enacted, the cancer research and biomedical science enterprise could be destroyed. For example, NIH would be able to fund 2,300 fewer grants than planned for 2013—a particularly devastating consequence at a time when the number of opportunities in cancer research has never been greater.

■

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

Reference 1. AACR Cancer Progress Report Writing Committee: AACR Cancer Progress Report 2012. Clin Cancer Res. September 11, 2012 (early release online).

News and Views from the World of Clinical Oncology and Hematology

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6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS. Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimens). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. 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. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA 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 using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. 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 clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. 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. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib 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 INLYTA, 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. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. 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). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

May 2012

ASCOPost.com | NOVEMBER 1, 2012

PAGE 41

Direct from ASCO

Philanthropy Spotlight Karnofsky Award Winner Honors Mentors through Gift to Conquer Cancer Foundation

Kanti R. Rai, MD

anti R. Rai, MD, and his wife Susan have been loyal donors to the Conquer Cancer Foundation for the past 9 years, but in 2012, a momentous occasion in his career inspired Dr. Rai to make a unique gift.

A Moment of Reflection In the spring of 2012, Dr. Rai, an internationally recognized expert on adult leukemia, learned that he would receive the David A. Karnofsky Memorial Award, ASCO’s highest scientific honor, at the ASCO Annual Meeting. The Karnofsky Award is presented in recognition of innovative clinical research and developments that have changed the way oncologists think about the general practice of oncology. For Dr. Rai, Chief of Chronic Lymphocytic Leukemia (CLL) Research and Treatment Program at North Shore–Long Island Jewish (LIJ) Health System, Joel Finkelstein Cancer Foundation Professor of Medicine at Hofstra North Shore–LIJ School of Medicine, and investigator at The Feinstein Insti-

tute for Medical Research, it was a moment for reflection. “When I was first notified of the award I felt humbled and honored. I started to reflect upon how I reached where I have reached in my career, and realized that it was important to remember and honor my two mentors,” he said. For Dr. Rai, that meant finding a way to honor Arthur Sawitsky, MD, and Eugene P. Cronkite, MD. It was Dr. Sawitsky who first taught Dr. Rai “to look at blood and bone marrow under the microscope, diagnose leukemia, and translate that information into caring for the living patient,” and it was Dr. Cronkite who taught Dr. Rai clinical research “step-bystep” and further guided him in his study of CLL.

Invaluable Support In Dr. Rai’s opinion, it is an important exercise for all oncologists who have obtained any measure of success in their careers to “think back to when we were nobodies, and consider, where would we be without support from our mentor?” “I was working in awe and admiration of this senior person who took a shine to me for some reason and took me under his umbrella, letting me see how that leader’s mind worked, day-to-day, week-toweek, [and seeing] how that mentor advised me and guided me in my research project, critiquing and providing encouragement without necessarily telling me what to do,” he said. “At each level the mentee receives

guidance from the mentor that you cannot duplicate in a classroom setting,” Dr. Rai continued. “I remember that each of my two mentors did that for me without any sense of obligation. That’s what came naturally to them.” Dr. Rai chose to pay tribute to the mentors who helped to shape his career by making a donation in their honor to the Conquer Cancer Foundation. “The amount that I contributed may have been larger than I easily could have afforded, but in my mind, it was no match for the unstinted generosity that my mentors provided me in my career,” he said.

Mentorship and the Conquer Cancer Foundation The Conquer Cancer Foundation has always emphasized the importance and strength of mentoring relationships in its programs. The Foundation’s flagship Young Investigator Award (YIA) and Career Development Award (CDA) programs have a critical mentorship component—with each recipient pursuing his or her research under the guidance of an experienced mentor. Programs like the International Development and Education Award (IDEA), and the Long-term International Fellowship (LIFe) pair early-career oncologists in developing nations with a U.S. or Canadian mentor. The Gianni Bonnadonna Breast Cancer Award and the Research Professorships are awarded to senior investigators with exemplary mentoring skills who provide mentorship to future researchers. “The mentors have an enormous impact on the quality of the proposals we see, as well as the execution of the research projects,” said Eileen Melnick, Director of the Conquer Cancer Foundation Grants & Award Program. “We’re actually at the point in our program’s history when many of our earlier grant recipients are advanced enough in their careers to act as mentors to our current young investigators, and that’s really rewarding to see.” As Dr. Rai put it, “It comes with

a sense of generosity that goes from generation to generation. It is the best way of perpetuating quality clinical investigations and quality science.”

A Fitting Tribute As a long-time and active ASCO Member, Dr. Rai has had a close-up view of the Foundation’s programs and progress since its inception in 1999. “I was very impressed by the altruism that the Foundation represents in terms of advancing cancer research, helping the right kind of causes in cancer education, and supporting young cancer researchers early in their investigative careers,” he said. “In the past few years the Foundation has made itself known for the kind of work it does,” Dr. Rai continued. “At the ASCO meeting, you can see wall after wall of what the Foundation does and stands for.” A gift to the Conquer Cancer Foundation in support of its mission to fund breakthrough research and share cutting-edge knowledge seemed a fitting tribute to those who had so generously shared their own knowledge early in his career. As he prepared to accept one of the most distinguished awards in oncology, it was important to Dr. Rai to remember that achievements in the field of oncology are always shared team efforts. Through his gift to the Conquer Cancer Foundation, Dr. Rai found that he could contribute to an overall professional atmosphere of appreciation and generosity, honoring the mentoring relationships that are improving the next generation of cancer care on a daily basis. “If we can recognize and honor our mentors in our own lifetimes,” he said, “it sets an important example to the upcoming younger generation of our colleagues.” To make a gift in honor of a mentor, colleague, or loved one, visit the Conquer Cancer Foundation online at www.conquercancerfoundation. org/donate. © 2012. American Society of Clinical Oncology. All Rights Reserved.

The ASCO Post | NOVEMBER 1, 2012

PAGE 42

Direct from ASCO

Fellowship Breathes ‘LIFe’ into the Careers of Young Oncologists in Developing Countries

he Conquer Cancer Foundation of the American Society of Clinical Oncology supports oneon-one training and research grants for the brightest minds in cancer care around the world through the Long-term International Fellowship (LIFe) and other programs. Through this 1-year fellowship, early-career oncologists in low- and middle-income nations are given the support and resources needed to advance their training by deepening their relationship with a U.S. or Canadian colleague and his or her institution. Recipients earn valu-

Through this 1-year fellowship, early-career oncologists in low- and middle-income nations are given the support and resources needed to advance their training by deepening their relationship with a U.S. or Canadian colleague and his or her institution. able experience with which they can then affect change in cancer care in their home country.

Two Outstanding Recipients In 2012 the Foundation awarded fellowships to two outstanding on-

cologists, both of whom are previous recipients of the Conquer Cancer Foundation of ASCO International Development and Education Award (IDEA). The first recipient, Luiz Henrique de Lima Araujo, MD, MSc, of the Brazilian National Can-

Volume 29, Issue 15

CancerProgress.Net Adds New Resources to Highlight Progress in Clinical Cancer Research

SCO’s CancerProgress.Net (www.CancerProgress.Net), a dynamic website demonstrating four decades of progress against cancer, has added new resources that will enable site users to learn more about progress in cancer treatment, prevention, screening, and diagnosis.

Interactive Cancer Timelines Three new cancer timelines—for liver, gastric, and head and neck cancer—were added to the 14 major cancers already chronicled on the site. The new timelines were curated by CancerProgress.Net speciality editors Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center (liver); David H. Ilson, MD, PhD, of Memorial Sloan-Kettering (gastric); and Everett E. Vokes, MD, of University of Chicago (head and neck).

In-depth Resources for Physicians and Patients To help users delve even more deeply into the significant progress made in recent decades, the CancerProgress.Net Editorial Board also reviewed thousands of journal

articles and added links to the primary research articles that led to the important advances chronicled on the website. The information may be of interest to medical fellows, policymakers, members of the media, patient advocates, or anyone interested in learning about progress against cancer. Launched in 2011, CancerProgress. Net provides an easily accessible, visual history of advances against major types of cancer in every area of patient care, from molecularly targeted therapies to quality of life. The site offers an interactive journey through 40 years of major advances, as well as video interviews with cancer experts, additional perspective on remaining challenges, downloadable slides and materials, and a data visualizer for cancer statistics. ASCO created CancerProgress. Net to mark the 40th anniversary of the National Cancer Act of 1971, which led to major new investments in cancer research and significant increases in cancer survival.

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May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

cer Institute (INCA), is studying “The Molecular Profile of Lung Adeno� carcinoma in Brazil” at the Vanderbilt-Ingram Cancer Center under the mentorship of David Carbone, MD, PhD. Lung cancer is a leading cause of death in Brazil and according to Dr. de Lima Araujo, better understanding of the epidemiological and molecular disparities among patients in each region is critical in helping define priorities for resource allocation. The second 2012 LIFe recipient, Guochun Zhang, MD, PhD, continued on page 43

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

What’s Hot in

JCO

JCO.org Timing of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Patients With Lung Cancer With EGFR Mutations

Oxaliplatin As Part of Adjuvant Therapy for Colon Cancer: More Complicated Than Once Thought

Cediranib With mFOLFOX6 Versus Bevacizumab With mFOLFOX6 As First-Line Treatment for Patients With Advanced Colorectal Cancer: A Double-Blind, Randomized Phase III Study (HORIZON III)

Top 50 Most-Cited Journal of Clinical Oncology Articles From 2009

KRAS Wild-Type Lung Cancer: A Moving Target in an Era of Genotype Migration

ASCOPost.com | NOVEMBER 1, 2012

PAGE 43

Direct from ASCO

Now in Spanish: Cancer in Older Adults

ell your patients about Can� cer in Older Adults, Cancer. Net’s newest Spanish language

booklet for older adults and their family and friends. The content of the booklet is adapted from the ASCO University Module, Can� cer Care for Older Patients. It provides information on the physical

and emotional changes that are associated with aging and cancer, including recommendations for coping with daily life, cancer treatment, coexisting conditions, and caregiving needs. Find it on-

line at www.cancer.net/espanol, and order copies at www.cancer. net/estore.

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Oncologists in Developing Countries continued from page 42

of Guangdong General Hospital in China, is studying “Inhibiting STAT5 in Breast Cancer Prevention” at Baylor College of Medicine under the mentorship of C. Kent Osbourne, MD, and Yi Li, PhD. In China, the number of breast

cancer cases is rapidly increasing. It is estimated that there will be more than 100 cases for every 100,000 women by 2021, creating a challenge for the nation’s limited supply of oncologists.1 In addition to identifying new ways to prevent breast cancer, Dr. Zhang plans to apply, and share with colleagues, his newfound knowledge to bridge the translation of research into clinical practice and increase the use of evidence-based treatment. His fellowship is supported by The Breast Cancer Research Foundation.

2013 Application Cycle The application cycle for the 2013 LIFe opens in November; visit www.conquercancerfoundation.org/life for more information. To join the Conquer Cancer Foundation in improving the care and treatment of people living with cancer in developing nations and around the world, make a gift today at www.conquercancerfoundation. org/donate.

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Reference 1. Linos E, Spanos D, Rosner BA, et al. Effects of reproductive and demographic changes on breast cancer incidence in China: A modeling analysis. J Natl Cancer Inst 100:1352-1360, 2008. © 2012. �� American Society of Clinical On� cology. All Rights Reserved.

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives. We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

This is our pledge. This is GSK Oncology. Learn more at the new GSKoncology.com

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The ASCO Post | NOVEMBER 1, 2012

PAGE 44

A Day in the Life Community Oncologist

The EMR Conundrum

continued from page 1

The national transition to a fully digitized health-care system is imminent, but our own transition to electronic medical records (EMRs), which began about 3 years ago, proved to be painful. EMRs are very expensive, not just the software and implementation process, but also the hidden costs for which we weren’t prepared. For example, our EMR did not interact well with our other systems, so we needed to hire technicians to develop interfaces that were interoperable. Each interface ran $20,000 to $40,000, and the process became like an unending house renovation nightmare. In short, electronic medical records have had a huge negative impact on our practice, in terms of costs as well as a decrease in efficiency. People picture the EMR’s functionality as similar to a smart phone or an iPad, but one should really think of the current EMR as more like the first version of Windows, or

changes that have affected our oncology services, in both positive and negative ways. On the positive side, I’m enjoying patient care more now than ever, and the main reason is that my cancer patients are living longer. When I first came into oncology, we had a limited number of drugs, most of which were highly toxic and not very effective. Consequently, most of our patients with metastatic disease died within the first year. In contrast, over the past decade we’ve had an explosion of exciting new drugs that have clearly improved survival rates. Today, it’s not surprising for patients with advanced disease to live beyond 5 years with good quality of life. For instance, I have a patient with metastatic lung cancer who is now 10 years out. She was thrilled because just this summer she attended her son’s wedding, something she never dreamed she would live to see. She gave me such a big hug of gratitude, which was an extraordinary high because in human terms it validated the care I deliver every day. On the negative side, over the past few years practice costs have skyrocketed. Staff salaries, benefits, and medical insurance have risen dramatically along with malpractice insurance, not to mention the dayto-day costs of running the office. Moreover, diminishing reimbursement for cancer drugs squeezes our margins so tight that it’s very challenging. We’re lucky in that our practice has seven doctors, so we’ve been able to defray and absorb the fiscal pain. But a lot of smaller and singledoctor practices operate on the verge of bankruptcy. Another negative is the sheer expense of the chemotherapeutics, which can cost $10,000 per month for a single drug, adding to upwards of $70,000 worth of therapy for a single patient. In some cases, the insurance company refuses to reimburse us, even after prior approval, citing any number of reasons, such as a prior existing condition of which we had no knowledge. We end up absorbing the loss. Occasionally a drug manufacturer will increase the price of an agent more than its Medicare reimbursement rate. It takes Medicare months to readjust the rate, so we end up losing money each time we administer that treatment—money we can’t recoup.

pital. We’re still independent, but we’ve partnered very closely with the hospital so we can continue to provide comprehensive oncology services. The benefit for us is that the hospital is much more effective in managing a large office staff and in dealing with the high operating and drug costs. Our physicians can now concentrate more on patient care than on business. The hospital has also picked up a lot of the administrative burdens involved in our clinical trials section. It was a tough decision, but in the end, given the changing environment, partnering with the hospital was a good strategic move for our practice and the hospital.

The Day Begins… I usually arrive at my office at about 7:00�� AM. I pick up faxes and paperwork from the night before, and then I cross my fingers and power up our office electronic medical records system. If everything is glitch-free, I power up

The problems associated with EMR and the requirements of QOPI, meaningful use, and insurance reimbursement have created a tsunami of demands on the private-practice oncologist… That said, the rewards in caring for patients with cancer still outweigh the growing challenges faced in community oncology practice. —K.M. Steve Lo, MD

maybe DOS. Naturally, these machines will, like all electronics, eventually improve vastly in functionality and decrease markedly in cost. But currently, our EMR is an expensive, clunky, inefficient machine. Laborious data-entry time aside, my biggest gripe with the EMR is that it takes away from the important face-toface interaction I have with my patients. I find myself spending more time inputting information than I do having eye contact with my patient. The machine, with its constant need for data entry, distracts me during important discussions with very vulnerable patients.

Hospital Collaboration By nature, community oncologists revere their autonomy. And the most drastic change to our practice—due largely to growing economic challenges and burdensome administrative issues—was integrating with the Bennett Cancer Center at Stamford Hos-

the hospital’s EMR—which is separate from our office EMR—and check out all the pertinent data, admissions, lab work, and so on. I typically have about three to six inpatients, so after I’ve gone over their charts electronically, I run over to the hospital and do my rounds. I wait until I get back to my office to enter the hospital notes into the EMR, which typically takes longer than the time I spent with the patients. Again, using the EMR is a finicky, labor-intensive process that has added extra layers of administrative time to my day. I usually finish the notes about 8:00 or 8:30, and then begin seeing my office patients. I schedule about 30 minutes for follow-ups and about an hour for a new patient consult. I try to save my consults for the end of the day, because in the more complicated cases, an hour simply isn’t enough time. I usually see between six and eight patients in the morning. Unfortunately, time that used to be reserved for important schmoozing, either

with colleagues or patients, is now consumed by inputting notes and documentation. If we do not document a patient’s visit properly, we may be reimbursed for only a fraction of what we have done. We also have to meet a host of different criteria, such as meaningful use for the EMR, which is incredibly complex and timeconsuming. Then there are the ABCs of QOPI, which I support in spirit, but the implementation process for certification adds a lot of extra work, without really improving care.

A Working Lunch that Blends into Night… I try to reserve an hour for lunch in the afternoon, usually to deal with any emergencies, patching up loose ends, running over to the hospital to see consults, or returning phone calls that have been triaged as semiurgent to urgent. We also have working lunches that might encompass tumor boards or a lunch seminar of invited speakers updating us on new things being done in the community, such as in pain management or palliative care. In between the multitude of issues that come up, I’ll run back to the office and grab a bite at my desk, all the while checking e-mail, voice mail, lab results, and preparing for my afternoon patients. At 1:00 PM, I begin seeing patients until 5:00 or 5:30 in the evening. If I have some walk-ins, hospital consults, or emergency admissions, I might not see my last patient until 7:00 PM. After that I work on some more notes, return calls, and head for home, making more return calls in the car. I get home between 7:00 and 8:00 PM, have a quick dinner and catch up with the family, and then I go up to my home office and spend another hour or so working. Since I can now access my office and hospital EMRs from home, which is good for patient care but bad for personal life. I spend that time checking labs, responding to e-mails, and reviewing treatment plans. Over the past few years, the problems associated with EMR and the requirements of Quality Oncology Practice Initiative (QOPI), meaningful use, and insurance reimbursement have created a tsunami of demands on the private-practice oncologist. They have taken time away from my patients and my family. That said, the rewards in caring for patients with cancer still outweigh the growing challenges faced in community oncology practice.

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

ASCOPost.com | NOVEMBER 1, 2012

PAGE 45

Expert’s Corner Hematology

Trials of Drug Combinations Present New Hope for More Effective Treatments in Multiple Myeloma A Conversation with Sagar Lonial, MD By Jo Cavallo

Sagar Lonial, MD

eveloping early-phase clinical trials that incorporate combinations of novel agents targeting different pathways in the hematologic cancer multiple myeloma is a leading focus of the work of Sagar Lonial, MD, Professor of Hematology and Vice Chair of Clinical Affairs in the Department of Hematology and Medical Oncology; and Director of the Translational B-cell Malignancy Program at Winship Cancer Institute at Emory University School of Medicine. Dr. Lonial’s laboratory is also investigating combinations of drugs that may inhibit the PI3 kinase/Akt pathway—a central gatekeeper for important cellular functions in myeloma cells, including the development of drug resistance— and facilitate myeloma cell death. While more effective therapies for myeloma as well as advances in the genomic sequencing of myeloma cells have succeeded in extending overall survival from 3 years to 7 years, the cancer remains incurable, resulting in the deaths of nearly 11,000 people each year, according to the American Cancer Society. To combat these statistics, Dr. Lonial is also investigating strategies to identify newly diagnosed myeloma patients at high risk for relapse and establishing a treatment plan to keep them in long-term remissions. The ASCO Post talked with Dr. Lonial about how innovative clinical trial designs and a better understanding of the genetic abnormalities in myeloma cells are leading to longer remissions and potential cures.

Evolving Concepts How has our understanding of multiple myeloma at the molecular level improved? Many of the cancers we treat, not

just in hematology but in all of oncology, are not simple diseases. That is, there is not one key that unlocks the door. Other than diseases like chronic myelogenous leukemia or gastrointestinal stromal tumor, where you use one drug that shuts down the tumor pretty significantly, most cancers (and certainly most hematologic malignancies) have a complicated genome with multiple areas that have gone awry. So the idea of sequencing single agents doesn’t make a lot of sense. And because these cancers are so complex, it’s going to take more than one drug to make them go away. As we have started to understand more about the basic biology of myeloma cells, we’ve also tried to understand what different pathways are involved. For instance, we know that plasma cells, which become myeloma cells, are particularly good at making lots of protein, and in order for those cells to survive, they need pathways

bortezomib and carfilzomib. The two most active classes of drugs we have in myeloma are proteasome inhibitors and immunomodulatory drugs, including thalidomide (Thalomid), lenalidomide (Revlimid), and now pomalidomide. Those three potent drugs can be made even more powerful by combining them with a proteasome inhibitor, or they can make an antibody more effective because they can enhance immune function. That discovery came from laboratory work and is now being borne out in phase I and II clinical trials.

Obstacles in Trial Design What are some of the obstacles in designing clinical trials that combine several agents? One of the challenges we struggle with in oncology generally is that multiple pathways are involved with drug resistance, so we want to begin to put together combinations of drugs

Whether you are a community oncologist or an academic oncologist, it is important to be connected to a myeloma center that has access to [investigational] drugs, so you can get them for your [myeloma] patient. —Sagar Lonial, MD

that enable them to deal with the production and maintenance of large protein loads. Chiefly, that is the proteasome pathway, so we use proteasome inhibitors like bortezomib (Velcade) and now carfilozomib (Kyprolis) in attempts to gum up a system that even a normal plasma cell depends on for survival. Once you’ve identified that one pathway, you start thinking about what else becomes active to help the cells stay alive, and that’s where a lot of the preclinical and clinical combination strategies come from. For example, we’ve looked at ways to block the heat shock protein response or DNA-repair response, both of which can be mediated through the proteasome inhibitors, and that accounts for why a drug like cyclophosphamide has a synergistic effect when combined with drugs like

that are not all FDA approved. That’s challenging from a regulatory and operational perspective; it can be very complicated to put together two nonapproved drugs in a clinical trial. What can be done to overcome those obstacles? In myeloma research, we are fortunate that the industry partners we work with understand the importance of testing combinations of agents in trials. They are more willing now than they were 10 years ago to talk about doing those challenging but groundbreaking clinical trials, even when the drugs are not FDA approved. The FDA is certainly willing to allow these trials of what we call novelnovel drug combinations—meaning neither drug is FDA approved—because it doesn’t want to hold up this

kind of progress.

Patient Selection Is participation in novel-novel clinical trials determined by a matchup between the patient’s specific myeloma character� istics and the agents’ ability to target the tumor’s pathways? Yes, but there are two answers to that question. First, we want to hone down and get to the genetic nuts and bolts of the different subsets of this disease, rather than treating it as a single entity. But you cannot put each patient in his own bucket. The lumping and splitting has got to occur somewhere in the middle, where you get a reasonable number of patients who may not be genomically identical but are genomically similar enough that a given treatment approach will work. Second, we often think we know how a drug works, but many drugs may go after one target and also have off-target effects. One of the potential dangers of being too focused on drugs for individual patients is that we may miss an active drug because we do not really understand the true mechanism at work.

PI3 Kinase Pathway What role does the PI3 kinase path� way play in the development of myeloma? One of the pathways that is highly overexpressed or highly active in almost all malignant plasma cells is the PI3 kinase pathway. PI3 kinase is a very important activator, and many of the external growth factors stimulate the plasma cell growth signal through PI3 kinase. A while ago, we noticed that multiple myeloma patients may have highly active PI3 kinase, but it is not for genetic reasons, like in renal cell carcinoma, where the cells have mutations in PTEN. It is because they are receiving growth factor stimuli from outside the cell. Early on, we found that while we did get an inhibition of growth with some PI3 kinase inhibitors, that didn’t really kill the cell by itself. What we are looking at now are ways to enhance the cell death associated with inhibiting PI3K and whether subsets like the specific isoform inhibitors, such as the gamma and delta inhibitors, can be more effective in inducing myeloma cell death. continued on page 48

For the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients

Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving

Important Safety Information

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. ÂŠ 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6397 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND... • 37% reduction in risk of death vs placebo

(P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 – In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1 • The most common adverse reactions (≥ 10%) in patients treated with XTANDI were asthenia/fatigue, peripheral edema, back pain, arthralgia, musculoskeletal pain, diarrhea, hot flush, headache, and upper respiratory tract infection1

XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

Learn more at XtandiHCP.com

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 1, 2012

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Expertâ&#x20AC;&#x2122;s Corner

Sagar Lonial, MD continued from page 45

High-risk Patients

While many newly diagnosed patients successfully achieve remission with stanďż˝ dard therapies, most eventually relapse. What treatments are you investigating for the high-risk myeloma patient who relapses repeatedly?

The high-risk subset of myeloma patients is particularly challenging. The key, at least with the medicines available, is to create a focused treatment algorithm for them from the very beginning. For example, in our center we give patients very effective induction therapy, typically with RVD (lenalidomide, bortezomib, and dexamethasone); then we give

them a single transplant, and afterwards, put them on RVD maintenance, with the idea that these are our three best drugs. We want to maintain high-risk patients in remission because we know that if we stopâ&#x20AC;&#x201D;if we pull our foot off the brakes for even a few monthsâ&#x20AC;&#x201D;the disease has a chance to ramp itself back up, and then it becomes resistant to therapy.

The idea of long-term maintenance has been around for a long time, but we now finally have more drugs that are effective and can be given in doses and schedules that are more tolerable, to try to keep those high-risk patients under better control. Still, itâ&#x20AC;&#x2122;s not a perfect strategy by any stretch of the imagination. How do you determine which newly

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI 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 and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders 9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 1, 2012

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Expertâ&#x20AC;&#x2122;s Corner

diagnosed patients fall into the high-risk category? There are a number of ways to define high risk in newly diagnosed patients. Fluorescence in situ hypridization (FISH) analysis can give you some clue about a certain subset of high-risk patients, and gene-expression profiling can give you another prediction of high-

risk patients. You can use genomic sequencing to identify patients who may or may not be at high risk as well. I wonâ&#x20AC;&#x2122;t say that we are perfect in identifying these patients, but in general, at diagnosis, we can identify patients with P53 deletion, 14;16 translocation, and even 4;14 translocation, which with modern therapy may not be as bad as

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI 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 XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI 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 XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

we thought it was 10 years ago. But this is an important point: You have to look for these genetic abnormalities at the time of diagnosis. If you donâ&#x20AC;&#x2122;t get the studies done when patients are diagnosed, you may not know their risk stratification until theyâ&#x20AC;&#x2122;ve relapsed. By that point, you may have missed an opportunity to

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-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

maintain that patient with high-risk disease.

Closing Thoughts What else would you like ASCO members to know about myeloma and advances in the field? Access to enrollment in clinical trials is key, because that has really contributed to extending patient survival. I do not want patients to die waiting for certain drugs that may put their disease in remission, and the only way to get a lot of these drugs is on trial. Whether you are a community oncologist or an academic oncologist, it is important to be connected to a myeloma center that has access to these drugs, so you can get them for your patient.

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Disclosure: Dr. Lonial has served in a consultant or advisory role with Millennium, Celgene, Novartis, Merck, Onyx, and BristolMyers Squibb.

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The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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The ASCO Post | NOVEMBER 1, 2012

PAGE 50

Best of ASCO® Annual Meeting ‘12 Major Strides Seen in Treatment of Gynecologic Cancers

esearch reported at this year’s ASCO Annual Meeting shows major strides in treating ovarian and cervical cancers, suggesting the potential of new agents and adding evidence in areas where optimal management is unclear, according to Jonathan S. Berek, MD, of the Stanford Women’s Cancer Center, Stanford Cancer Institute, Stanford, California, who discussed these investigations at the Best of ASCO San Diego meeting.

phase was generally similar between arms, and toxicity during olaparib maintenance was consistent with previous experience. “This was a positive trial.… The toxicity overall was quite acceptable, certainly compared to what we usually use for either relapse treatment or maintenance therapy,” Dr. Berek commented. “The group that did this study, which includes many of us, is doing a biomarker analysis, and we are pushing very hard to enable a larger, phase III trial, while we await the overall survival data,” he added. He also noted that there has been some reluctance to develop olaparib further in this disease (see sidebar, “Future of PARP Inhibitors in Ovarian Cancer Hangs in Balance”).

Bevacizumab in Platinumresistant Ovarian Cancer

Jonathan S. Berek, MD

Olaparib in Platinumsensitive Ovarian Cancer A randomized phase II trial tested olaparib, an oral inhibitor of polyADP-ribose polymerase (PARP), in platinum-sensitive recurrent serous ovarian cancer.1 A total of 162 patients were assigned to carboplatin/paclitaxel chemotherapy, with vs without olaparib during cheSee Page 75 motherapy and also as maintenance. With a median 5-month follow-up, the median progression-free survival was superior with olaparib vs without it (12.2 vs 9.6 months, P = .0012). Toxicity during the combination

The randomized phase�� III�� AURELIA trial evaluated the addition of the antiangiogenic agent bevacizumab (Avastin) to chemotherapy in 361 patients with platinum-resistant recurrent ovarian cancer.2 With a median 18-month followup, progression-free survival was almost doubled with bevacizumab vs without it (6.7 vs 3.4 months, HR = <�� .001). Patients in the bevaci0.48, P �� zumab group were significantly more likely to have both radiographic and biochemical responses (Fig. 1). Overall survival data are still immature. “A lot of these patients of course go on for even more treatment, and one can always be a bit concerned about what you do subsequently that might influence the overall survival

Future of PARP Inhibitors in Ovarian Cancer Hangs in Balance

“I

t’s become clear that the PARP inhibitors in general … are active in this disease, and we are just trying to find out the level of activity and … get to the point hopefully where at least one of these agents will be approved for use” in ovarian and related cancers, commented Jonathan S. Berek, MD, of the Stanford Women’s Cancer Center, Stanford, California. He noted that shortly before the ASCO Annual Meeting, the manufacturer of olaparib announced that it would not advance the drug into phase III trials. “This actually kind of surprised many of us,” he recalled. “This appears to be an active agent, and we need active agents in this disease.” The company’s concern stemmed from the lack of a survival benefit in trials thus far, according to Dr. Berek.

■

Patients (%)

By Susan London

50 45 40 35 30 25 20 15 10 5 0

CT P < .001a 30.9%

12.6%

BEV + CT

P < .001a 27.3%

11.8%

P < .001a 31.8%

11.6%

Responders RECIST responders (RECIST and/or CA-125) (n=287) (n=350)

CA-125 responders (n=297)

Fig. 1: Summary of best overall response rates in the AURELIA trial. BEV = bevacizumab; CT = chemotherapy. P values based on two-sided chi-square test with Schouten correction. Reprinted with permission from Pujade-Lauraine et al.2

data in any given study,” Dr. Berek cautioned. The study was important in that it adds to data showing benefit of bevacizumab in the front-line setting and in the platinum-sensitive recurrence setting, although clear evidence of an overall survival benefit is still limited. “It may be that bevacizumab over time will in fact be incorporated into both upfront maintenance and for the treatment of relapse,” he commented.

Dose-dense Paclitaxel in Ovarian Cancer The randomized NOVEL trial ( Japanese Gynecologic Oncology Group [ JGOG] 3016) compared dose-dense weekly paclitaxel plus carboplatin vs conventional triweekly paclitaxel plus carboplatin in 631 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.3 Initial results, reported at a median follow-up of 29 months, had shown significantly better progression-free and overall survival with the dose-dense approach. Updated results reported this year, now with a median follow-up of 6.4 years, still favored the dose-dense approach in terms of progression-free survival (28.2 vs 17.5 months) and overall survival (not reached vs 62.2 months). But in stratified analyses of overall survival, the dose-dense approach was significantly superior only among patients who had had residual disease measuring more than 1 cm (HR = 0.75) or serous histology (HR = 0.76). “This is a very, very important finding, and probably the most important finding of the gynecologic cancer

abstracts. This was a very impressive study, very well done,” Dr. Berek maintained. He noted that the gain in overall survival was similar to that seen with intraperitoneal regimens in other trials (see sidebar, “All Eyes on Trials of IV vs IP Chemotherapy for Ovarian Cancer”). “Ongoing trials compare this dose-dense regiment to intraperitoneal chemotherapy, and these comparisons will help to define how best to treat the majority of patients with these diseases,” he said.

Erlotinib Maintenance Falls Short in Ovarian Cancer A randomized phase�� III�� cooperative group trial compared maintenance with erlotinib (Tarceva)—an epidermal growth factor receptor (EGFR) inhibitor—with observation in 835 patients with high-risk ovarian cancer who had no evidence of progression after first-line platinumbased chemotherapy.4 Fully 25% of patients in the erlotinib group stopped the drug because of adverse effects, mainly rash. With a median 26-month follow-up, erlotinib did not significantly improve median progression-free survival (12.7 vs 12.4 months) or overall survival (51 vs 59 months). Additional analyses failed to identify any subgroup of patients who derived benefit from the drug. “Basically, this is a negative trial… This is in spite of the fact that we have pretty good phase�� I�� /II data that suggested that there should be some activity in this group of patients,” Dr. Berek commented. “Why? Well it’s really not clear,” he continued. “Part of it, of course, is

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Best of ASCO® Annual Meeting ‘12 that EGFR-activating mutations are rare in ovarian cancer, and that may have something to do with why this is not a useful target.”

Carboplatin Is Alternate Partner to Paclitaxel in Advanced Cervical Cancer The Japan Clinical Oncology Group ( JCOG) 0505 randomized phase III trial pitted carboplatin plus paclitaxel against cisplatin plus paclitaxel in patients with stage IVB, persistent or recurrent cervical cancer.5 Among the 253 patients studied, carboplatin/paclitaxel was not inferior to cisplatin/paclitaxel in terms of median progression-free survival (6.2 vs 6.9 months, Pnoninferiority = .053) and overall survival (17.5 vs 18.3 months, Pnoninferiority = .032). The rate of some adverse effects— neutropenia, and nausea and vomiting—and the percentage of days spent hospitalized were lower with carboplatin/paclitaxel.

“So can we recommend based on this that [carboplatin/paclitaxel] should be the new standard; is this conclusion justified? Well it appears to be a valid alternative,” at least for patients who have had prior cisplatin, as shown in subgroup analyses, Dr. Berek said. “It may be that the overall survival is not quite as good in cisplatin-naive patients, but that’s not clear from these data,” he noted. “It’s basically balancing the side effects of one regimen to the other. We didn’t have in this study a good quality-of-life piggyback, which is really kind of frustrating, but I think because we are not going to cure this group of patients, you have to just be cautious about using a lot of cisplatin with them,” he concluded. “My personal preference is to switch to carboplatin…I have kind of been doing that for the last few years anyway, and now I just feel more comfortable about it based on this report.”

■

Disclosure: Dr. Berek receives research funding from AstraZeneca and Genentech.

Key Gynecologic Cancer Findings Presented at Best of ASCO® ‘12 ■■ Adding olaparib to chemotherapy prolongs progression-free survival in platinum-sensitive ovarian cancer.

■■ Adding bevacizumab to chemotherapy prolongs progression-free survival in platinum-resistant ovarian cancer.

■■ Dose-dense paclitaxel is superior to conventional paclitaxel in advanced ovarian cancer in the long term.

■■ Maintenance erlotinib after first-line chemotherapy does not improve outcomes in ovarian cancer.

■■ Carboplatin is a noninferior alternative to cisplatin as a partner for paclitaxel in advanced cervical cancer.

All Eyes on Trials of IV vs IP Chemotherapy for Ovarian Cancer

he positive findings from the NOVEL trial add to the debate about how intravenous (IV) chemotherapy stacks up against intraperitoneal (IP) chemotherapy when treating ovarian cancer and the role of dose-dense approaches in general, according to Jonathan S. Berek, MD, of the Stanford Women’s Cancer Center, Stanford, California. A host of ongoing trials—GOG0252, GOG0262, ICON8, MITO 7, and iPOCC—are sorting out the impact of the route of administration and specific drugs, in addition to dose-dense strategies. “In the next 2 to 3 years, we are going to start to see mature data that will help us decide what’s best for our patients,” he predicted. “What should we do now for our patients? I think you have to individualize,” Dr. Berek recommended. “I have been doing IP therapy for several decades…, but certainly giving a dose-dense regimen is a lot easier than maintaining intraperitoneal catheters.”

■

References 1. Amit M. Oza, David Cibula, Ana Oaknin, et al: Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): A randomized, open-label phase II study. 2012 ASCO Annual Meeting. Abstract 5001. Presented June 2, 2012. 2. Pujade-Lauraine E, Hilpert F, Weber B, et al: AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). 2012 ASCO Annual Meeting. Abstract LBA5002. Presented June 2, 2012. 3. Katsumata N, Yasuda M, Isonishi S, et al: Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly

paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. 2012 ASCO Annual Meeting. Abstract 5003. Presented June 2, 2012. 4. Vergote IB, Joly F, Katsaros D, et al: Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A GCIG and EORTC-GCG study. 2012 ASCO Annual Meeting. Abstract LBA5000. Presented June 2, 2012. 5. Kitagawa R, Katsumata N, Shibata T, et al: A randomized, phase III trial of paclitaxel plus carboplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent or recurrent cervical cancer: Japan Clinical Oncology Group study ( JCOG0505). 2012 ASCO Annual Meeting. Abstract 5006. Presented June 2, 2012.

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TREANDA (bendamustine HCI) for Injection is his chemo. 速

This is his therapy.

Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001

HR†=0.27 (95% CI‡: 0.17, 0.43)

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. ‡ CI=confidence interval.

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatmentnaïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301) • TREANDA is administered with a convenient dosing schedule – The recommended dose for TREANDA is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles – In the phase 3 trial, patients received chlorambucil at a dose of 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • In the pivotal phase 3 trial, the most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150) Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur •Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment •TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA •The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August

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2012-2013 Oncology Meetings November 2012 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 2012 Science of Global Prostate Cancer Disparities Conference November 1-4 • Nassau, The Bahamas For more information: cancer.ufl.edu/research/symposiaand-conferences 7th Urologic Oncology Conference: Advances in Clinical Practice November 2-3 • Houston, Texas For more information: www.mdanderson.org/conferences Oregon Society of Medical Oncology & Oregon Radiation Oncology Society Fall 2012 Oncology Conference November 3 • Portland, Oregon For more information: www.osmo.org 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 8th NCRI Cancer Conference November 4-7 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ 2nd International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation November 5-6 • Bethesda, Maryland For more information: http://ncifrederick.cancer.gov/events/ relapse2012/ 24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu

PEGS Europe – The Essential Protein & Antibody Engineering Summit November 6-9 • Vienna, Austria For more information: www.pegsummiteurope.com Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org

Massachusetts Society of Clinical Oncologists 2012 Annual Meeting: Burkitt’s Lymphoma November 8 • Dedham, Massachusetts For more information: www.mass-oncologists.org

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com Current Concepts in Head and Neck Surgery November 10-11 • Houston, Texas For more information: www.mdanderson.org/conferences Joint Meeting of IPOS 14th World Congress and COSA’s 39th Annual Scientific Meeting November 11-15 • Brisbane, Australia For more information: www.ipos-cosa.org World Circulating Tumor Cells Summit November 12-15 • Boston, Massachusetts For more information: www.ctc-summit.com

The Arizona Clinical Oncology Society Fall Membership Conference November 9 • Phoenix, Arizona For more information: www.tacos-oncology.com Missouri Oncology Society Membership Conference November 9 • St. Louis, Missouri For more information: www.accc-cancer.org/ossn_network/ mo/MOevents.asp The Second International Conference on Cancer and the Heart November 9-10 • Houston, Texas For more information: www.mdanderson.org/conferences

Iowa Oncology Society Fall Membership Conference: New Directions in Healthcare and Cancer Management November 16 • West Des Moines, Iowa For more information: www.ios-iowa.com/ 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com Cancer Survivorship: Advancements in Research and Care November 17 • Honolulu, Hawaii For more information: www.hsco-hawaii.com/ 2nd Symposium Targeted Cancer Therapy November 19-20 • Heidelberg, Germany For more information: www.dfkz.de/en/symposiumTCT/

Cancer Summit: Novel Approaches to Drug Discovery November 8-9 • Boston, Massachusetts For more information: www.gtcbio.com BCY1 – Breast Cancer in Young Women Conference November 8-10 • Dublin, Ireland For more information: www.eso.net/events-2.html

Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org

AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Connective Tissue Oncology Society 17th Annual Meeting November 14-17 • Prague, Czech Republic For more information: www.ctos.org Controversies in the Management of DCIS of the Breast November 15 • Wilmington, Delaware For more information: www.dsco-delawareoncology.org Washington State Medical Oncology Society Fall Conference 2012 November 15 • SeaTac, Washington For more information: www.wsmos.org

RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp 2nd Annual Best of Oncology Conference November 30 • Toronto, Ontario For more information: www.oncologyeducation.com/ conferences/best-of-oncology-2012. html ASCO’s Quality Care Symposium November 30-December 1 • San Diego, California For more information: quality2012.asco.org continued on page 58

Soft Tissue Sarcoma... Most common primary sites of soft tissue sarcoma.1

HEAD AND NECK

[9%]

TRUNK

[19%] RETROPERITONEUM

[15%]

EXTREMITIES

[60%]

Raising Awareness of a Challenging Disease Soft tissue sarcomas are a heterogeneous group of more than 50 distinct histological subtypes with an estimated incidence of more than 10,000 cases per year in the United States.1 They can originate from connective tissue, including fat, muscle, nerve and nerve sheath, vasculature, and other connective tissues.1 They most commonly arise in the extremities, trunk and retroperitoneum. 1 The presentation of soft tissue sarcomas is variable, but patients often present with a painless mass that is increasing in size.2 Guidelines recommend a biopsy for diagnosis and histopathological classification of soft tissue sarcomas. The biopsy should be performed by an experienced surgeon or radiologist and assessed by a pathologist with sarcoma expertise.1 Guidelines also recommend that magnetic resonance imaging with or without computed tomography be performed for all masses with a chance of being malignant.1 1.

NCCN Guidelines速: Soft Tissue Sarcoma, V.1.2012. NCCN.org. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 05/01/2012. NCCN速 and NCCN GUIDELINES速 are trademarks owned by the National Comprehensive Cancer Network, Inc.

Ilaslan H, Schils J, Nageotte W, Lietman SA, Sundaram M. Clinical presentation and imaging of bone and soft-tissue sarcomas. Cleveland Clinic Journal of Medicine. 2010;77:S2-7.

息2012 The GlaxoSmithKline Group of Companies ONO528R0 Printed in USA. May 2012

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2012-2013 Oncology Meetings continued from page 55

Global Conference on Perioperative Medicine: Care of the Elderly and the Cancer Patient November 28-December 2 • Houston, Texas For more information: www.mdanderson.org/conferences Oklahoma Society of Clinical Oncology November 30-December 1 • Grapevine, Texas For more information: www.oscook.org

2013 Gastrointestinal Cancers Symposium January 24-26 • San Francisco, California For more information: www.gicasymposium.org T-cell Lymphoma Forum January 24-26 • San Francisco, California For more information: www.tcellforum.com The 15th International Symposium on Anti-Angiogenic

December 2012

Therapy: Recent Advances and

IDIBELL Cancer Conference on Personalized Cancer Medicine December 3-4 • Barcelona, Spain For more information: www.bocemtium.com/icc2012

Clinical Cancer Research

35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

Future Directions in Basic and January 31-February 2 • San Diego, California For more information: www.mdanderson.org/conferences

February 2013 Integrative Medicine Program’s 1st Annual Integrative Oncology Healthcare Professional Training Conference February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences ASCO-MECC Palliative Care

Second Annual Targeting Cancer Stem Cells: Promising New Therapeutics for Oncology February 11-12 • San Francisco, California For more information: www.triconference.com/targetingcancer-stem-cells/ Quantitative Real-time PCR: Applications for Molecular Diagnostics February 11-12 • San Francisco, California For more information: www.triconference.com/ Quantitative-Pcr/ Molecular Med Tri-Con 2013 February 11-15 • San Francisco, California For more information: www.triconference.com American Psychosocial Oncology Society 10th Annual Conference February 14-16 • Huntington Beach, California For more information: www.apos-society.org 2013 Genitourinary Cancers Symposium February 14-16 • Orlando, Florida For more information: www.gucasymposium.org

Workshop The Second Montréal Conference on Focal Therapy for Prostate Cancer December 7-8 • Montreal, Canada For more information: www.focaltherapymontreal.com 2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

January 2013 Breast-Gynecological International Cancer Congress January 17-18 • Cairo, Egypt For more information: www.bgicc.eg.net/

February 10-13 • Muscat, Oman For more information: www.asco.org/palliativecare Genomics in Medicine: Individualized Care for Improved Outcomes February 11-12 • San Francisco, California For more information: www.triconference.com/genomicspersonalized-medicine

North Carolina Oncology Association & South Carolina Oncology Society Joint Membership Conference February 14-16 • Greenville, South Carolina For more information: www.ncoa-northcarolina.com 2013 Multidisciplinary Head and Neck Cancer Update February 22-23 • Weston, Florida For more information: www.clevelandclinicmeded.com 2nd Novel Cancer Therapeutics Summit February 25-26 • Las Vegas, Nevada For more information: www.gtcbio.com/

March 2013 Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec.wfubmc.edu NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org

April 2013 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org

May 2013 European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

June 2013 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch

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Journal Spotlight Gastrointestinal Oncology

Socioeconomic Disparity in Colorectal Cancer Rates Attributed to Obesity and Behavioral Risks By Charlotte Bath

ore than one-third of the excess risk of invasive adenocarcinoma of the colon and rectum resulting from low socioeconomic status “could be explained by differences in exposure to behavioral risk factors, particularly a healthy diet,” researchers recently reported in the Journal of the National Cancer Institute.1 The investigators analyzed prospective data on 506,488 participants in the National Institutes of Health–AARP Diet and Health Study, including 7,676 who developed colorectal cancer during follow-up. They then quantified the contribution of behavioral risk factors and obesity, separately and together, to socioeconomic status disparities in colorectal cancer risk. Body mass index was used to identify patients at unhealthy weight, and dietary patterns were meaSee Page 75 sured using a Mediterranean diet score. Socioeconomic status was measured at the individual level (based on education) and the neighborhood level (based on a multifactor index). Compared with people in high socioeconomic status groups, study participants in low socioeconomic status groups were more likely to have low Mediterranean diet scores and unhealthy weight, and to be physically inactive.

findings support recommendations advocating a healthy lifestyle to reduce the risk of colorectal cancer, “as an observational study, our findings suggest

■

Reference 1. Doubeni CA, Major JM, Laiyemo AO, et al: J Natl Cancer Inst 104:13531362, 2012.

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases CabOzantinib MET Inhibition CRPC Efficacy Trials KEY ELIGIBILITY CRITERIA •Diagnosis of CRPC •Presence of bone metastases •Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) •No limit to the number of prior therapies

Lifestyle and Cancer Risk “[Socioeconomic status] differences in prevalence of physical inactivity, unhealthy diet, smoking, and unhealthy weight each explained between 11.3% (body mass index) and 21.6% (diet) of the association between education and risk of colorectal cancer and between 8.6% (smoking) and 15.3% (diet) of the association between neighborhood [socioeconomic status] and risk of colorectal cancer,” the researchers reported. “Health behaviors and [body mass index] combined explained approximately 43.9% (95% CI = 35.1%–57.9%) of the association of education and 36.2% (95% CI = 28.0%–51.2%) of the association of neighborhood [socioeconomic status] with risk of colorectal cancer. The percentage explained by all factors and [body mass index] combined was largest for right colon cancers and smallest for rectal cancers.” The authors noted that while their

B:8.625”

but do not definitively prove causal reT:7.625” lationships betweenS:6.75” [socioeconomic status], behavioral factors, obesity, and the risk of colorectal cancer.”

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib (60 mg qd) Randomization Prednisone

Randomized, double-blind, controlled trial

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

Randomized, double-blind, controlled trial

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PAGE 60

Issues in Oncology Cost of Care

Despite the Rhetoric, Cancer Care Costs Keep Skyrocketing: Is There a Solution? By Ronald Piana

lthough health-care experts routinely agree that the rising costs of oncology services are untenable, there is disagreement about how to reduce expenditures without harming access and quality of care. At this year’s ASCO Annual Meeting, Thomas J. Smith, MD, FACP, offered some interesting ideas about how to bend the cancer care curve downward.1

Thomas J. Smith, MD, FACP

Recognizing the Problem According to Dr. Smith, to maintain our ability to deliver high-quality cancer care, the oncology community must begin bending the cost curve downward, and the first step is an honest recognition of the problem. “The costs of cancer care are rising at an unsustainable rate, and the quality and value of the care is often suboptimal,” said Dr. Smith. Dr. Smith made the case that health care is often less than optimal with data from studies that looked at care patterns for patients with cancer. The findings he presented—such as inadequate use of hospice benefits, a lack of doctor-patient conversations about advance directives, and overuse of chemotherapy in the final weeks of life—are well documented in the literature, as is the disproportionate health-care spending in the United States compared with other Organisation for Economic Coordination and Development (OECD) nations. “We spend about $8,000 per person per year, nearly double the expenditures in Canada, which spends about $4,500 per person with equivalent or better national health-care outcomes than the United States,” said Dr. Smith. Dr. Smith stated the hard facts: “Our yearly health-care budget is approaching $3 trillion, which is devouring our [gross domestic product]. Insurance premiums have doubled over the past decade, as have out-of-pocket patient costs. These

unsustainable costs have resulted in 1 million health-related bankruptcies in the United States this year alone.”

Value Needs to Reflect Price Balancing value vs the cost of drugs and services is rapidly becoming a central theme in the health-care narrative. Dr. Smith gave several examples in which cost has outstripped value. “Some of the workhorse oncology drugs that have real clinical value are priced relatively inexpensively. For instance, paclitaxel and trastuzumab [Herceptin] cost less than $5,000 per month; however, some of the newer drugs such as pemetrexed [Alimta] cost about twice that at $10,000 per month. And, in the extreme cases we have drugs such as sipuleucel T [Provenge], which cost almost $100,000 for one administration,” noted Dr. Smith, adding that data show that many of the newer drugs do not add enough clinical value to warrant the sticker-shock costs. Dr. Smith stressed that most of the spending increases are well within our control. “Based on geographic variations, the congressional budget office (CBO) estimated that upward of 30% of clinical care is not evidence-based

affordable cost. And some of the most expensive treatments are no better than things they replace; for instance, Memorial Sloan-Kettering Cancer Center just elected to not cover ziv-aflibercept (Zaltrap), which costs twice as much as the comparison drug. In an effort to curb unnecessary spending, ASCO has joined the American Board of Internal Medicine in the “Choosing Wisely” campaign, which encourages medical groups to select five areas in which they can improve care and reduce costs. Dr. Smith highlighted the ground rules for the campaign. “Everything is on the table for discussion. We need to accept data where it exists, curative and adjuvant care along with clinical trials are always exempt, and perhaps most importantly, we need to recognize that this is going to be painful,” he said. “For instance, “ he continued, “supportive care and chemotherapy administration represent a main source of an oncologist’s income, so modifying certain practice methods to save money will ultimately reduce practice revenue—painful but necessary. Also, patients with cancer are a hefty source of hospital income; reducing hospital days will affect the institution’s bottom line.”

The consequences of changing our practice habits will result in equal or better care and sustainable growth in our delivery system. —Thomas J. Smith, MD, FACP

and does not add value for the patient. Things that oncologists do have control over are the use of imaging, chemotherapy selection, supportive care services, surveillance after curative care, proper and timely use of palliative care and hospice, and avoiding unnecessary therapy and hospitalization near the end of life,” said Dr. Smith.

Another bridge to cross is the initiation of comprehensive discussions about death and medical costs, subjects that both doctors and patients traditionally shy away from. “These discussions have been shown to save money and add to a patient’s quality of life,” said Dr. Smith.

Behavior Modification

Targeting Overvalued Treatment

As Dr. Smith pointed out, part of the rise in oncology costs is driven by physicians’ practice behavior, with respect to the underuse of cost-saving interventions such as palliative care and hospice, and overuse of unwarranted services and therapies. Palliative care and hospice actually improve the quality of care, at an

“The first area we targeted was aligning surveillance procedures to patients who were most likely to derive benefit. For instance, in 1990 we spent at least $1 billion in breast cancer screening [for recurrence]. Today that number is several billion dollars. However, the ASCO and National Com-

prehensive Cancer Network (NCCN) guidelines agree that in the absence of symptoms, there is no evidence that CEA, CA 27-29, positron-emission tomography, computed tomography, and bone scans have any value as screening tools to follow women,” said Dr. Smith. He emphasized that screening guidelines can be reviewed in less than 10 minutes, giving doctors the opportunity to explain to their patients that these expensive screening methods have no guideline-proven benefits for their breast health. “Instead, we should stress breast care that is effective, such as timely mammograms and maintaining a healthy lifestyle. The solutions that we proposed are that payers simply should not reimburse for these tests and the ASCO Quality Oncology Practice Initiative (QOPI) committee should audit for overuse,” said Dr. Smith. Another recommendation was to only use sequential or monotherapies in the second-line setting or later metastatic treatments. Dr. Smith explained why this approach was important. “Patients will live just as long, and they will avoid unnecessary toxicity. This will result in fewer supportive care costs, fewer hospitalizations, and will ultimately lower oncology costs. Naturally, this approach requires honest discussions about goals of care.” Dr. Smith remarked that it is also important to limit active therapy to patients with good performance status. “A good screening question to ask is, ‘Did this patient walk unaided to the clinic?’ If a patient’s ECOG performance status is 3 or 4, a discussion of prognosis and realistic treatment expectations should ensue,” noted Dr. Smith, adding that he and his colleague Bruce E. Hillner, MD, have written extensively about dose reductions that can obviate the need for granulocyte colony-stimulating factors (G-CSF) in solid tumors. “The United States has 3% of the world’s population, but buys 75% of the world’s G-CSF. These drugs are essential when using certain types of chemotherapy, but we have not found any trial that shows better survival rates when using G-CSF in solid tumors,” said Dr. Smith. One other “Choosing Wisely” recommendation was to switch to nonchemotherapy palliative care after the

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Issues in Oncology

cancer grows through two or three regimens. “Using NSCLC as an example, we see that the use of chemotherapy after two or three regimens is toxic, expensive, rarely helpful, and prevents the planning for transitions to end-oflife care, such as timely entry into hospice,” said Dr. Smith.

Conclusions Along with ASCO’s “Choosing Wisely” recommendations, Dr. Smith stressed that we need to change payment methods from those that incentivize overuse of testing and treatment to mechanisms that reward best practices. “Under the current fee-for-service practice, oncologists derive more than 50% of their revenue from the drugs they prescribe. I think this system will face continued pressure to change,” said Dr. Smith. “One alternative is fixed provider payment systems (ie, salaried physicians), in which physicians will trade lower revenue streams for more secure incomes. It’s important to note

that the Veterans Affairs systems have equivalent outcomes to private practices while working on a fixed budget. Moreover, as a community, we eventually need to see Medicare as a scarce resource, not a profit center.” Dr. Smith said that the oncology community could provide actionable solutions to improve both quality and

cost of care by using treatments based on evidence, better end-of-life care and coordination, more standardized practice methods, using clinical pathways, and more auditing with the intent of practice change. “The consequences of changing our practice habits will result in equal or better care and sustainable growth in our deliv-

For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

37%

changed

63% confirmed

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions

e-mail: Permissions@harborsidepress.com

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Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 • Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

‡

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010.

Now available for patients with ductal carcinoma in situ (DCIS) Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0712

ery system,” concluded Dr. Smith.

■

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

Reference 1. Smith TJ: Reducing the costs of cancer care: Bending the curve and how. 2012 ASCO Annual Meeting. Education Session. Presented June 2, 2012.

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PAGE 62

Patient’s Corner

A Series of Medical Missteps

After nearly 2 decades of intermittent gastrointestinal pain, I was finally diagnosed with pancreatic neuroendocrine tumor. By Debi Rutkowski, as told to Jo Cavallo

ince the beginning of my symptoms—occasional pain on the upper left side of my abdomen, accompanied at times by nausea—which started nearly 20 years ago, my condition, pancreatic neuroendocrine tumor, either remained undetected or was completely misdiagnosed until just recently. A series of diagnostic tests over the years, including a colonoscopy, barium enema, and three endoscopies failed to show any gastrointestinal disease. Four years ago, the pain in the left area of my abdomen became so strong, my primary care physician finally sent me for a CT scan. The results showed a mass in the middle of my pancreas, and I was referred to a specialist who biopsied the tumor. The pathology examination found the tumor to be a benign solid pseudopapillary neoplasm, but because there were some neoplastic cells contained in the mass, it was recommended that I get a CT scan every year for the next 5 years. By the following year, the pain in my left side was back, my pancreatic enzymes were elevated, and I was diabetic. Although an MRI showed a regional lymph node near my pancreas, my doctor said it was so small it was nothing to worry about and to come back in a year for another MRI. Now I realize that the lymph node should have been a red flag that the tumor was recurring. In 2010, the mass was in

my liver, and that’s when I finally got a diagnosis of nonfunctional pancreatic neuroendocrine tumor.

Lessons Learned The medical missteps didn’t end there. The oncologist I was initially referred to had never treated a patient with my type of cancer, so she recom-

but that was not yet FDA-approved for pancreatic neuroendocrine tumor. While I was on the drug, my local oncologist prescribed an antibiotic for a sinus infection (amoxicillin, and then azithromycin when the infection persisted). I experienced an adverse drug interaction that nearly caused liver failure. The antibiotics were stopped and I improved.

I realize that the symptoms associated with neuroendocrine cancer can be elusive. Still, I wonder, if my doctors had been more vigilant—or if I had been more proactive earlier on— might the outcome have been different? —Debi Rutkowski

mended that I see a specialist in pancreatic neuroendocrine cancer who was located out of state, and she agreed to treat me based on his protocol. I later learned that when a patient has a rare cancer like mine, she should be treated solely by an expert in that cancer type. Because the number of tumors in my liver made me ineligible for immediate surgery, my oncologist prescribed sunitinib (Sutent), a drug that had shown positive results in clinical trials for shrinking my type of cancer

The good news was that after 8 months on sunitinib, the tumors had shrunk enough for me to have the surgery. During the procedure, the lymph node was excised and examined, but it turned out not to be cancerous. However, the right lobe of my liver had to be removed because it was riddled with cancerous tumors and several small tumors were removed from the left lobe. Although the surrounding tissue margins of the tumors were clean, the cancer has since recurred on the left lobe of

my liver, and I’m back on sunitinib.

Missed Opportunities I now know that I’ll never be rid of this cancer. My oncologist reassures me that while my disease is not curable, it is manageable, and I see him every 6 weeks so he can monitor my status. Having cancer has interrupted my life and leaves me exhausted from the treatment and running from one specialist to another and from one test to another. However, my family and my faith keep me positive and hopeful. With six children, four of whom still live at home, I’m often too busy to even remember that I have cancer. Nevertheless, when I look back over the past 2 decades, I can’t help but think that if only someone had prescribed a CT or MRI scan of my abdominal area when I first began experiencing gastrointestinal pain, the cancer might have been detected at a much earlier stage, when it was potentially curable. I realize that the symptoms associated with neuroendocrine cancer can be elusive, fitting a variety of less serious diseases and making a definitive diagnosis especially difficult. Still, I wonder, if my doctors had been more vigilant—or if I had been more proactive earlier on— might the outcome have been different?

■

Debi Rutkowski lives in Royersford, Penn� sylvania.

Don’t Miss These Important Reports in this Issue of The ASCO Post

Level 1 Evidence in Bladder Cancer, by Derek Raghavan, MD, see page 1

William G. Wierda, MD, PhD, on Elderly Patients with CLL, see page 10

Visit The ASCO Post online at ASCOPost.com

Dacomitinib in Advanced NSCLC, by Tony Mok, MD, see page 14

In metastatic melanoma

MAKE TREATMENT PERSONAL by testing for the BRAF V600E mutation with the cobas test 速

Test at diagnosis. Test with the cobas 4800 BRAF V600 Mutation Test. 速

Only FDA-approved BRAF PCR diagnostic1 20% more accurate than Sanger Sequencing with fewer false negatives and invalid results1

Indication and Usage: ZELBORAF速 (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60

Not reached

7.9

OS=overall survival HR=hazard ratio CI=confidence interval *Patients crossing over to ZELBORAF were censored.2

20 0

At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡

There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) 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 cutaneous squamous cell carcinoma and rash Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, generalized rash and erythema, or hypotension, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT prolongation Exposure-dependent QT prolongation has been reported, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes. Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval.

Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred. Monitor liver enzymes 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. Photosensitivity Mild to severe photosensitivity has been reported. Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Routinely monitor patients for uveitis.

SURVIVAL Updated Significant OS improvement confirmed in an updated analysis3§ OS update at ASCO 20123||¶ 100

HR=0.70 (95% CI, 0.57-0.87), P<0.001

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

At the time of updated analysis, median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine.3,4

At the time of the ASCO 2012 updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.4

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)3,4

Additionally, blurry vision, iritis, and photophobia were observed. New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC]. Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm. BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events 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 predefined as a grade 3 event. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (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 July 23, 2012. 3. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 8502. 4. Data on file. Genentech, Inc.

zelboraf.com

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Journal Spotlight Breast Cancer

Cancer Genome Atlas Network Reports Comprehensive Molecular Portraits of Breast Tumors

he Cancer Genome Atlas Network recently reported findings of analyses of primary breast cancers in a total of 825 patients using genomic DNA copy number arrays, DNA meth-

ZELBORAF ® (vemurafenib) tablet, oral 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 recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may 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)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

ylation, exome sequencing, mRNA arrays, microRNA sequencing, and reverse-phase protein arrays.1 Integration of information across these platforms allowed the investigators to gain deep-

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 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. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported 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. 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.

er knowledge of previously defined gene-expression subtypes in breast cancer and confirmed the existence of four main breast cancer classes—luminal A, luminal B, HER2-enriched, and

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 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 3 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

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

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

basal-like—when data from five of the platforms were combined, with each of these classes See Page 75 showing significant molecular heterogeneity. As noted by the authors, the finding of four main subtypes caused by different subsets of genetic and epigenetic abnormalities suggests that much of the clinically observed heterogeneity of tumor behavior occurs within rather than across these major biologic subtypes.

Other Key Findings Major findings of the analyses included identification of somatic mutations in only three genes (TP53, PIK3CA, and GATA3) with an incidence of >�� 10% across all breast cancers. Numerous subtype-associated and novel gene mutations were identified, including enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1 in the luminal A subtype. For HER2-classified tumors, two novel protein expression–defined subgroups were identified, possibly produced by stromal/microenvironment elements; specific signaling pathways characterized the two molecular subtypes, including an EGFR/phosphorylated EGFR/HER2/phosphorylated HER2 signature within the HER2-enriched subtype. Basal-like tumors showed many molecular similarities with highgrade serous ovarian tumors, suggesting a related etiology and the potential utility of investigating similar therapeutic approaches to the two cancers. In addition to identifying nearly all genes previously implicated in breast cancer (PIK3CA, PTEN, AKT1, TP53, GATA3, CDH1, RB1, MLL3, MAP3K1, and CDKN1B), the investigators identified numerous novel significant mutations, including those in TBX3, RUNX1, CBFB, AFF2, PIK3R1, PTPN22, PTPRD, NF1, SF3B1, and CCND3. Of note, RUNX1 and CBFB, both of which are rearranged in acute myeloid leukemia and mutations in which interfere with hematopoietic differentiation, contained 19 and 9 mutations, respectively. PIK3R1 contained 14 mutations, with clustering in the PIK3CA interaction domain similar to previously identified mutations in glioma and endo-

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Journal Spotlight

metrial cancer. A significant exclusion pattern was observed among PIK3R1, PIK3CA, PTEN, and AKT1 mutations (P = .025). SF3B1 had 15 mutations, including recurrent K700E substitutions; SF3B1 mutations have also been identified in myelodysplastic syndromes and chronic leukocytic leukemia.

Luminal Tumors Notable findings in luminal/estrogen receptor (ER)-positive subtypes included the greatest heterogeneity of gene expression and the largest number of significantly mutated genes. The analyses confirmed the high rate of PIK3CA mutation in luminal/ER-positive cancers, identified a high frequency of MAP3K1 and MAP2K4 mutations (which were largely mutually exclusive), and a higher rate of TP53 mutation in luminal B vs luminal A cancers. Additional investigation suggested that the TP53 pathway remains largely intact in luminal A cancers but often is inactivated in the more aggressive luminal�� B cancers. The tumor suppressor RB1 had higher levels in luminal A tumors, as well. Pathway differences associated with luminal B vs luminal A cancers included hyperactivation of transcriptional activity associated with MYC and FOXM1 proliferation. Based on the genomic characterizations, potential therapeutic approaches include use of inhibitors of the activated PIK3CA kinase or its signaling pathway, AKT1 inhibitors, since 11 of 12 identified AKT1 variants were luminal, and PARP inhibitors for BRCA1/ BRCA2 mutations. Based on amplification of genomic DNA copy number, other targets might include FGFR, IGFR1, cyclin D1, CDK4, and CDK6.

HER2-based Classification Of all HER2-enriched tumors, 20% were ER-positive/HER2-negative, 68% were HER2-positive, and 9% were triple-negative (ie, negative for ER, HER2, and progesterone receptor). Analysis of these tumors strongly indicated that there are at least two types of clinically defined HER2-positive tumors. Not all clini-

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cally HER2 protein–positive tumors were of the HER2-enriched mRNA subtype and vice versa. When HER2positive protein and HER2-enriched mRNA subtypes overlapped, there was a strong signal of EGFR/phosphorylated EGFR/HER2/phosphorylated HER2. Approximately 50% of clinically HER2-positive tumors fell into this category, with the remainder predominantly being of the luminal mRNA subtype.

tions, and genomic loss of PTEN and INPP4B. Other potentially druggable mutations included variants in HER family members, including two somatic mutations in HER2, two in EGFR, and five in HER3, with these findings suggesting that joint targeting of EGFR and HER2 could be beneficial. The HER2-enriched mRNA subtype showed high aneuploidy, the highest somatic mutation rate, and DNA amplification of other potential targets,

Genetics of Breast Cancer ■■ Molecular analyses indicate four main breast cancer classes. ■■ New insights into molecular architecture of subtypes suggest new therapeutic targets.

BRCA1 inactivation, RB1 loss and cyclin E1 amplification, high expression of AKT3, MYC amplification and high expression, and high frequency of TP53 mutation. Pathway analysis showed comparably high activity of HIF1-α/ ARNT, MYC, and FOXM1 regulatory hubs in the two cancers. As noted by the authors, the common findings of TP53, RB1, and BRCA1 loss with MYC amplification strongly indicate that these are shared driving events in carcinogenesis for the two types of cancer. Moreover, as suggested by the activity of platinum compounds and taxanes in both types, common therapeutic approaches should be considered in both.

Therapeutic Targets Gene-expression analysis for these subtypes showed that genes largely tracked with ER status but also indicated that the HER2-enriched-mRNAsubtype/HER2-positive tumors had significantly higher expression of a number of receptor tyrosine kinases, including those for FGFR4, EGFR, and HER2, as well as genes within the HER2 amplicon (including GRB7);

including FGFRs, EGFR, CDK4, and cyclin D1.

Basal-like Tumors Most of the basal-like tumors (80%) were triple-negative cancers. Basal-like tumors had a high frequency of TP53 mutation (80%), with inferred effect on TP53 pathway activation suggesting that most, if not all, basal-like

Approximately 20% of basal-like tumors had a germline or somatic BRCA1 or BRCA2 variants, suggesting that 20% of patients might benefit from a PARP inhibitor or platinum compound. the luminal-mRNA-subtype/HER2positive tumors showed higher expression of the luminal cluster of genes, including GATA3, BCL2, and ESR1. Other notable findings included significant enrichment of TP53 mutations in HER2-enriched or ER-negative tumors and exclusive presence of GATA3 mutations in luminal subtype or ERpositive tumors. Findings in this study that suggest therapeutic targets in HER2-positive disease include a high frequency of PIK3CA mutations (39%), lower frequencies of PTEN and PIK3RI muta-

cancers have loss of TP53 function. Although PIK3CA was the next most frequently mutated gene (9%), inferred PI3K pathway activity was highest in basal-like cancers; alternative means of activating this pathway might include loss of PTEN and INPP4B or amplification of PIK3CA. Basal-like tumors had numerous features in common with serous ovarian tumors, including widespread genomic instability and common gains of 1q, 3q, 8q, and 12p, and loss of 4q, 5q, and 8p. When both types of tumor were compared with luminal tumors, they shared

With regard to potential therapeutic approaches, it was found that approximately 20% of basal-like tumors had a germline or somatic BRCA1 or BRCA2 variants, suggesting that 20% of patients might benefit from a PARP inhibitor or platinum compound. Observed amplifications and deletions in copy number analysis suggested a number of targets including PTEN and INPP4B loss, both of which have been shown to promote sensitivity to PI3K pathway inhibitors. Many components of the PI3K and RAS-RAF-MEK pathway were amplified, though not typically mutated, including PIK3CA (49%), KRAS (32%), BRAF (30%), and EGFR (23%). Receptor tyrosine kinases that were amplified in some tumors and could constitute drug targets included those for FGFR1, FGFR2, IGFR1, KIT, MET, and PDGFRA. The high HIF1-α/ ARNT pathway activity suggests that the basal-like cancers might be susceptible to angiogenesis inhibitors or bioreductive drugs that are activated under hypoxic conditions.

■

Reference 1. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61-70, 2012.

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LET US HELP YOU PROVE IT. JOIN THE OVER 140 ONCOLOGY PRACTICES IN THE U.S. WHO HAVE RECEIVED QOPI CERTIFICATION AND DISTINGUISH YOUR PRACTICE. BENEFITS OF QOPI CERTIFICATION INCLUDE: • Practice Improvement – Benchmark performance, implement improved systems, and provides structural standards to aid practice management. • A Demonstration of Quality – Benchmark against national standards and demonstrate improved standards and processes to safeguard both practice and patients. • Improved Efficiency, Effectiveness – Translate policies and procedures into practice and streamline interdepartmental communications to keep better records and avoid costly errors. • Public Trust, Competitive Edge – Achieve recognition from health plans and incorporate QOPI Certification status in practice marketing materials to patients, caregivers, and your medical community.

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PAGE 69

In the News Supportive Care

Pain Remains Prevalent among Oncology Outpatients, with Odds of Undertreatment Twice as High among Minority Patients By Charlotte Bath

n 1994, a landmark study of pain among oncology outpatients prompted a host of pain management initiatives.1 More than 18 years laterd, a recent study among more than 2,000 cancer outpatients has found that “one-third of the patients who had pain or used analgesics received inadequate treatment for pain.” In addition, the investigators reported in the Journal of Clinical Oncology,2 “the odds of inadequate analgesic prescribing are twice as high for minority patients compared with non-Hispanic white patients.” An editorial accompanying the article asserted, “it should definitely surprise and disappoint us that analgesic prescribing was still inadequate in 33% of these patients.”3 Echoing that disappointment, the study’s lead author, Michael J. Fisch, MD, MPH, told The ASCO Post, “The disappointing thing is seeing patients struggle, seeing what happens to them and their family in the face of undertreated pain or unmanaged pain or underassessed pain problems.” Dr. Fisch is Chair of the Department of General Oncology at The University of Texas MD Anderson Cancer Center in Houston.

found that some people got better, but most people were not better.” Dr. Fisch noted. Of the 3,023 patients identified to be at risk for pain in the recent study, 2,026 (67%) reported having pain or requiring analgesics at initial assessment and were included in the statistical analysis. Among these patients, “670 (33%) were receiving inadequate analgesic prescribing. We found no difference in treatment adequacy between the initial and follow-up visits.” the investigators reported.

Common Solid Tumors The patients had invasive cancer of the breast (50%), colon/rectum (21%), lung (19%), or prostate (10%). These common solid tumors

0 to 627 months),” according to the study report. “The investigators were not involved in patient care,” Dr. Fisch explained. “The patient care was being done 90% of the time by community oncologists, but these were community oncologists who are affiliated with the clinical cooperative group system through the Eastern Cooperative Oncology Group (ECOG) and they all knew that they were doing a symptom management study.” Because of that, some people had expressed concern that there would be a Hawthorne effect, whereby just paying attention to the problem would produce good results. “Our response to that critique was, ‘If only that were the case,’ Dr. Fisch said. “Wouldn’t it

Patients with nonadvanced cancers who were not receiving cancer-directed treatment were especially likely to be undertreated for pain. —Michael J. Fisch, MD, MPH

Revised Methodology The previous pain study was led by Charles S. Cleeland, PhD, currently Chair of the Department of Symptom Research at MD Anderson, who also served as a coauthor of the new study. “Dr. Cleeland’s study only had one point in time,” Dr. Fisch pointed out, when physicians prescribed pain treatment based on patient ratings of

Charles S. Cleeland, PhD

the severity of their pain. Some people had argued that a follow-up was needed to reflect the effects of the prescribed pain treatment. “So in this trial, we came back a month later and

were chosen because of their dominance in outpatient care. At the initial study visit, 78% of the patients were receiving cancer therapy. The median age was 60 years old. At the initial study visits and follow-up visits 4 to 5 weeks later, patients completed a 25-item measure of pain, functional interference, and other symptoms. “Providers recorded analgesic prescribing. The pain management index was calculated to assess treatment adequacy,” according to the study report. Patients were enrolled in the study “at any point in their trajectory of care,” so the initial visit refers to the first visit after patients agreed to participate in the study, not necessarily their first outpatient visit. “Some patients might have been new to the oncologist and some patients might have been there for 10 years for follow-up,” Dr. Fisch noted. “The median time from initial disease diagnosis to study registration was 16 months (range,

be a great world if just paying more attention in the context of the study would make this a much easier issue.”

Predictors of Inadequate Pain Treatment Close to 25% of the study participants were minority patients (12% black, 9% Hispanic or Latino, 1% Asian, 1% other minority. “Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were approximately half those of a minority patient after adjusting for other explanatory variables,” the investigators reported. “Other significant predictors of inadequate pain treatment were having a good performance status, being treated at a site with mostly minority patients, and having nonadvanced disease without concurrent treatment.” Dr. Fisch said that the doubling of odds of inadequate analgesic prescribing for minority patients could

be attributed to a number of factors including “perception, beliefs, concerns about employment, concerns about the cost of opioids, sometimes language, sometimes literacy independent of language, sometimes See Page 75 comorbidity to the extent that minority populations often have other health concerns that make them need to take a large number of medicines,” he continued. “Probably 25% of the whole cohort was on 10 or more medicines,” he noted. “When you are already on 10 medicines, sometimes you don’t want to be on your 11th or 12th. Or when we prescribe pain medications, we say, ‘Well, you also should take some laxatives with that,’ so then it is 13 or 14.” The study also found that non-Hispanic white patients are more likely to be undertreated for pain at sites with mostly minority patients. The investigators suggested that system factors, such as opioid availability, could be contributing to the disparity. Dr. Fisch explained that minority sites may have more limited supplies and might not have an opioid in the dose a physician wants to prescribe. The overall flow of patients through these sites may not be efficient. Locating competent translators may also pose challenges. The nuances of eliciting information from patients “take time and attention to get through,” Dr. Fisch noted. “If your system isn’t efficient and if you are a little bit strapped, you might not have that patience to drive through all that. So you start being really limited in how you go about doing things because of the system,” he said.

Transition to Primary Care “Patients with nonadvanced cancers who were not receiving cancer-directed treatment were especially likely to be undertreated for pain,” the study found. These would be patients who are no longer receiving active treatment for cancer and are ready to transition back to primary care. At that point, oncolocontinued on page 70

The ASCO Post | NOVEMBER 1, 2012

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In the News

Pain Remains Prevalent continued from page 69

gists “don’t want to pick a fight with you about your pain,” Dr. Fisch said. A New York Times article about the pain study quoted Dr. Fisch as saying, “A doctor can’t help but wonder, ‘Am I going to be the one responsible for refilling those pre-

scriptions until the end of a patient’s life?’”4 He explained to The ASCO Post that maintaining connections to patients because of a pain prescription may not be “doing them a favor.” Moreover, he said, “it may not be doing the practice a favor,” if following survivors reduces the ability to see new patients on a timely basis.

Planning for ‘Best Case Scenarios’ Physicians and patients “need to be better prepared for the best case scenario that patients with cancer will survive. That means dealing with the whole person, including pain,” Dr. Fisch said. “When I talk to individual patients with cancer, some of them

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may have a difficult prognosis and sometimes they can only think about the best case scenario, and they refuse to imagine doing end-of-life planning or discussing difficult issues with their family. But sometimes it is the opposite. They do all that planning in case they might die, but they actually haven’t figured out what they’d do if they don’t die.” He continued, “Some of them do decidedly well, and that is what they were hoping for, but they actually had no plans around that. Then they start to struggle with their survivorship because they had no game plan.” Physicians can assist with planning by asking patients to think about all the possible scenarios and what will happen if all goes well. “The whole issue of survivorship care plans is very tricky,” Dr. Fisch said. “Ask patients who they want to see for their continued care. Who will accept them? When will they get that first visit? What would that doctor need to know to be prepared? Start to develop it along the way so patients have time, because it might take them 2 months to get an appointment in primary care.” “This potential gap in pain management could be bridged with improved coordination of care between oncologists and nononcologists,” according to the study report, but Dr. Fisch noted that currently that “happens here and there, but it does not happen pervasively.” Patients who are part of a vertically integrated health system have a better chance of coordinated care, “but most of the patients in this country, when they transition from an oncologist to other providers, are moving across a system of care to providers who have no natural linkage,” he stated. Some providers have forged relationships and figured out how to bridge that gap, “but for the average patient it is very ad hoc and not well worked out. Patients find it very frustrating, and a lot of their needs go unmet.”

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Patients may resist suggestions to let their ongoing care be taken over by a primary care physician. A study among 42 cancer survivors found that most “expressed strong preferences to receive follow-up care from their cancer specialists,” and only 38% “believed there was a role for primary care in cancer follow-up.”5

ASCOPost.com | NOVEMBER 1, 2012

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In the News

“Patients get very well cared for during their cancer care. They develop relationships with the infusion nurses, the front office staff, other patients, the midlevel provider, and the oncologist. They have a whole network of people who have met various needs for them,” Dr. Fisch commented. “So it is pretty understandable the patient might say, ‘I’ll just stay with what I’ve got.’”

No Fundamental Changes in Pain Treatment While in many cases, the treatment of cancer is much different than it was when the Cleeland pain study came out, “there is almost nothing of consequence that is different about how we fundamentally should and do approach that patient’s pain,” Dr. Fisch stated. “There are technological

things, but implantable pumps and the like have such a little role. They are just not used, or rarely used, and often don’t work. In practical terms, it is the same kind of drugs prescribed in the same kinds of ways.” Major progress against pain in cancer patients continues to be thwarted by a lack of clinical trials and resources devoted to understanding pain mechanisms and developing analgesics that are nonaddictive, with side effects that do not compromise a patient’s alertness and ability to work and care for children, according to Dr. Fisch. The study report noted that the Institute of Medicine has called for a “cultural transformation” in the understanding, management, and prevention of pain. For that to happen, “there is going to have to be a determination at both the scientific

and clinical levels, along with quality systems and careful pain monitoring. Currently, it is just not prioritized as a problem to attack,” Dr. Fisch said. “I am not hopeless about it,” he continued. “I think preventing and curing disease will also be a great way to reduce pain. One way to reduce this pain is to succeed in the Moon Shots Program,” he said, referring to MD Anderson’s recently announced initiative to dramatically reduce cancer deaths by allocating an estimated $3 billion over the next 10 years. “But if we end up moving the needle without eradicating the suffering, then we will have a lot of patients with a lot of unmet needs for a while. We have to figure out how to make sure we take good care of people.”

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

References 1. Cleeland CS, Gonin R, Hatfield AK, et al: Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 330:592-596, 1994. 2. Fisch MJ, Lee J-W, Weiss M, et al: Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer. J Clin Oncol 30:1980-1988, 2012. 3. Stockler MR, Wilcken NRC: Why is management of cancer pain still a problem? J Clin Oncol 30:1907-1908, 2012. 4. Chen PW: Poor pain control for cancer patients. New York Times. September 20, 2012. 5. Hudson SV, Miller SM, Hemler J, et al: Adult cancer survivors discuss followup in primary care: ‘Not what I want, but maybe what I need?’ Ann Fam Med 10:418-427, 2012.

Don’t Expect Direct Questions from Patients about Pain But do ask open-ended questions about how they are doing

ust asking patients “Is there something else you want to address in the visit,” rather than “Is there anything else you want to address in the visit today,” dramatically reduced patients’ unmet concerns during a primary care visit, according to a 2007 study.1 That learning can be applied to talking to cancer patients about pain. “If you say ‘anything else’ or if your hand is on the doorknob, you are sending a little message, ‘Are we done yet?’” Michael J. Fisch, MD, MPH, told The ASCO Post. Lead author of a cancer pain study recently published in the Jour� nal of Clinical Oncology,2 Dr. Fisch is Chair of the Department of General Oncology at The University of Texas MD Anderson Cancer Center in Houston.

Recommendations Asking open-ended questions during—and not just at the very end of—a visit, and letting patients offer enough clues about what is troubling them can provide the information physicians need to help patients manage cancer pain. “I think that is a skill that can be learned,” Dr. Fisch said. You don’t have to He suggested the following opensolve everything in one ended questions: • Take me through your day. What visit. Sometimes you are things like for you these days? You learn things in one visit may have to prompt patients by saying, “You wake up and have a cup of that open the door for coffee and then what happens?” By usyou next time. ing that line of questioning, physicians —Michael J. Fisch, MD, MPH might find out that a patient gets tired from a short walk or needs somebody to bring food because leg pain is preventing the patient from standing up to use the stove. “By the time you take me through your day, I have a pretty good sense of your functional levels and limitations are,” Dr. Fisch explained. • What was your life like before you started cancer treatment? This question can provide a sense of what functions patients have lost and how that affects them. For example, a patient might say, “I was the kind of person who was very busy. I

did it all. I had lots of energy. Now I can’t do anything. I can’t remember things. I hurt all the time.” These questions and the conversations that flow from them can help physicians understand what patients think is really important to their lifestyle and quality of life and build trust. “You don’t have to solve everything in one visit,” Dr. Fisch advised. “Sometimes you learn things in one visit that open the door for you next time. In real time, that ‘something else?’ question may not have done much more than plant the seed, but that seed can help you understand the patient in the most robust way, as a whole person, so you can figure out how to help in all possible ways, not just during chemo or when the next scan is ordered. It is saying to the patient, ‘That’s not all I am interested in.’”

Team Work Not all the talking needs to be done by the oncologist. “The oncologist can set that tone, and then the midlevel providers—the other people in the office— can pull together these clues about the patient that inform you how to focus the care and get better results,” Dr. Fisch said. “That is an integrated systems and team work issue, using your own systems, your own personal clues, and the people you consider your own microteam over time, and figuring out what you can do to help the patient,” he added. “You shouldn’t just go through your own agenda, your predetermined check list, because patients do not experience things in the linear and limited way that you wish they would. If you accept that you are dealing with complex issues, then you have to let your techniques inform how you can be successful in the face of that complexity.”

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

References 1. Heritage J. Robinson JD, Elliott MN, et al: Reducing patients’ unmet concerns in primary care: The difference one word can make. J Gen Intern Med 22:1429-1423, 2007. 2. Fisch MJ, Lee J-W, Weiss M, et al: Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer. J Clin Oncol 30:1980-1988, 2012.

The ASCO Post | NOVEMBER 1, 2012

PAGE 72

Awards

Daniel Von Hoff, MD, Recognized with Award as Research Leader in Pancreatic Cancer

aniel Von Hoff, MD, PhysicianIn-Chief of the Translational Genomics Research Institute (TGen) is the first recipient of the Lori Groetken

Memorial Lecture and Award presented recently at Washington University in St. Louis. He delivered his lecture “A Relentless Molecular Pursuit Approach to

Take Out Pancreatic Cancer,” at the Siteman Cancer Center in St. Louis. “I am extremely honored and humbled to be the first recipient of the

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Look inside for these important topics! • Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

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About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

Daniel Von Hoff, MD

Lori Groetken Memorial Lecture, and I look forward to the opportunity to present this lecture and discuss how we can make advances together against this terrible cancer,” said Dr. Von Hoff. The lecture and award is in memory of Lori Groetken, a pancreatic cancer patient who fought the disease for 2 years. She and her husband, Cecil, were at the forefront of raising funds for pancreatic cancer research at the Siteman Cancer Center. The annual lecture series in her name has been created to recognize individuals whose research makes substantial contributions to the field of pancreatic cancer research.

Contributions to Drug Development Dr. Von Hoff has contributed to the development of numerous anticancer agents, including paclitaxel, docetaxel, irinotecan and gemcitabine. He also is the Chief Scientific Officer of TGen’s clinical trials at Scottsdale Healthcare’s Virginia G. Piper Cancer Center, Chief Scientific Officer at US Oncology, Professor of Medicine at Mayo Clinic, and Clinical Professor of Medicine at the University of Arizona College of Medicine. Dr. Von Hoff founded the Pancreatic Cancer Research Team (PCRT), an international network of clinical trials sites organized under TGen Drug Development (TD2), a TGen subsidiary. PCRT represents a consortium of 45 highly experienced investigators and clinics from across the United States and Europe, dedicated to finding a cure for pancreatic cancer, which is the nation’s 4th leading cause of cancer death.

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

ASCOPost.com | NOVEMBER 1, 2012

PAGE 73

Pioneers in Oncology Feminist Author Babette Rosmond Helped Propel the Adoption of Patients’ Rights to Choose Their Cancer Treatment

Courtesy of Jim Stone and Barron Lerner, MD

By Jo Cavallo

hen writer and editor Babette Rosmond was diagnosed with breast cancer in 1971, the second wave of the Women’s Liberation Movement that began in the mid-1960s was in its infancy. Still, when told by her doctor that she would need a radical mastectomy—a procedure developed by William Stewart Halsted in 1882—to remove her cancerous left breast, plus underarm lymph nodes and her chest wall muscles, Ms. Rosmond rebelled and said she wanted 3 weeks to think it over. “In 3 weeks you may be dead,” said her doctor.1

Second Opinion Undeterred, Ms. Rosmond, then 49, sought a second opinion with George Crile, Jr, MD, a surgeon at the Cleveland Clinic and a pioneer in breast-conserving surgery. Seven years earlier, at the Annual Scientific Assembly of the American Academy of General Practice (later renamed the American Academy of Family Physicians), Dr. Crile told physicians that too much tissue was being removed in the surgical treatment of many women with malignant and benign breast tumors. He cited results from a study of

nearly 200 patients with breast cancer. While 75% of the cancers in the study were operable, half of the patients were treated by a form of radical mastectomy and the other half were treated with a simple mastectomy, in which the cancerous breast is removed but lymph nodes and chest muscles are left intact. Most of the study participants received no adjuvant radiation therapy. The 5- and 6-year survival rates of patients treated with the less invasive procedure, Dr. Crile said, were “a little higher” than those for patients given radical mastectomies. And, he noted, the survival rate was higher for patients of surgeons who chiefly performed simple mastectomies than for surgeons performing radical mastectomies.2 Because Ms. Rosmond’s tumor was small and localized, Dr. Crile suggest-

ever, Ms. Rosmond was quick to point out in articles she wrote for women’s magazines such as McCall’s that while the choice she made was right for her, “I did not, do not, cannot recommend it for every woman.”

Speaking Out An outspoken critic of radical mastectomies not just within the medical establishment but in the public arena as well, Dr. Crile joined Ms. Rosmond on a 1973 episode of The David Susskind Show. Along with breast surgeon Jerome A. Urban, MD, a developer of the extended radical mastectomy for advanced breast cancer, and oncologist Ezra Greenspan, MD, founder of The Chemotherapy Foundation, they debated the merits of breast-sparing surgery vs the more conventional radical mastectomy in the treatment of

I think what I did was the highest level of women’s liberation…. I said ‘no’ to a group of doctors who told me, ‘You must sign this paper, you don’t have to know what it’s all about. —Babette Rosmond [writing as Rosamond Campion]

ed she have an even less invasive procedure than the simple mastectomy— a partial mastectomy, now known as a lumpectomy, in which only small amounts of tissue are removed. He also offered her adjuvant radiation therapy, which she refused. Happy with the results of her surgery, Ms. Rosmond wrote about her experience in The Invisible Worm: A Woman’s Right to Choose an Alternate to Radical Surgery,3 under the pseudonym Rosamond Campion. “I think what I did was the highest level of women’s liberation,” she wrote. “I said ‘no’ to a group of doctors who told me, ‘You must sign this paper, you don’t have to know what it’s all about.’” How-

breast cancer. Because the safety and efficacy of breast-conservation surgeries were not yet known, Dr. Urban and Dr. Greenspan voiced their concern that Ms. Rosmond’s decision would lead other women to choose similar procedures, resulting in more women needlessly dying from breast cancer. The discussion became heated, with Ms. Rosmond fiercely defending her decision. Ultimately, the show’s host felt compelled to support Dr. Urban and Dr. Greenspan, at one point referring to Ms. Rosmond as “Mrs. Civilian.”

A New Era of Care As the 1970s wore on and the femi-

nist movement grew—and buoyed by Ms. Rosmond’s public activism— more women began writing magazine articles and books encouraging women with breast cancer and other conditions to become more proactive in their treatment decisions and challenge their doctors to inform them of their best options. In 1985, the results of randomized clinical trials comparing surgical strategies for primary breast cancer were published in The New England Journal of Medicine.4 Led by University of Pittsburgh surgeon Bernard Fisher, MD, the investigators found that lumpectomy—at this point called segmental mastectomy—plus radiotherapy is equivalent to mastectomy in breast cancer survival. (The findings were challenged nearly a decade later when one of the researchers involved in the studies was found to have falsified data. However, subsequent analysis of the data found no change in outcomes.) Today, lumpectomy and adjuvant radiation therapy is standard of care for early-stage breast cancers. Ms. Rosmond’s breast cancer never recurred. She died in 1997 at the age of 75.

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References 1. Lerner B: The Breast Cancer Wars: Hope, Fear, and the Pursuit of a Cure in Twentieth-Century America. New York, Oxford University Press USA, 2003. 2. Too much tissue often removed in mastectomy, general practitioners told (medical news). JAMA 188:35-35, 1964. 3. Campion R: The Invisible Worm: A Woman’s Right to Choose an Alternate to Radical Surgery. New York, Macmillan, 1972. 4. Fisher B, Bauer M, Margolese R, et al: Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 312:665-673, 1985.

The ASCO Post | NOVEMBER 1, 2012

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Pathologic Nodal Status and Tumor Response Can Predict Risk of Locoregional Recurrence

Pathologic nodal status/breast tumor response following neoadjuvant chemotherapy can be used to predict locoregional recurrence in women with operable, palpable breast cancer (T1-3, N0-1, M0) previously treated

with mastectomy or lumpectomy plus radiotherapy. These results from the combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 trials were published in the

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Journal of Clinical Oncology. The neoadjuvant chemotherapy used in the NSABP trials was either AC (doxorubicin/cyclophosphamide) alone or AC followed by neoadjuvant/adjuvant docetaxel. After 10 years of follow-up, 335 locoregional recurrence events had occurred in 3,088 patients. “The 10-year cumulative incidence of [locoregional recurrence] was 12.3% for mastectomy patients (8.9% local; 3.4% regional) and 10.3% for lumpectomy plus breast radiotherapy patients (8.1% local; 2.2% regional),” the researchers reported. “Independent predictors of [locoregional recurrence] in lumpecSee Page 75 tomy patients were age, clinical nodal status (before [neoadjuvant chemotherapy]), and pathologic nodal status/breast tumor response; in mastectomy patients, they were clinical tumor size (before [neoadjuvant chemotherapy]), clinical nodal status (before [neoadjuvant chemotherapy]), and pathologic nodal status/breast tumor response. By using these independent predictors, groups at low, intermediate, and high risk [of locoregional recurrence] could be identified. Nomograms that incorporate these independent predictors were created.”

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9/26/12 2:36 PM

The authors noted that their nomograms could be useful in predicting the risk of locoregional recurrence and the optimal use of adjuvant radiotherapy in patients with neoadjuvant chemotherapy. Before such nomograms are used clinically, however, they need to be independently validated. The authors also recommended that future versions of the nomograms include information on the effect of hormone receptor status, HER2/neu status, and the therapeutic effect of adding trastuzumab (Herceptin) to chemotherapy in patients with HER2-positive disease. NSABP B-18 and B-27 did not allow chest wall or regional nodal external radiation therapy after mastectomy. Although lumpectomy patients were required to have breast radiotherapy, they were not permit-

ASCOPost.com | NOVEMBER 1, 2012

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In the Literature

ted to receive additional regional nodal radiotherapy. “To that extent, the two trials provide us with a large cohort of patients for whom the natural history of [locoregional recurrence] can be assessed without the confounding effects of nonuniform postmastectomy chest wall radiation or radiation to regional nodal basins,” the investigators stated. Mamounas EP, et al: J Clin Oncol. Oc� tober 1, 2012 (published early online).

Short Interval between Initial and Contralateral Breast Cancer Increases Risk of Dying Breast cancer survivors who develop contralateral breast cancer have an increased risk of dying from breast cancer throughout a follow-up period of 10 or more years, according to a study of a cohort of 42,670 women diagnosed with breast cancer in Sweden. “The added risk is considerable if the [contralateral breast cancer] adds substantially to the total tumor burden and the interval time between the two tumors is short,” the investigators reported in the Journal of Clinical On� cology. The risk of dying from breast cancer after contralateral breast cancer developed was also increased if the contralateral disease was advancedstage, high-grade, and hormonenegative. Endocrine therapy not only reduced the risk of developing contralateral breast cancer, but also improved the prognosis if it did develop. The median survival time for women in the study was 6.7 years. “The risk of developing [contra-

lateral breast cancer] tended to be higher when women were young at diagnosis of the initial breast cancer, but the association was not statistically significant. The risk of [contralateral breast cancer] was almost twice as high for women with more than 10 metastatic lymph nodes vs women who were node negative. Large tumor size was associated with a modestly increased risk, but an extension of cancer to the chest wall and/or to the skin (T4) more than doubled the risk,” the authors noted. “Our findings also indicate that some [contralateral breast cancers] may be metastases from the initial cancer and/or markers of active breast cancer disease and/or an undermined host defense. The findings suggest that the event of [contralateral breast cancer] marks a new clinical situation in terms of the investigation for metastases, treatment considerations, and follow-up strategy, and this situation needs to be covered in clinical guidelines,” the authors concluded. Vichapat V, et al: J Clin Oncol 30:3478-3485, 2012.

COLORECTAL CANCER Patients with Lynch Syndrome Who Have Had Colorectal Cancer Are at Increased Risk of Other Cancers

range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers,” according to a study in the Journal of the National Cancer Institute. Previous studies had shown that mutation carriers “are at a substantially increased risk of cancers of the colon, rectum, endometrium, stomach, ovary, ureter, renal pelvis, brain, small bowel, hepatobiliary tract, and pancreas,” the authors noted. A major inherited cancer syndrome, Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC). The study was based on data for 764 patients from the Colon Cancer Family Registry, evenly divided between men and women, who were carriers of the mismatch repair gene mutation and previously diagnosed with colorectal cancer. Most of the carriers (52%) were recruited in Australia and New Zealand, with 33% from the United States and 15% from Canada. The average age at diagnosis of colorectal cancer was 44 years. Compared with the general population, following colorectal cancer, carriers of mismatch repair gene mutations had a 70-fold increased risk for cancer of the small intestine,

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In the Literature is written and compiled by Charlotte Bath.

Using QR Codes

Patients who have had colorectal cancer and who are carriers of the DNA mismatch repair gene mutations that cause Lynch syndrome “have an increased risk of a greater

a 13-fold increased risk for cancer of the kidney, renal pelvis, and ureter or urethra, a 7-fold increased risk for cancer of the bladder, a 6-fold increased risk for hepatobiliary tract cancer, and a nearly 6-fold increased risk for gastric cancer. Men had a 2-fold increased risk of prostate cancer. The most common primary cancer following colorectal cancer for women with Lynch syndrome was endometrial cancer, with a 40fold increased risk compared to the general population. There were 20 breast cancers and 6 ovarian cancers in the study population. “These new data provide further determination of cancer risks, potentially informing and justifying ongoing studies to create the evidence for effective screening methodologies and intervals in [mismatch repair] gene mutation carriers,” the researchers concluded. “Larger studies are needed to refine risk estimates separately for specific [mismatch repair] gene mutations to best inform policies on clinical risk management.” Win AK, et al: J Natl Cancer Inst 104:1363-1372, 2012.

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