Jan 2015 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • January 2015 • Vol. 10, No. 1

SOLID TUMORS Report From SABCS: Nab-paclitaxel faces off against paclitaxel presurgery ................................

Checkpoint inhibitors show promise for bladder and lung cancers ..................

CURRENT PRACTICE Patients battle financial toxicity of cancer treatment ..................................

HEMATOLOGIC DISEASE Clinical Conundrums ...........................

see BRENTUXIMAB, B page 26

numbers

Cervical cancer survival by stage of disease, showing importance of early diagnosis.

16 Distant disease

57 Regional disease

91 Localized disease 20

5-year survival, % Source: American Cancer Society

Metastatic breast cancer in the lymph nodes; Massimo Cristofanilli, MD, describes how he manages metastatic breast cancer on page 8.

Vogl, NY on SOFT:

January is Cervical Cancer Awareness Month.

San Francisco—In high-risk Hodgkin lymphoma (HL), consolidation therapy after autologous hematopoietic cell transplant (auto-HCT) with the CD30directed monoclonal antibody brentuximab vedotin provides a major extension of progression-free survival (PFS), according to an interim analysis of the Phase III AETHERA trial. The benefit relative to placebo was consistent across subgroups. Emphasizing the significance of the data, principal investigator Craig H. Moskowitz, MD, noted that it has been 20 years since any new treatment for

Phase III trial supports pomalidomide as standard of care for refractory MM ...

by the

IMAGES in ONCOLOGY

Brentuximab After Transplant May Be New Standard for HL

INSIDE

100

Debating Value of Ultrasound In Breast Cancer Screening

Ovarian Suppression Adds Little or Nothing To Tamoxifen

he key message from the SOFT report at the 2014 San Antonio Breast Cancer Symposium and in The New England Journal of Medicine1 is negative— the study failed to dem- Steven Vogl, MD onstrate a significant benefit from adding ovarian function suppression (OFS) to tamoxifen (TAM) therapy for premenopausal women with resected breast cancer. This is a question that never had been properly asked before because earlier studies had not collected data on ovarian function at entry. As breast cancer physicians, we should be grateful for the see VOGL, NY, Y page 6

San Antonio—Results from a Connecticut study have some clinicians proclaiming that all women with dense breasts who have a negative mammogram should be offered an ultrasound. The study, presented at the 2014 San Antonio Breast Cancer Symposium (SABCS; abstract S5-01), found that ultrasound identified an additional 3.2 cancers per 1,000 women. “It is time to think of a new paradigm of utilizing screening ultrasound,” said the lead author of the study Jean Weigert, MD, a radiologist and the director of Breast Imaging at the Hospital of Central Connecticut, in New Britain. Since October 2009, Connecticut law has required clinicians to use certain language when providing mammographic results to women with dense breasts (approximately 40%-50% of women). Clinicians are required to say, “Your mammogram demonstrates that you have dense breast tissue, which could hide small abnormalities, and you might benefit from supplementary screening tests, which can include a breast ultrasound screening or a breast [magnetic resonance imaging] examination, or both, depending on your individual risk factors.” Connecticut is one of 19 states, to date, that mandate that clinicians include information on breast density when providing mammogram results to patients, according to Jafi Lipson, MD, an assistant professor of radiology at Stanford University Medical see ULTRASOUND, D page 12

Essential Oncology™

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CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Albumin Linked to Survival Odds in Esophageal Cancer Philadelphia—In patients with esophageal cancer (EC), serum albumin levels may predict outcomes and be a useful marker for guiding treatment, researchers have found. Why albumin levels might correlate with poor outcomes is not clear, experts said, but the relationship likely reflects the nutritional status of patients with the disease. “The overall survival for EC is disappointing, with reported five-year survival

[of ] less than 5% for advanced-stage disease,” said Zeeshan Ramzan, MD, an assistant professor of medicine in the Division of Gastroenterology and Hepatology, at the University of Texas Southwestern Medical Center, in Dallas. “Our goal was to identify predictors of early mortality and determine if this can potentially improve overall survival.” At the 2014 annual meeting of the American College of Gastroenterology (abstract P615), Dr. Ramzan and his

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i V ,Õ«ÌÕÀi Qsee Warnings and Precautions (5.1)] UÊ VÕÌi ,iÃ« À>Ì ÀÞ ÃÌÀiÃÃ -Þ `À i Qsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃ iÀ} V ,i>VÌ Ã Qsee Warnings and Precautions (5.3)] UÊ 1Ãi *>Ì i ÌÃ Ü Ì - V i i Ãi>Ãi Qsee Warnings and Precautions (5.4)] UÊ * Ìi Ì > v À /Õ À À ÜÌ -Ì Õ >Ì ÀÞ vviVÌÃ > } > Ì i Ã Qsee Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 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 clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

colleagues reported the results of their retrospective review of data from all 122 patients diagnosed with EC at their center between 2005 and 2010. Adenocarcinoma was present in 61.4% of the patients and squamous cell carcinoma in 33.4%. (The percentages do not add up to 100% because some patients had cell types that were neither adenocarcinoma nor squamous cell carcinoma.) Esophageal tumors and lower esophageal tumors comprised 26.2% and 73.8%,

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

respectively, and stage at presentation was I in 13.9%, II in 14.8%, III in 25.4% and IV in 40.2% (accurate staging was not documented in a few patients). The researchers first divided the patients into two groups: those with survival less than six months (41) and those who lived longer (81). They evaluated demographic and clinical characteristics, symptoms at presentation and risk factors such as smoking, as well as other variables to identify predictors of early death. “On univariate analysis, we found a few factors that turned out to be significant: decreased albumin at time of diagnosis, poor functional status and high white blood cell count,” Dr. Ramzan said. “But on the multivariate analysis, only serum albumin was an independent predictor of early mortality.” Up to that point, the researchers had been evaluating data on patients at every stage of disease. To investigate if the difference in mortality was due to the presence of more late-stage patients in the early mortality group, they focused on only stage IV patients, again dividing them into early and late mortality groups. “We reviewed all demographic and clinical data in these patients, and again low serum albumin at diagnosis turned out to be an independent predictor of mortality,” Dr. Ramzan said. “Having identified that, we now know that probably the first thing we need to do with EC patients is to evaluate their nutritional status rather than hit them with all the chemotherapy and radiotherapy options we have.” Given that low serum albumin has been associated with high mortality for other chronic diseases, Prateek Sharma, MD, a professor of medicine at the University of Kansas School of Medicine, in Kansas City, said the latest findings were not surprising. “It’s probably a reflection of the nutritional status of the patient,” Dr. Sharma said. “This was a retrospective, single-center study, and they lump both squamous and adenomatous cancer together, so these results would need to be confirmed in a larger population. If we could show that improving nutritional status in patients with low serum albumin could help increase their survival, that would be beneficial to clinical management,” he added. “But this study does hint at that, and suggests that improving the nutritional status in our patients with chronic diseases and cancer is an important thing to do.” —Monica J. Smith

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Hematologic Malignancies Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

Paul J. Ford, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Pharmacy Harry Erba, MD, PhD

Breast Cancer

Michele Neskey, MMSc, PA-C

University of Alabama Birmingham, AL

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Policy and Management

Cindy O’Bryant, PharmD

Mary Lou Bowers, MBA

University of Colorado Cancer Center Denver, CO

Mitchell Cancer Institute Mobile, AL The Pritchard Group Rockville, MD

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Matt Brow VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

Bioethics Joseph P. DeMarco, PhD

Infection Control

Cleveland State University Cleveland, OH

Susan K. Seo, MD

Edward Chu, MD University of Pittsburgh Cancer Institute Pittsburgh, PA

Memorial Sloan-Kettering Cancer Center New York, NY

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

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SOLID TUMORS

VOGL, NY continued from page 1

efforts of the International Breast Cancer Study Group (IBCSG) and the cooperating groups that conducted and analyzed this difficult and large trial and presented the results so honestly and completely. Adding OFS for 5 years to TAM decreased decline in disease-free survival (DFS) by a nonsignficant 17% at a median follow-up of 67 months with a hazard rate (HR) of 0.83. This just became significant, with an HR of 0.78 at P=0.03 in a multivariate analysis.

Low-Risk Women Do Not Need Ovarian Suppression! Nor Do They Need Chemotherapy! About half the women entered into SOFT (Suppression of Ovarian Function Trial) had largely small, node-negative, well-differentiated tumors. Their doctors did not give them chemotherapy, and their outcomes with TAM alone for 5 years were superb! With about 473 women in each arm who chose, with their physicians, not to get chemotherapy, the number with distant metastases at a median follow-up of 67 months was 6 with TAM, 7 with 5 years of OFS plus TAM, and 3 with 5 years OFS plus exemestane (EXE). For these women with a very good prognosis, OFS, with its increases in hot flashes, joint pain, sweats, hypertension, osteoporosis, sexual dysfunction, and vaginal dryness— clearly shown in this trial and others—is not justified.

Estrogen Suppression Beyond OFS Prevents Distant Metastases The SOFT and TEXT (Tamoxifen and Exemestane Trial) analyses show, for the first time, that suppression of aromatase (producing very low estrogen levels in circulation and tissue) for 5 years adds to the tumor control achieved by OFS. The conclusion is that even lower estrogen levels are worse for the tumor and better for the patient! ABCSG (Austrian Breast and Colorectal Cancer Study Group) Study 12 had made the opposite observation in a population that was largely at lower risk and, for the most part, had been spared chemotherapy.2 In ABCSG 12, all women received only 3 years of OFS. Like the SOFT patients who had been spared chemotherapy, ABCSG 12 patients did very well, regardless of the treatment arm. In SOFT patients treated with prior chemotherapy (each of whom had premenopausal estradiol levels up to 8 months after diagnosis), 67 of those assigned to receive OFS plus EXE had distant metastases at a median follow-up of 67 months, compared with 82 of those given OFS plus TAM and 90 of those given TAM alone, with approximately 542 patients per arm (Table 1). Meredith Regan, the primary statistician for SOFT, was careful not to test the significance of these differences because she felt that this was not statistically appropriate.3

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD COMMENTARY

Table 1. Distant Recurrence-Free Interval In SOFT Patients After Chemotherapya Arm

Number

Events

Hazard Rate

95% Confidence Limits

TAM

542

TAM + OFS

542

EXE + OFS

544

0.87

0.64-1.17

0.72

0.52-0.98

EXE, exemestane; OFS, ovarian function suppression; TAM, tamoxifen a

Median follow-up, follow up, 67 mo.

That said, there was a separation in the 95% confidence limits of the time to distant recurrence only for the comparison of TAM against EXE plus OFS. The degree of separation (lack of overlap) was very small between these 2 cohorts. In my mind, there had been some question about whether adding an aromatase inhibitor (AI) produced further benefit after ovarian function had been lost or suppressed. A recently published subgroup analysis of MA.17 suggested that premenopausal women who lost their menses before the 5-year point derived much more benefit from adjuvant letrozole after 5 years of TAM than did women who were postmenopausal at breast cancer diagnosis (HR, 0.26 vs 0.67).4 Both MA.17 and SOFT suggest that AI-induced deep suppression of estrogen synthesis adds value much above that of ovarian suppression (or ovarian failure) alone.

AI Plus OFS: a Valid Option For Women at Very High Risk If physician and patient are still very worried about the risk of systemic relapse despite optimal chemotherapy and with planned TAM therapy, it is reasonable to consider ovarian ablation plus an AI for the first 5 years. It seems from SOFT that most of the benefit in terms of prevention or delay of eventually lethal distant metastases comes from the additional estrogen suppression produced by the AI, so OFS added to TAM makes little sense. Because of the small number of distant first events in the prior chemotherapy cohort of SOFT, our confidence as to the size of the benefit should be limited—the 95% confidence limits for the HR of 0.72 for EXE plus OFS versus TAM were 0.52 and 0.98. The possibility that the benefit from AI plus OFS is quite small (as little as a 2% relative reduction in distant metastases at 5.5 years) compared with TAM alone would make me give up both OFS and AI therapy if toxicity (be it sexual dysfunction, joint pain, or hot flashes) made life intolerable for the patient.

Analysis Suffers From Inclusion of Many Low-Risk Women Because women with low-risk tumors do very well regardless of therapy, their inclusion makes the analysis much more challenging and makes statistical significance harder to achieve. It drives the statistician

to analyses in subgroups enriched for events. To the extent that these are not corrected for the number of analyses, they should be considered exploratory and hypothesis-generating only. The initial low event rate (good results for the patients) made the investigators rewrite the statistical considerations in 2011, before they had seen the comparative results.

SOFT Suffers From Usual End-Point Muddle In my opinion and that of many others, the correct end point for a trial of toxic therapy in women with no evidence of cancer and no symptoms has to be overall survival (OS). All other end points are subjective in assessment and questionable in relevance. SOFT follow-up is far too short for OS because it takes up to 15 years for most of the eventually lethal metastases to manifest themselves, and several more years for those who develop metastases to die from them. One could argue that, in the relatively low-risk breast cancer population in SOFT, intercurrent deaths from noncancer causes might dilute the OS end point, even though patients were quite young at entry. We could miss some clinically significant benefit from OFS plus an AI because all groups in the study commonly had deaths from heart disease, stroke, auto accidents, and smoking-related cancers. Implicit in the analysis published in The New England Journal of Medicinee is the suggestion that the statisticians had similar thoughts, and so turned to distant recurrence-free interval (DRFI) as an alternative.1 Distant recurrence is an augur of death from breast cancer with very rare reprieve. In the DRFI analysis, death without distant recurrence is censored in the event curve. I have chosen to use this end point in this editorial to describe the SOFT results. In 2000, when SOFT was in the design phase, the investigators chose the usual primary end point of disease-free survival (DFS). The major drawbacks to DFS analyses are the inclusion of events in ipsilateral and contralateral breasts that generally are not lethal, and certainly are not ominous in the next several years. Additionally, DFS events include new cancers, whether or not they are related to the breast primary or its treatment. The latter were excluded in an end point used by the SOFT presenters called breast cancer–free interval

Steven Vogl, MD Medical Oncologist New York City

(BCFI). As a compassionate physician, I rarely would subject a young woman to 5 years of medical castration just to prevent a local recurrence or a contralateral breast cancer that could be effectively treated when it occurs. Therefore, DFS and BCFI are poor end points that muddle the presentation, and we should ignore them.

SOFT Specified 5 Years Of Therapy in a 15-Year Disease It now is clear from MA.17,4 ATLAS (Adjuvant Tamoxifen: Longer Against Shorter),5 and aTTom (adjuvant Tamoxifen: To offer more?)6 that, even for women who are premenopausal at diagnosis, benefits exist from therapy given after the first 5 years of endocrine therapy. In MA.17 these are substantial, with an early 72% reduction in DFS events with a switch to letrozole after 5 years of TAM for women who were premenopausal at diagnosis. Two problems in this regard come from SOFT. First, it did not specify further therapy beyond the 5 years of protocol treatment. Presumably, some women in the higher-risk groups will not receive any further therapy, some will get more TAM, some will receive more OFS plus an AI, and some will get an AI after their eventual menopause. All of these will be bedeviled by tolerance and compliance issues, with stops, restarts, switches, and refusals. These will prove difficult to sort out and analyze. Second, the oncology literature suffers from a dearth of experience with therapy following 5 years of an AI, from the points of safety, tolerance, and efficacy. We really do not know whether adding 5 years of TAM in this circumstance works at all. One could imagine it works better than it did in ATLAS and aTTom after 5 years of TAM, but we do not know. In ATLAS and aTTom, benefits from 5 more years of TAM did not appear until about 9 years after the initiation of hormonal adjuvant therapy. Oncologists and their patients choosing OFS plus AI as initial therapy over TAM in 2015 should realize that they may well have little more information on these issues in 2020. They then will want to continue endocrine therapy because more was clearly better in MA.17, ATLAS, and aTTom, but they may have no data to guide them in the choice of precisely which endocrine therapy to choose or how long to recommend it.

Women Younger Than Age 35 Had Worse BCFI, Greater Benefit The slide with the greatest impact during the SABCS presentation was one comparing BCFI (excludes other primary

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

cancers and deaths not related to breast cancer from analysis) among the 3 treatment groups in women younger than 35 years of age. Nearly all of these women had chemotherapy before entry (94%). As shown in Table 2, BCFI increased from 68% at 5 years with TAM alone, to 83% with EXE plus OFS. The 95% confidence limits of the best and worst arms just overlapped. This analysis was prespecified. It was of interest based on an earlier metaanalysis that included data from the IBCSG and other groups showing that women under 35 did worse than other premenopausal women with adjuvant chemotherapy only.7 However, the study analysts did not do a formal statistical comparison because they did not think it statistically appropriate. Unfortunately, the analysis is of BCFI, not DRFI. Probably more than one-third of the events shown in Table 2 were not distant metastases. Using DRFI instead of BCFI would reduce the absolute difference in the number of events separating the TAM and EXE plus OFS cohorts from 15 down to 9 or 10, making the results even less impressive. One might guess that many women younger than age 35 years with estrogen receptor-positive breast cancer would have undocumented BRCA-2 mutations, and so BCFI events in these BRCA-2 mutation carriers prone to multiple breast cancers would more likely be new primaries (both ipsilateral and contralateral) than in older women not carrying mutations. In correspondence, the statistician for SOFT assured me that more than 60% of the BCFI events in women younger than age 35 years were distant metastases,3 so an excess in breast events in this population was not a problem. Also unfortunately, age younger than 35 years was not a stratification variable, so balance with regard to prognostic factors was not assured in this subgroup, nor even sought. Neither the The New England Journal of Medicine report1 nor the SABCS presentation assured us that the treatment groups younger than age 35 years were balanced for tumor size, degree of estrogen receptor expression, progesterone receptor expression,

Table 2. BCFI in SOFT Patients <35 Years Old

Arm

Number

Events

5-y, %

95% Confidence Limits

TAM

112

57-76

TAM + OFS

112

70-86

EXE + OFS

117

75-89

BCFI, breast cancer–free Interval; EXE, exemestane; OFS, ovarian function suppression; TAM, tamoxifen a

BCFI events include distant metastases, ipsilateral in-breast recurrences and new invasive cancers, contralateral invasive e new primary breast cancer, and d regional recurre recurrences. ences.

Adding OFS for 5 years to TAM decreased decline in disease-free survival (DFS) by a nonsignificant 17% at a median follow-up of 67 months with a hazard rate (HR) of 0.83. type and intensity of prior chemotherapy administered, number of positive nodes, tumor grade, and measures of tumor proliferation by either immunohistochemistry or gene expression profiling. Finally, only 341 of the more than 3,000 women in the trial were younger than 35. Putting all our emphasis on an analysis of just over 11% of those entered is inappropriate.

Could “Softer” SOFT Be an Option for High-Risk Young Women? Given the limited benefits of OFS added to TAM (only 8 fewer distant metastases among 472 higher-risk women who had “premenopausal” estradiol levels after chemotherapy), one could interpret SOFT as showing the benefits of AI plus OFS as a unit in premenopausal women (ie, do OFS only if one intends to give an AI). Analogous to the switching studies such as BIG (Breast International Group) 1-98 and TEAM (Tamoxifen and Exemestane Adjuvant Multinational) in postmenopausal women with resected breast cancer, 2.5 years of TAM followed by 2.5 years of an AI plus OFS may be a less toxic option of equal efficacy to 5 years of an AI plus OFS. This is a valid hypothesis for study among those considered at high risk even after modern chemotherapy. I would not recommend employing such a “switch therapy” that includes OFS outside a well-designed

clinical trial. Endocrine therapy should be specified for at least the first 10 years in such a trial. This should be an essential element of well-designed adjuvant endocrine therapy trials.

Where Are We in 2015? Eleven years after the first of more than 3,000 women were entered into SOFT, we are only a little further into defining the role of OFS in the adjuvant therapy of resected breast cancer. We can be confident that low-risk women do not need it, and that their results with TAM alone are excellent. OFS plus TAM should probably not be used because it is inferior to OFS plus EXE. The latter may confer some benefits over TAM alone in women at higher risk, especially among women under 35. The evidence favoring OFS plus AI for such women is not strong, nor can we be confident in the extent of the benefit they may expect in exchange for sacrificing ovarian function for 5 years. When the SOFT investigators were designing their trial around 2000, they expected their patients would do much worse and that they would be able to answer these questions in 2014. For the sake of their patients and mine, I am gratified that their patients did much better than they expected. I share both their joy at the improving prognosis of resected breast cancer patients, and their frustration that these improving results make it

much harder to answer therapeutic questions for the next generation of women with resected breast cancer.

References 1. Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014; Dec 11. [Epub ahead of print], PMID: 25495490. 2. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360(7):679-691, PMID: 19213681. 3. Meredith Regan, personal communication. December 18, 2014. 4. Goss PE, Ingle JN, Martino S, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebocontrolled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol. 2013;24(2):355-361, PMID: 23028039. 5. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816, PMID: 23219286. 6. Gray RG, Rea DW, Handley K, et al. aTTom (adjuvant Tamoxifen To offer more): randomized trial of 10 versus 5 years of adjuvant tamoxifen among 6,934 women with estrogen receptor-positive (ER+) or ER untested breast cancer—preliminary results. J Clin Oncol. 2008;26(suppl): abstract 513. 7.

Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr. 2001;(30):44-51, PMID: 11773291.

For additional coverage of the SOFT trial results, see story on page 13.

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to smtilyou@mcmahonmed.com

LOOK AHEAD

Next month in Clinical Oncology News: Dr. Vogl’s commentary on the IBIS breast cancer prevention trial: Tamoxifen Chemoprevention After 20 Years: A Lot of Concern Amidst Unexpectedly Prolonged Activity

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How I Manage ...

Metastatic Breast Cancer M

Massimo Cristofanilli, MD Director of the Breast Care Center Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia, Pennsylvania

uch of the excitement in breast cancer treatment in the past decade has focused on genomic profiling that helps stratify patients into subgroups at diagnosis, helping clinicians identify patients in need of treatment and then provide the most appropriate therapy. The subgroups, luminal A, luminal B, HER2, and triple negative, listed in order from least to most aggressive, have helped guide treatment choices and have given doctors much more clarity about when aggressive therapy should be used versus when it can be avoided. This means that patients are selected for the most appropriate standard therapies that will increase the chance of a cure. Revolutionary as these subtypes have been, the real advances and changes to treatment protocols have come in the area of metastatic breast cancer. Indeed, once the disease progresses to a metastatic state, it is even more important to track the genetic changes driving the cancer and treat accordingly. Recent clinical trials have shown new combinations of hormonal, chemotherapeutic, and new molecular drugs to be more effective than single-therapy options for certain populations of women.1 These combinations demonstrate that it may be more important to hit an oncologic signaling pathway, rather than a single gene mutation. Although this makes sense from a molecular perspective, this approach has not been put into widespread practice. Likewise, when molecular diagnostics reveal no discrete signaling pathway driving tumor growth, patients may benefit more from a general attack via chemotherapy alone.

What are your first steps for treating patients with metastatic breast cancer? Our first course of action for metastatic disease is to try to define more precisely the disease biology and aggressive behavior. We order a circulating tumor cell (CTC) test to help give us a sense of disease severity (Figures 1 and 2). The test enumerates metastatic cells circulating in the blood. Less than 5 cells in a 7.5-mL blood sample indicates a disease with high likelihood of its being managed effectively with standard therapies (eg, chemotherapy and endocrine therapy), whereas more than 5 cells indicates aggressive and potentially rapidly progressing disease. Several clinical studies have

demonstrated the utility of CTCs in predicting disease outcome.2,3 Although a recent trial called into question whether changing treatment regimens based on CTCs alone would improve survival,4 the trial did not use any additional diagnostics to stratify patients into therapies that would have greater chance of impact—and did not report the treatment selections made. Although we use CTC testing regularly, it is important not to use it exclusively and to understand its limitations. If the patient’s CTC is less than 5, we feel confident starting the patient on a standard first-line therapy. At this point, the disease is relatively indolent and the patient can be spared the side effects of more aggressive therapy. We biopsy the tumor when possible (including the

bone) and check estrogen receptor (ER), progesterone receptor (PR), and HER2 status and compare these results with primary tumor status. Endocrine therapy still is the most important systemic therapy for hormone receptor–positive disease. Depending on menopausal status and previous adjuvant therapy, we would give the patient either an ER blocker, such as fulvestrant (Faslodex, AstraZeneca), or an aromatase inhibitor (AI) to block estrogen production. Additionally, we expect a new drug palbociclib (Pfizer) to soon become available for patients with progressive disease after or during adjuvant AI therapy. Studies have shown that a combination of palbociclib, a drug that targets the CDK 4/6 pathway, with letrozole, a nonsteroidal AI, dramatically increases

AT A GLANCE • Treatment of primary and metastatic breast cancer is becoming more complex, with the availability of novel drugs and the understanding of the mechanisms driving resistance to endocrine and HER2-targeted therapies. • Combinations of HER2 inhibitor therapy with AI therapy might delay the onset of hormone therapy resistance. • Combining 2 hormone therapies, an ER-blocking drug with an AI, is appropriate for de novo stage IV disease or aggressive disease as assessed by genomic or CTC analysis. • Genomic analysis allows the identification of patients with actionable mutations. • CTC analysis combined with genomic analysis allows for patient risk stratification, predictive assessment, and identification of molecular pathways for more personalized treatments. In the near future, this approach should become the standard for patients.

progression-free survival (PFS) in women with ER-positive HER2-negative disease. This will likely become the first choice of treatment if the drug, currently being fast-tracked, is approved.5

Is there research on extending the efficacy of hormone therapy? Over time, most patients develop resistance to hormone therapy, leading to progression of disease. However, a number of recent clinical trials have suggested that there may be benefit to combining hormone therapy with growth factor–targeting agents, such as those that target HER2 or insulin-like growth factor I (IGF-I), to delay resistance.6 Indeed, increased expression of HER2 signaling by breast cancers is associated with acquired resistance to hormone therapy.7 The first-line therapy for patients with HER2- and ER-positive disease is a combination of HER2targeting therapies such as trastuzumab (Herceptin, Genentech) or lapatinib (Tykerb, GlaxoSmithKline), with hormone therapy. Ideally, however, the combination could be given in patients before they develop overexpression of HER2 signaling. To that end, we explored the combination of epidermal growth factor receptor (EGFR)-targeted therapy in HER2-negative patients. Despite an early discontinuation of the trial due to low enrollment, the combination of anastrozole, an AI, with gefitinib (IRESSA, AstraZeneca), an EGFR inhibitor, showed nearly a doubling of PFS (from 8.4 to 14.7 months), although the results were

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CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

more pronounced in patients who had not been exposed to hormone therapy before study participation.8 More work is needed in this area.

5. Finn RS, Crown JP, Lang I, et al. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). Presented at: American Association for Cancer Research Annual Meeting; April 6, 2014; Abstract CT101.

When do you use more aggressive or second-line therapy? In general, the second-line treatment would be an inhibitor of mammalian target of rapamycin (mTOR), such as everolimus (Afinitor, Novartis), together with an AI. In ER-positive patients who had progressed on AIs as first-line treatment in the metastatic setting, a recent clinical study supported the use of mTOR inhibitor plus the steroidal AI inhibitor exemestane as the standard of care for these patients.9 Additionally, if there are bone metastases, a bone-targeting agent, such as a bisphosphonate or denosumab (Xgeva, Amgen), should be added. However, starting with a combination endocrine therapy may be the appropriate choice for patients who are less likely to benefit from a standard first-line therapy. One obvious instance is de novo stage IV disease. Research has shown that a combination of hormone therapies— an ER blocker plus an AI that blocks estrogen production—is more effective than a single-agent hormone therapy to treat this type of breast cancer.10 Recent research has shown that a combination of fulvestrant with anastrozole is particularly effective for this patient population.11 Additionally, we may consider incorporating the information derived by CTC count in the decision for patients progressing after AI. In those cases, studies have shown that the benefit from single-drug endocrine therapy is limited in patients whose CTC count on first assessment is high (more than 5 cells/7.5 mL). Theoretically, these patients need more aggressive treatments, either combination hormone therapy or chemotherapy, and time should not be wasted on first-line therapy that is less likely to be effective.

What are the choices when second-line therapy fails? In disease that continues to progress, and indeed for any patients with high-risk disease, we use CTC biopsy as a monitoring tool, one that quickly and inexpensively gives us a picture

6. Guiliani M, Trivedi MV, Schiff R. Bidirectional crosstalk between the estrogen receptor and human epidermal growth factor receptor 2 signaling pathways in breast cancer: molecular basis and clinical implications. Breast Care. 2013;8:256-262, PMID: 24415978.

Figure 1. A circulating tumor cell (green) from a metastatic breast cancer patient, is surrounded by 3 lymphocytes (purple); 5 or more of these cells in a 7.5 mL blood sample indicates progressing disease.

7. Arpino G, Green SJ, Allred DC, et al. HER2 amplification, HER-1 expression, and tamoxifen response in estrogen receptorpositive metastatic breast cancer: a southwest oncology group study. Clin Cancer Res. 2004;10:5670-5676, PMID: 15355892.

Figure 2. A circulating tumor cell during cell division.

Credit: Thomas Jefferson University.

of how well our treatment selection is working. But it is just the first step. In aggressive disease, we always request additional genomic tests, either from the primary or metastatic tumor biopsy, when available, or from the blood sample to help guide us to other opportunities for treatment. In general, the more mutations we see, the more unstable the disease and the less likely it is to respond to first-line endocrine therapy. This indicates that genomic tests should be done frequently to assess the cancer’s current genomic expression. For example, one of our patients developed resistance to endocrine therapy after several years of successful treatment. We changed her regimen, and again brought her cancer to a stable state. However, when she progressed again, her CTCs increased and some of those cells were positive for HER-2, which allowed us to offer trastuzumab. When we put her on trastuzumab, her CTC count dropped, indicating remission, and her symptoms improved.

benefit from ALK- or EGFR-targeted therapy approved for lung cancer. Although such diagnostic tests are not in wide clinical use, they offer the patient and the physician the ability to treat that particular patient’s cancer with precision, rather than going by the trial-and-error approach that we have followed in the past. In other words, it provides the treating physician with the option to use the most appropriate drug based on identification of a commonly available pathway.

Summary Genomic analysis also can suggest that the use of other targeted therapies originally developed for other cancers might be of benefit. For example, we have seen metastatic breast cancers with the anaplastic lymphoma kinase ((ALK K) mutation

References 1. Cristofanilli M. Update on novel drug targets in metastatic breast cancer. Contemporary Oncology. 2014;2. http://www.onclive. com/publications/contemporary-oncology/2014/april-2014/update-on-novel-drugtargets-in-metastatic-breast-cancer/1. Accessed December 17, 2014. 2. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791, PMID: 15317891. 3. Bidard FC, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15:406-414, PMID: 24636208. 4. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014 Jun 2. [Epub ahead of print], PMID: 24888818.

8. Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res. 2010;16:1904-1914, PMID: 20215537. 9. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med. 2012;366:520-529, PMID: 22149876. 10. Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919-1925, PMID: 22370325. 11. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14:989-998, PMID: 23902874.

Coming Soon Dr. Cristofanilli will discuss how he manages treatment of the 4 main genomic subtypes of breast cancer in upcoming articles.

SEND US YOUR NEWS Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication.

Write to managing editor Sarah Tilyou at smtilyou@mcmahonmed.com

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Report From SABCS

Nab-Paclitaxel Faces Off Against Paclitaxel Presurgery San Antonio—Using nanoparticle albumin-bound (nab)-paclitaxel rather than paclitaxel in a presurgery chemotherapy regimen for patients with early-stage breast cancer increased the pathologic complete response (pCR) rate by 10% during the German GeparSepto trial. “Long-term follow-up is needed to validate if the increase in pCR rate translates into a better disease-free and overall survival,” said principal investigator Michael Untch, MD, PhD, the chief of the Clinic for Gynecology, Gynecologic Oncology and Obstetrics and the head of the Multidisciplinary Breast Cancer Center at the Helios Clinic in Berlin-Buch, Germany. Dr. Untch presented the trial at the San Antonio Breast Cancer Symposium (abstract S2-07) for the German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische OnkologieBreast (AGO-B) Study Group. GeparSepto enrolled 1,200 patients with early breast cancer. All patients received 12 weeks of treatment with either weekly paclitaxel (80 mg/m2) or weekly nab-paclitaxel (Abraxane, Celgene; 150 mg/m2 for the first 400 patients and 125 mg/m2 for the remainder) followed by four cycles of epirubicin (90 mg/m2) plus cylophosphamide (600 mg/m2) over 12 weeks. All patients with HER2 neu-overexpressing tumors received neoadjuvant treatment with trastuzumab (Herceptin, Genentech; 8-mg/kg loading dose followed by 6 mg/kg) plus pertuzumab (Perjeta, Genentech; 840-mg loading dose followed by 420 mg) for 24 weeks, as well as trastuzumab after surgery. The primary end point was pCR, defined as complete disappearance of tumor cells in the breast and lymph nodes. The pCR was 29% in the paclitaxel arm and 38% in the nab-paclitaxel arm (odds ratio [OR], 1.53; P=0.001). “This effect was seen in all subgroups,” said Dr. Untch, but patients with triplenegative breast cancer (TNBC) benefited more (OR, 2.69). The discontinuation rate due to adverse events was higher in patients taking nabpaclitaxel (17%) than in patients taking paclitaxel (6.2%; P<0.001). Individuals receiving nab-paclitaxel had higher rates of peripheral sensory neuropathy, fatigue, diarrhea and hand–foot syndrome (Table), but after reducing the dose of nab-paclitaxel from 150 to 125 mg/m2, these differences in toxicities were smaller and clinically manageable, according to the researchers. Dr. Untch said the study met its primary end point by proving a substantial increase in pCR, especially in patients with TNBC. “The pCR was almost doubled, and this has the potential to

‘The results are potentially practice-changing, depending on how far the data can be used in the recently initiated new approval process for compounds achieving superior pCR rates.’ —Gunter von Minckwitz, MD

Table. Adverse Events in the GeparSepto Adverse Events Of Any Grade

Paclitaxel, %

Nab-Paclitaxel, %

P Value

Anemia

88.3

92.4

0.019

Neutropenia

81.5

87.3

0.007

Fatigue

77.8

82.8

0.030

Diarrhea

44.1

51.2

0.015

Rash

23.1

33.2

<0.001

Hand–foot syndrome

17.6

27.7

<0.001

Peripheral sensory neuropathy, all grades

65.2

84.3

<0.001

Grade 3/4

2.7

10.3

<0.001

‘What has been demonstrated in this study is that [nab-paclitaxel] is as good as paclitaxel, or maybe a little better for a surrogate end point. … A more fundamental question is whether a 10% difference in pCR is meaningful, and all the evidence to date is that it is probably not for long-term outcomes.’ —Clifford Hudis, MD translate into a better survival in patients with this very aggressive form of breast cancer,” Dr. Untch predicted. Clifford Hudis, MD, the chief of the Breast Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City, said the study sparks a fundamental discussion about the meaning of surrogate end points. It was only a little more than two years ago that the FDA outlined a pathway whereby a drug could be approved based on pCR rates in breast cancer, and pertuzumab was the

first drug to take advantage of that pathway. (Pertuzumab received accelerated approval based on an end point of pCR; full approval is contingent on more data.) According to Dr. Hudis, the only clear immediate advantage of providing preoperative therapy to a breast cancer patient is if therapy can change the surgical approach by making an inoperable tumor operable or converting a mastectomy to a lumpectomy. The German study “did not present any evidence of greater achievement of surgery nor

greater lumpectomy rates,” Dr. Hudis told Clinical Oncology News. Dr. Hudis said that if he were providing preoperative chemotherapy to a patient in an attempt to convert the patient from a mastectomy to a lumpectomy, or make an inoperable patient operable, then the nab-paclitaxel regimen is an option. “What has been demonstrated in this study is that [nab-paclitaxel] is as good as paclitaxel, or maybe a little better for a surrogate end point, but that improvement is modest overall,” said Dr. Hudis. “A more fundamental question is whether a 10% difference in pCR is meaningful, and all the evidence to date is that it is probably not for long-term outcomes.” To date, no clinical trial has proven that modest increases in pCR rate before surgery can improve progression-free survival or overall survival. At the 2014 annual meeting of the American Society of Clinical Oncology, results from the Phase III ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) trial showed that adding lapatinib (Tykerb, GlaxoSmithKline) to trastuzumab in the adjuvant treatment of patients with HER2-positive breast cancer had no effect on disease-free survival. An earlier trial, NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), had demonstrated that the lapatinib-trastuzumab combination doubled the pCR rate in the neoadjuvant setting. Dr. Untch pointed out that NeoALTTO was not powered to show a survival benefit and that patients in the ALTTO trial had a risk profile that was different from that of patients in NeoALTTO. “In the ALTTO trial, a significant proportion of the patients had uninvolved axillary lymph nodes, and the overall survival in the chemotherapy plus trastuzumab arm was 95% after four years, which can hardly be topped with any combination therapy,” said Dr. Untch. According to Dr. Untch, GeparSepto could change practice, “since it was powered to see an increase in pCR compared to the routinely used standard paclitaxel.” Gunter von Minckwitz, MD, the managing director of the GBG, in Neu-Isenburg, Germany, agreed. “The results are potentially practice-changing, depending on how far the data can be used in the recently initiated new approval process for compounds achieving superior pCR rates.” —Kate O’Rourke Drs. Untch and Hudis reported no relevant financial relationships. Dr. von Minckwitz reported research funding from Celgene and Roche.

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Abiraterone Shows Long-Term OS Benefit in Prostate Cancer Madrid—In first-line therapy for metastatic castration-resistant prostate cancer (mCRPC), abiraterone added to prednisone provides an overall survival (OS) benefit greater than that seen with prednisone alone, according to the final analysis of the Phase III COU-AA-302 trial. The benefit, observed after a median follow-up of more than four years, was achieved despite a substantial crossover to abiraterone (Zytiga, Janssen) from the control arm of the study, reported investigator Charles J. Ryan, MD, at the 2014 Congress of the European Society for Medical Oncology (ESMO; abstract 7530). “With completion of the final analysis of this trial, we see that therapy with abiraterone delayed the onset of every one of the meaningful clinical end points evaluated, including, but not limited to, a statistical and clinically significant improvement in overall survival,” said Dr. Ryan, the clinical program leader of genitourinary medical oncology at the University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center. The COU-AA-302 investigators previously reported an advantage of abiraterone plus prednisone over prednisone alone for progression-free survival (PFS) when the trial was terminated at an interim analysis (N Engl J Med d 2013;368[2]:138148, PMID: 23228172). During that analysis, the investigators found that 1,000 mg of abiraterone plus 5 mg of prednisone twice daily increased PFS by approximately eight months (16.5 vs. 8.3 months), for a highly significant hazard ratio (HR) advantage (HR, 0.53; P<0.001). In the new analysis, median OS improved by approximately five months (35.3 vs. 30.1 months), for a gain that exceeded the prespecified definition of efficacy (HR, 0.79; P=0.051). The notable advantages in secondary end points for abiraterone plus prednisone versus prednisone alone included a delay in clinical deterioration measured by Eastern Cooperative Oncology Group performance status, and a 10-month gain in the time to opiate use for cancer-related pain (33.4 vs. 23.4 months; HR 0.72; P<0.0001). The relative OS advantage of abiraterone was consistent across a large variety of subgroups, including those defined by age and exposure to subsequent therapies. In the multinational COU-AA-302 trial, investigators randomized 1,088 patients with mCRPC. After the blinded phase, 67% of abiraterone-treated patients and 80% of the control group received one or more subsequent therapies. In the control arm, this included abiraterone in 44%. Approximately 80% of patients in both arms received subsequent chemotherapy with docetaxel, cabazitaxel (Jevtana, Sanofi) or both. Enzalutamide (Xtandi,

The OS data are less important for confirming that abiraterone is effective than for demonstrating that early abiraterone is better than late abiraterone. —Bernard Tombal, MD Astellas), which, like abiraterone, inhibits the activity of androgen, was used subsequently in 10% of patients in the control arm and 16% of patients who received

abiraterone. Other therapies, such as sipuleucel and radium-233 (Xofigo, Bayer), were employed in very small proportions of patients in both arms.

The OS advantage provides further evidence that androgen suppression is an appropriate first-line therapy in mCRPC. This was the key message from see PROSTATE, E page 27

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ULTRASOUND continued from page 1

Center, in Palo Alto, Calif. Additionally, Dr. Lipson said, “Insurance coverage for supplemental tests is now mandated [for patients with dense breasts] in four states, and there is federal legislation pending at this point.” This flurry of legislation was spurred, in part, by a multicenter 3,000-patient study that demonstrated that adding a single, bilateral screening ultrasound to mammography detected an additional 4.2 cancers per 1,000 in women with dense breast tissue and a family history or prior history of breast cancer (JAMA ( 2008;299[18]:2151-2163, PMID: 18477782). This almost doubled the number of cancers found by mammography alone. In the new study, researchers evaluated the effect of the new Connecticut law at two radiology practices with multiple sites in the state during the first four years after the legislation was enacted. Overall, 30% of women with dense breasts and a negative mammogram chose to have an ultrasound, and this rate was steady over the four years. “This may be due to lack of education and insurance issues,” said Dr. Weigert, who thought the rate should have been higher. “There are many high-deductible plans, and women do not want to pay for the test.” The positive predictive value (PPV) of ultrasound improved over time, indicating that, as expected, there was a learning curve in determining which identified lesions needed to be followed and which needed to be biopsied (Table). By year 4, the PPV was 17.2%, with 3.2 additional cancers detected per 1,000 women. “The first three years, we were

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Table. Positive Predictive Value of Ultrasound in Connecticut Practices Studied PPV of Ultrasound, %

Screening Mammogram

Screening Ultrasound

BIRADS 1 or 2

BIRADS 3

BIRADS 4 or 5

Positive Biopsy

7.1

30,679

2,706

2,377

174

151

6.1

32,500

3,351

3,000

168

180

8.1

32,230

4,128

3,819

168

148

17.2

27,937

3,331

2,889

358

Year

BIRADS, Breast Imaging Reporting and Data System; BIRADS 1, negative; BIRADS 2, benign; BIRADS 3, probably benign; BIRADS 4, suspicious abnormality; BIRADS 5, highly suggestive malignancy; malignan ncy; PPV, positive predictive e value

‘The true clinical impact of finding these additional cancers is really unknown.’ —Jafi Lipson, MD still doing a significant number of biopsies on patients with findings that we didn’t know whether they were positive or negative, but in the fourth year, there was a significant [improvement],” said Dr. Weigert. The cancers detected were of all histologic grades but predominantly grade 2 and 3, hormone-positive and nodenegative. Very few patients had risk factors other than dense breast tissue. Cancers were detected in patients who were in their mid-40s to mid-70s. Although the study was limited in that it did not include a cost analysis, she pointed out that it is easier and less costly to treat a cancer if it is detected at an early stage, noting that in patients who returned for an ultrasound in a subsequent year, the cancers detected were extremely small, typically less than 1 cm. A recent study estimated that supplemental ultrasonography screening for women with extremely dense breasts

would cost $246,000 per quality-adjusted life-year gained ((Ann Intern Med 2014 Dec 9. [Epub ahead of print], PMID: 25486550). This is well above $50,000, often touted as a reasonable threshold for cost-effective care ((N Engl J Med 2014;371[9]:796-797, PMID: 25162885). Dr. Lipson, who served as the discussant of the Connecticut study, pointed out that most of the PPV improvement in Dr. Weigert’s study was due to a shift of patients from a recommendation for biopsy to a recommendation for shortterm follow-up, and this could be seen as a benefit or harm. “It’s not that the patient is returned to annual screening. She is kind of sucked into a vortex of short-term follow-up,” said Dr. Lipson. Dr. Lipson also noted that none of the breast cancer ultrasound studies conducted so far have used a control group, and none have long-term follow-up. “The true clinical impact of finding these additional cancers is really unknown,” Dr. Lipson said.

“Specifically,” she added, “would these additional cancers otherwise be detected at the next mammography screen while still small, node-negative, and at the early stage, and does the detection of these early cancers have an impact on mortality?” —Kate O’Rourke Dr. Weigert disclosed being on the advisory board for Tractus. Dr. Lipson reported no relevant financial relationships.

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Report From SABCS

SOFT Trial Provides Hard Data on Ovarian Suppression San Antonio—Results from the highly anticipated SOFT (Suppression of Ovarian Function Trial) are expected to spur a new treatment paradigm for premenopausal women with hormone receptor (HR)-positive, early breast cancer. The International Breast Cancer Study Group (IBCSG) coordinated trial was reported at the 2014 San Antonio Breast Cancer Symposium (SABCS; abstract S3-08). “For premenopausal women with hormone receptor–positive, early-stage breast cancer, our biggest question has always been ‘how much is enough?’” said Hope Rugo, MD, the director of the Breast Oncology and Clinical Trials Education at the University of California, San Francisco, who was not a primary author of the study but discussed the results at SABCS following the presentation. “Should all or any women have their ovaries suppressed? The SOFT trial tried to answer that question, and I think we have made significant progress.” The SOFT investigators concluded that the addition of ovarian function suppression (OFS) to tamoxifen reduces the risk for breast cancer recurrence in women with HR-positive, early-stage breast cancer who are at sufficient risk for breast cancer recurrence to warrant adjuvant chemotherapy and who subsequently remain premenopausal. In this subpopulation, breast cancer recurrence risk was even lower when the women received OFS and the aromatase inhibitor exemestane (Aromasin, Pfizer) was substituted for tamoxifen. SOFT evaluated 3,047 premenopausal women with HR-positive breast cancer between December 2003 and January 2011. The patients were randomized to receive five years of tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS, and they were stratified by whether they had received chemotherapy or not. Individuals who received chemotherapy were more likely to be young and have positive lymph nodes and larger tumors (Table 1).

Need To Look Beyond Primary Analysis for Benefit In the primary analysis of 2,033 patients, there was no significant benefit from adding OFS to tamoxifen overall. However, in patients who received chemotherapy and remained premenopausal (n=1,628), exemestane plus OFS resulted in a 35% reduction in the relative risk of recurrence versus tamoxifen alone (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87) and tamoxifen plus OFS resulted in a 22% reduction in the relative risk of recurrence versus tamoxifen alone (HR, 0.78;

Table 1. Patient Characteristics in the SOFT Primary Analysis by Chemotherapy Stratum No Chemotherapya

Prior Chemotherapyb

Patients (n)

949; 47%

949; 53%

Median age, y

Lymph node–positive, %

Tumor >2 cm, %

Grade 1, %

Grade 3, %

HER2-positive, %

SOFT, Suppression of Ovarian Function Trial a No chemotherapy: premenopausal patients randomized within 12 wk of surgery; median time since surgery, 1.8 mo. b Prior chemotherapy: premenopausal (by estradiol level) after completing chemotherapy and randomized within 8 mo of completion; med median dian time since surgery, 8 mo.

Table 2. Women Who Remained Premenopausal After Receiving Chemotherapy Treatment Group

Patients Without Breast Cancer at 5 y, %

Tamoxifen

78.0

Tamoxifen plus OFS

82.5

Exemestane plus OFS

85.7

O S, ova OFS, ovarian a function u ct o suppression supp ess o

95% CI, 0.60-1.02) (Table 2). Women younger than age 35, 94% of whom had received chemotherapy, had a greater benefit from OFS. In this group, only 67.7% of the women in the tamoxifen arm remained free from breast cancer at five years of follow-up compared with 78.9% of women in the tamoxifen plus OFS arm and 83.4% of women in the exemestane plus OFS arm. “For women under 35 years with hormone receptor–positive breast cancer, ovarian suppression is an important treatment,” said Prudence Francis, MD, a medical oncologist at the Peter MacCallum Cancer Centre, in Melbourne, Australia, who presented the efficacy results of SOFT at SABCS.

Women who were premenopausal and did not receive chemotherapy (median age, 46 years) did well even with tamoxifen alone, with 95.8% remaining free from breast cancer at five years, compared with 95.1% in the tamoxifen plus OFS arm and 97.1% in the exemestane plus OFS arm. “The decision to forgo chemotherapy was made with the doctor, with these women selected for better prognosis pathology and [being] closer to the usual age of menopause,” said Dr. Francis. At the meeting, Karen Ribi, PhD, from the IBCSG, in Bern, Switzerland, presented a rigorous quality-of-life analysis of the SOFT data (abstract S3-09). Patient-reported global quality of life

did not differ between the tamoxifenalone arm and the tamoxifen plus OFS arm. Patients were substantially affected by vasomotor symptoms (hot flushes, sweats) over the whole treatment period, regardless of treatment. However, patients receiving tamoxifen plus OFS experienced worse endocrine symptoms and sexual functioning (i.e., hot flushes, sweating, vaginal dryness, loss of sexual interest and sleep problems) than those receiving tamoxifen alone. Patients receiving exemestane plus OFS reported more bone and joint pain and worse sexual functioning than the other two treatment groups. “Most differences in symptoms between treatments were seen during the first two years of treatment and were no longer apparent at five years,” said Dr. Ribi. She further noted that among the patients who received prior chemotherapy, the “differences in endocrine symptoms between tamoxifen plus OFS and tamoxifen were less pronounced.” During her presentation at SABCS, Dr. Rugo said it was time for a new treatment algorithm for premenopausal women with early-stage, HR-positive breast cancer. “Patients who are older, still premenopausal, and who receive no chemotherapy for lower-risk, smaller and node-negative tumors, can reasonably be treated with tamoxifen for at least five years,” said Dr. Rugo. “For patients with high-risk disease and, in particular for those who are [younger] than 35, ovarian suppression appears to provide a marked and clinical significant reduction in breast cancer recurrence. The question is whether we should be using exemestane versus tamoxifen in all patients, given the differential toxicity. I think this decision needs to be made on an individual basis.” Dr. Rugo said it remained unclear how clinicians should manage patients with intermediate-risk disease, including those that have low-grade but larger tumors, and low-grade tumors that were node-positive. “My argument,” she said, “would be that in premenopausal women, ovarian suppression and endocrine therapy without chemotherapy would be a reasonable treatment approach for at least some of these patients.” —Kate O’Rourke Drs. Francis, Ribi and Rugo reported no relevant financial relationships.

For additional commentary on the SOFT trial results by Vogl, NY, see page 1.

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Checkpoint Inhibitors Show Promise in Bladder, Lung Cancers Madrid—The likelihood of an objective response increases with the degree of checkpoint protein expression, according to the results of two studies of checkpoint inhibitors in patients with advanced cancers presented at the 2014 Congress of the European Society for Medical Oncology (ESMO). In both studies, one evaluating patients with bladder cancer and the other evaluating patients with non-small cell lung cancer (NSCLC), investigators found a correlation between response and expression of the target checkpoint protein by immunohistochemistry (IHC) assay. In patients with metastatic bladder cancer (abstract 8080), the objective response rate (ORR) achieved with the checkpoint inhibitor MPDL3280A jumped from 11% in those with an IHC score of 1 or 0 for the checkpoint protein, to 43% in those with a score of 2 or 3 (Table). In the NSCLC group (abstract LBA43), ORR climbed from 9% for those with an IHC score of 0, to 23% for those with an IHC score of 1 or higher (Table). Checkpoint inhibitors are directed at cell surface proteins, such as programmed death ligand-1 (PD-L1) or its receptor (PD-1), which turn off the immune response. The goal of blocking the proteins is to induce T cells to recognize malignant cells as non-self and mount an attack. Typical of past reports on such therapies, some proportion of responders in each of the studies presented at ESMO achieved remarkably durable responses despite advanced disease and extensive previous treatment. In one of the patients with bladder cancer, for example, response persisted after more than 30 weeks, despite very advanced disease, according to the investigator, Joaquim Bellmunt, MD, PhD, the director of Dana-Farber Cancer Institute’s Bladder Cancer Center, in Boston. From the Phase I bladder cancer study, data were available for 67 patients receiving the checkpoint inhibitor MPDL3280A, a monoclonal antibody that targets PD-L1. More than 90% of the patients had previously received platinum-based chemotherapy and more than 70% had received at least two prior regimens. In general, MPDL3280A was well tolerated, with only 4% of the patients experiencing an adverse event of grade 3 or higher. Of the 17 objective responses in this patient series, 13 occurred in those with an IHC score of 2 or greater. This included both of the complete responses. The median time to first response was 42 days. It is notable that although PD-L1 status correlated with the activity of MPDL3280A, the partial responses in those with no or weak evidence of PD-L1 on IHC suggest IHC evidence of

Table. Correlation of Response and Expression of Checkpoint Target Protein by IHC Cancer Type

Checkpoint Inhibitor

IHC Score

Objective Response Rate, %

Bladder

MPDL3280A

0 or 1

2 or 3

≥1

NSCLC

Pembrolizumab

IHC, immunohistochemistry; immunohistochem mistry; NSCLC, non-small non small cell lung g cancer

‘The fact that some patients whose tumors are read as PD-L1–negative nonetheless respond means that the test, in its current form, should not be used to exclude patients from therapy with a PD-1 pathwayblocking antibody.’ —Drew M. Pardoll, MD, PhD PD-L1 expression is not required for a response to occur. In the study of NSCLC, 282 patients with advanced disease were treated with pembrolizumab (Keytruda, Merck), also a monoclonal antibody that targets PD-1. The pattern of response was similar to that reported for MPDL3280A in bladder cancer, particularly with regard to expression of the target protein. In patients with an IHC score of 1 or greater for PD-1 expression, the ORR was more than twice as high. Based on these data, those “with strong PD-L1 tumor expression” appear to derive the greatest relative benefit from this targeted therapy, according to Edward B. Garon, MD, the director of the Medical Oncology Program in Thoracic Oncology at the University of

California, Los Angeles David Geffen School of Medicine. As measured with RECIST (Response Evaluation Criteria in Solid Tumors) at central review, overall ORR to pembrolizumab—which was given in three different schedules that varied the dose or dosing intervals—ranged from 20% in those previously treated to 26% in those who were treatment-naive. However, when patients with the strongest PD-1 expression were compared with those with the weakest, the ORR climbed to 39% from 16%. Moreover, this preliminary analysis also found that progression-free survival and overall survival were longer in patients strongly positive relative to those weakly positive or negative, generating hazard ratios of 0.52 and 0.59,

respectively, for these outcomes. Pembrolizumab, which also has been associated with relatively low rates of grade 3 or higher adverse events, was approved in September 2014 for secondline therapy in unresectable, metastatic melanoma, becoming the first licensed checkpoint inhibitor.

Checkpoint Inhibitors Being Studied for Many Cancers The proliferation of clinical studies of checkpoint inhibitors is impressive. At ESMO, data were presented for these agents in a diverse array of advanced malignancies, including gastric cancer, urothelial tract cancer, and HPV-positive head and neck cancer. Although there are now “a multitude of reports” that PD-L1 expression predicts a greater response to checkpoint inhibitors, Drew M. Pardoll, MD, PhD, the director of the Cancer Immunology Program at Johns Hopkins School of Medicine, in Baltimore, provided a note of caution about the immediate significance. “The fact that some patients whose tumors are read as PD-L1–negative nonetheless respond means that the test, in its current form, should not be used to exclude patients from therapy with a PD-1 pathway-blocking antibody,” Dr. Pardoll told Clinical Oncology News. “More work needs to be done in refining the test, and its ultimate utility will likely be to prioritize therapy with PD-1 blockers relative to other available therapies [for] a given tumor type.” —Ted Bosworth Dr. Bellmunt reported a financial relationship with Genentech. Dr. Garon reported financial relationships with AstraZeneca, Celgene, Genentech, MedImmune, Merck, Novartis and Pfizer. Dr. Pardoll reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Battling the Financial Toxicity of Cancer Treatment Boston—At age 39, Chris was diagnosed with localized rectal cancer. He received treatment with capecitabine (Xeloda, Roche) and radiation and initially responded well to therapy. Immediately before surgery, however, his doctor discovered the cancer had metastasized and began talking to him about further chemotherapy options, including capecitabine. Chris flatly rejected this option. “It wasn’t the physical toxicity that Chris was concerned about; it was the financial toxicity,” said Yousuf Zafar, MD, MHS, an associate professor of medicine at Duke Cancer Institute, in Durham, N.C. “Chris had a job and was insured, but he had no prescription drug coverage. For the five and a half weeks he was taking oral capecitabine, he was paying for all of it out of pocket. He never once mentioned to me his problem, and what is worse, I never asked him.” As a result, Chris was in serious medical debt, a common outcome for cancer patients. The average amount that an insured cancer patient pays out of pocket per year is $4,800 ((J Clin Oncol 2011:29[20]2821-2826, PMID: 21632508). Fifty percent of Medicare beneficiaries with cancer spend more than 10% of their income on out-ofpocket health care costs; 28% spend more than 20% (Cancer 2013;119[6]:12571265, PMID: 23225522). “Our patients are paying a lot, probably more than we realize,” Dr. Zafar said, presenting some of the latest financial toxicity data at the American Society of Clinical Oncology Quality Care Symposium. Drug prices are a common scapegoat

for spiraling health care costs. According to Peter Bach, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, from the 1970s to the 1990s, the average cost of a month of

chemotherapy was roughly $100. Today, the average price is $10,000 per month. Biologics, with their hefty price tags, are a huge factor (see related story on drug prices, page 17).

‘It wasn’t the physical toxicity that Chris was concerned about; it was the financial toxicity. ... For the five and a half weeks he was taking oral capecitabine, he was paying for all of it out of pocket. He never once mentioned to me his problem, and what is worse, I never asked him.’ —Yousuf Zafar, MD, MHS

In some cases, drugs have risen in price after entering the market. According to a recent investigation by Bloomberg News, between 2007 and 2014, the price of 100 mg erlotinib (Tarceva, Genentech) increased by 91% and the price of 400 mg imatinib (Gleevec, Novartis) increased by 158%. According to Dana Cooper, a Novartis spokesperson, the company periodically adjusts the prices of its products to balance the cost of current products with the cost of developing new drugs. “The majority of CML [chronic myeloid leukemia] patients pay less than $100 out of pocket per month for our CML treatments,” said Ms. Cooper. Susan Wilson, a spokesperson for Genentech, offered a similar comment, saying that prices are occasionally adjusted, so that the company can continue drug development. As drug prices surge, patients are bearing a greater burden of the cost in the form of cost sharing. According to the 2013 Kaiser Family Foundation/ Health Research and Educational Trust Survey of Employer-Sponsored Health Benefits, between 1999 and 2013, inflation was 40%, worker earnings rose 50%, and premiums jumped 182%. Worker contributions to premiums have increased by 196%. Deductibles have almost doubled, with the average deductible in 2013 at $1,135. In a recent survey of 174 individuals being treated for cancer, onethird of participants reported hardship as a result of their cancer costs, with 16% reporting difficulty paying for basic necessities and 19% reporting using up all or most of their savings see TOXICITY, Y page 18

Financial Toxicity Tool Undergoes Validation BOSTON—The first instrument developed specifically for measuring financial toxicity in cancer patients has just been validated, according to results presented at the American Society of Clinical Oncology (ASCO) Palliative Care in Oncology Symposium (abstract 222). “We developed a questionnaire called COST [COmprehensive Score for financial Toxicity], which is a patient-reported outcome measure [PROM],” said Jeremy O’Connor, MD, an internal medicine resident at the University of Chicago Medical Center. “The questionnaire is designed to quantify the amount of financial toxicity that a patient is experiencing.” COST-PROM includes 11 statements, such as “I am unable to meet my monthly expenses,” and “my outof-pocket medical expenses are more than I thought they would be.” Patients answer the questions on a scale ranging from 0 to 5 (not at all, a little bit, somewhat, quite a bit, or very much, respectively). The total score is calculated using a formula that is easy for physicians to tally. “The issue of financial toxicity is something that a lot of clinicians and a lot of patients acknowledge is important, but nobody really talks about it,” said Dr. O’Connor. “It is a difficult thing for the patient to bring up, and physicians are not very comfortable talking to

patients about this sort of issue.” The tool is aimed at helping physicians jump this communication hurdle. COST-PROM was originally described in an article published in Cancerr (2014;120[20]:3245-3253, PMID: 24954516). In the study presented at the ASCO Palliative Care in Oncology Symposium, researchers presented preliminary data of an ongoing larger validation study in 200 cancer patients that demonstrated that it was correlated with five tools, including the FACT-G (Functional Assessment of Cancer Therapy-General) and the EORTC-36 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 36). “As financial toxicity worsens in the COST questionnaire, scores on different instruments that measure health-related quality of life decreased in a systematic fashion, which is what you would expect,” said Dr. O’Connor. “We also broke it down by employment status, to show that the amount of toxicity that these patients are experiencing is what you would expect for someone in their employment group. These preliminary data suggest that the COST-PROM is an effective way to quantify the financial toxicity.” If validated further, Dr. O’Connor said COST-PROM “will be useful for physicians to screen their patients

for financial toxicity, so they can intervene early, by either referring them to a financial counselor or just [making them] aware of the fact that finance is becoming a problem and choosing more cost-effective treatments.” He noted that it is not a binary symptom of “you either have it” or “you do not,” but a continuum, with many levels of toxicity. “As such, as we design interventions to mitigate this toxicity, we will need validated instruments to assess their effectiveness,” Dr. O’Connor said. According to Yousuf Zafar, MD, MHS, an associate professor of medicine at Duke Cancer Institute, in Durham, N.C., measuring financial distress with a validated assessment tool is a relatively novel concept. “Payors are shifting a growing proportion of treatment costs to patients in the form of rising premiums, deductibles, copayments and co-insurance,” he said. “We need to pay more attention to how that financial burden impacts our patients’ well-being and the quality of their cancer care. Reliably measuring financial distress is an important step in that process.” —K.O. Drs. O’Connor and Zafar reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Cancer Survivors Face Ongoing Financial, Work Challenges Boston—Although the financial difficulties of patients undergoing cancer treatment have been well documented, little data exist on financial and workrelated problems in cancer survivors. Now, a study presented at the inaugural Palliative Care in Oncology Symposium (abstract 238) has painted a financial picture of survivors based on a large database, and it’s a rather bleak one. “Cancer survivors are at increased risk for financial hardship,” said the study’s lead author, Robin Whitney, RN, a doctoral student at the University California, Davis Betty Irene Moore School of Nursing, in Sacramento. “There is an urgent need for screening and support for financial and work challenges across the cancer survivorship trajectory, from diagnosis to long-term survivorship.” Ms. Whitney has a personal interest in survivorship as a non-Hodgkin lymphoma survivor. In the new study, Ms. Whitney and her colleagues performed a cross-sectional analysis of 1,592 adult cancer survivors

Table. Comparison of Cancer-Related Financial Difficulties and Work Modifications Any Financial Difficulty, OR

Any Work Modification

<5 years post-treatment

Reference group

Active treatment

3.68

5.7

≥5 years post-treatment

1.36

2.42

O , odds ratio OR, at o

(aged ≥18 years) in the Experiences with Cancer Survivorship Supplement to the 2011 Medical Expenditures Panel Survey, a set of large-scale, nationwide surveys of families and individuals, their medical providers and their employers. In the study, patients were divided into three groups based on treatment status: active treatment, less than five years after treatment, and five or more years after treatment. The less-than-five-years

post-treatment group served as the reference group. Overall, 27% of the cancer survivors responding reported that they had experienced at least one of five problems: borrowing money, incurring debt, filing for bankruptcy, worrying about or being unable to cover medical costs, and making financial sacrifices. Researchers also assessed work modifications, such as changing to a less demanding job or to a

flexible schedule; taking retirement early or delaying it; or taking extended or unpaid time off because of their illness. In the group of working survivors, 37% reported work modifications. Individuals in active treatment or those who were longer-term survivors (at least five years post-treatment) were more likely to report having financial problems and work modification than individuals surveyed less than five years after their treatment (Table). Ms. Whitney attributed the findings in the long-term survivors to late effects of treatment. Patients were more likely to experience financial difficulties if they were uninsured, younger than age 65 years and not white. Patients were more likely to experience work modifications if they were in active treatment, five or more years post-treatment, female, or a minority. —Kate O’Rourke Ms. Whitney reported no relevant financial relationships.

Social Norms, not Market Forces, Dictate Cancer Drug Prices T

he launch prices of contemporary oncology drugs have more than doubled since 1995, and the cost of increased survival has risen along with them, according to a model by investigators at Emory University, in Atlanta. According to the model, patients and their insurers paid $54,100 for a year of life in 1995. By 2005, they paid $139,100 for the same benefit, and by 2013, they paid $207,000. “Our results confirm what many suspect: Newer anticancer drugs are more expensive than older agents,” said study author David H. Howard, PhD, an associate professor in health policy and management at Emory. Dr. Howard and his colleagues collected data on 56 anticancer drugs approved between 1995 and 2013. They measured launch prices using Medicare’s reimbursement formula for oral and IV drugs. The analysis showed that the price of an additional month of survival time increased by $600 per year (95% confidence interval, $100-$1,100; P=0.02). That equates to an increase of about 5% each year in price per year of survival benefit. The investigators also looked at price increases for drugs indicated for various cancers. The number of drugs for each indication was too few to demonstrate any significant differences, but prices rose across all areas of oncology, said Dr. Howard. Yousuf Zafar, MD, MHS, an associate

professor of medicine at Duke Cancer Institute, in Durham, N.C., said this study quantifies the trend in rising drug prices and suggests that rising prices are not just isolated to a few examples. He added that it’s important for oncologists and patients to understand trends in drug prices as cost-shar-

rather than market forces, dictate priccing decisions,” he said. In a presentation at the 2014 annuaal meeting of the American Society of Clinical Oncology (ASCO), Dr. Howard said that the Centers for Medicare & Medicaid Services (CMS) does not set coverage policies and

‘We are not trying to bash drugs by any means; rather, since patients have to pay for the treatment they receive, we believe that it’s reasonable to help them be aware of these trade-offs and understand what’s the right decision for them.’ —Lowell E. Schnipper, MD ing increases. “If patients have more ‘skin in the game’ in terms of higher out-of-pocket costs, then, according to these data, that financial burden will increase over time. As a result, we should pay more attention to how the drugs we prescribe impact our patients’ financial well-being” (see related story, page 16). Dr. Howard previously authored an editorial outlining the forces at play when it comes to prices of new cancer drugs and describing how pricing patterns for chemotherapeutics do not fit into standard economic models ( (JAMA 2011;305[22]:2347-2348, PMID: 21642689). “It seems as if social norms,

reimbursement rates based on druggs’ cost-effectiveness, the way many Euro opean countries and Canada do. Moreeover, he said, programs with limiteed cost sharing provide little incentive to economize care for privately insured or Medicaid patients. Finally, the 340B drug-pricing program, which requires manufacturers to give discounts to eligible buyers, also contributes to price increases, said Dr. Howard. “That gives manufacturers more leeway [in oncology] than they have in other markets.” He said that one possible solution would be for Congress to limit the growth of the 340B program, and “reduce the number of providers

eligible for the discount.” Holli Dickson, a spokesperson for Genentech, said the company sets prices based on a number of factors, including a drug’s efficacy, how it compares with other available treatments and the company’s need to support more research into new medications. She added that Genentech strives to ensure that price does not prevent medicines from getting to the people who need see DRUG PRICES, S page 18

CURRENT PRACTICE

TOXICITY continued from page 16

(Oncologist 2014;19[4]:414-420, PMID: 24668333). A pivotal study by Ramsey et al found that cancer patients were 2.65 times more likely to go bankrupt than people without cancer ((Health Aff 2013;32[6]:1143-1152, PMID: 23676531).

Impact on Treatment Adherence Treatment adherence often is one of the first victims of financial toxicity. One study revealed that patients with higher copayments were more likely to be nonadherent to imatinib treatment for CML ((J Clin Oncol 2014; 32[4]:306-311, PMID: 24366936). “Our high copayments were defined by the upper quartile of cost sharing in each calendar year. Over the study period, this meant that ‘high’ cost sharing was $53 or more, but it varied a bit by year. Overall, we found that people in the high copayment category were 70% more likely to discontinue therapy in the first six months of treatment,” explained lead author of the study Stacie B. Dusetzina, PhD, an assistant professor of pharmacy and health policy and management at the University of North Carolina at Chapel Hill’s Eshelman School of Pharmacy and Gillings School of Global Public Health. The financial toxicity of cancer treatments can reduce quality care by encouraging patients to spread out chemotherapy appointments, decline tests, delay care and replace prescriptions with

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

over-the-counter medications. So, what can be done to combat financial toxicity? Promoting health care literacy is a start. A 2014 survey showed that only 60% of U.S. citizens understood what a deductible was ((Proc Natl Acad Sci 2014;111[15]:5497-502, PMID: 24706843). In another survey, roughly half of patients expressed interest in talking to doctors about cost, but only 19% had such a discussion (J ( Clin Oncol 2013;31[suppl]; abstract 6506). “We saw a disconnect between the desire to talk about cost and actually having the discussion,” said Dr. Zafar. Of those who discussed costs with their doctor, 57% reported that they felt the discussion helped decrease costs. Cost containment was achieved through various mechanisms: physician referrals to financial assistance (53%), clinicians advocating for patients with insurance companies (25%), a switch to a less expensive medication (19%), a decrease in tests (13%) and a decrease in doctor visits (6%). “When I talk about financial toxicity with oncologists,” said Dr. Zafar, “I often am asked, ‘I have no idea how much these drugs cost, and even if I did, most of the time, I would not have an alternative treatment for my patients; so what do I do?”

with high out-of-pocket costs,” said Ms. Wilson. The company also provides assistance with copays, such as an oncology copay card that helps people with commercial insurance so they will not pay more than $100 per copay, she explained. Although these programs exist, it is clear that many patients don’t know about them. “Our studies have shown

‘Financial counselors and social workers have told us that it is much easier to help patients early than it is to actually dig them out of that medical debt.’ —Yousuf Zafar, MD, MHS that patients are signed up for inappropriate, insufficient insurance plans. They don’t know that patient assistance programs exist, and when they get to those programs, it might be too late,” said Dr. Zafar. “We have done a lot to describe this problem of financial toxicity, but now is the time to intervene. We need to start corralling our resources in health literacy, patient– physician communication and patient engagement in health system delivery, and start intervening on this problem of financial toxicity.”

Pointing patients to financial assistance is one solution, and identifying patients at risk for financial toxicity early is key. “Financial counselors

Many companies, including Novartis and Genentech, have patient access programs, copay cards and other initiatives to help patients who are uninsured, underinsured or unable to afford their medicines. “We [Novartis] estimate that we provide support to approximately 35% of the CML patients taking one of our medicines, either through offering our CML medicines for free or providing copay support through our own copay card or through our financial support of charitable copay foundations,” said Ms. Cooper. Genentech also provides similar programs. “We announced [recently] that the Genentech Access to Care Foundation, which provides free medicine to people without insurance, changed its eligibility criteria, with the goal of helping more people who may be struggling

cancer care, Dr. Schnipper said that both sides are right. “Sometimes the drugs are absurdly costly, and for not a whole lot of real benefit, but on the other hand, you can say the same for many aspects of hospital care,” he said. “We are not trying to bash drugs by any means; rather, since patients have to pay for the treatment they receive, we believe that it’s reasonable to help them be aware of these tradeoffs and understand what’s the right decision for them.”

it will be presented to the ASCO board and published as a way to invite commentary, said Lowell E. Schnipper, MD, the chair of ASCO’s Value in Cancer Care Task Force and the chief of hematology/oncology at Beth Israel Deaconess Medical

Center, in n Boston. “The alggorithm is under a fair degree of scrutiny, both externally from ind dustry and patient groups, and in nternally from ASCO members,” Dr. Schnipper said. “We b are trying to determine how effective a particular therapy is on a specific disease, and p wh hat, if any, toxicities it exhibits when ccompared with standard care. Our main n focus is that when speaking about the available regimens, we have to be mindful that patients need to be involved in the decision of whether a drug is worth its price tag.” Regarding the argument that this project might put too much emphasis on drug costs, as opposed to the costs of hospitalization and other factors related to

Identifying Patients at Risk For Financial Toxicity

DRUG PRICES continued from page 17

them. “We understand thatt our medicines can only help people who have access to them, which h is why we provide a variety of o services to people who arre having trouble accessing ou ur medicines.”

ASCO Developing Rela ative Value Algorithm ASCO is developing an algorithm gorithm to determine the relative value of cancer drugs. The first therapies ASCO will be evaluating for cost and effectiveness are those for advanced non–small cell lung cancer, prostate cancer and multiple myeloma. The algorithm is not yet final, but

and social workers have told us that it is much easier to help patients early than it is to actually dig them out of that medical debt,” said Dr. Zafar. New tools to identify patients at risk for financial toxicity should help (sidebar, page 16). Once patients are identified as being at risk, they can be directed to resources such as company-run patient assistance programs.

—Kate O’Rourke Dr. Zafar has served as an unpaid consultant for Genentech and his spouse is employed by GlaxoSmithKline. Dr. Dusetzina reported no relevant financial relationships.

—Christina Frangou with additional reporting by Paul Bufano Dr. Howard reported no relevant financial relationships. Dr. Zafar’s spouse is an employee of GlaxoSmithKline.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Assessing the ‘Value’ of Cancer Treatments:

It’s About More Than Just Improvement in Overall Survival EDITORIAL BOARD COMMENTARY Maurie Markman, MD President CTCA Medicine & Science Cancer Treatment Centers of America Clinical Professor of Medicine Drexel University College of Medicine Philadelphia, Pennsylvania

he question of cost of antineoplastic agents is an increasingly palpable issue for multiple interested parties (patients, families, government regulators and payors, health insurers, employers, pharmaceutical and biotech companies, and investors).1 Simply stated, the current system in which a drug is developed, and a company “wins the lottery” when the agent is approved and is able to charge whatever it wants for its “highly innovative product,” is unquestionably unsustainable. Of course, a critical unanswered question is what, ultimately, will replace this most irrational system? It is essential to acknowledge that mandatory changes in the drug-pricing paradigm are not limited to the relationship between manufacturers and payors, but must absolutely include the current highly complex, confusing, and surely outdated regulatory approval process, and the profoundly inappropriate/irrational legal prohibition of federal agencies to consider cost in their decisions to approve an agent for commercial sale (FDA) or the price to be paid for its use (Centers for Medicare & Medicaid Services). One conceptually attractive suggestion for a fundamental modification in the price–payment paradigm is to focus on value, rather than cost being based solely on what the market will bear. The simple idea here is to attempt to align the specific cost and the subsequent

payment for a drug to its documented clinical utility, y as revealed in one or more well-designed and conducted evidence-based clinical trials. However, in the discussion of value, it is essential that the benefit parameter employed in any analysis is a truly meaningful end point in a particular clinical setting and its measurement is objectively valid. In this regard, it is disappointing that in a well-considered and widely reported commentary on value, a nationally recognized expert in this arena focused his entire attention on a single parameter of clinical utility: overall survival (OS).2 No one in the cancer clinical care or clinical research arenas would ever reject the concept that a major goal of all antineoplastic therapy is to improve survival (median, 1-year, 5-year, etc.) of a population of patients, and in the case of the individual practitioner, a given patient. However, it is essential to also formally acknowledge the increasing difficulty associated with documenting improvement in OS within a specific clinical trial due to the availability of multiple biologically and clinically active antineoplastic strategies that may be employed following the completion of a study.3 Such therapy surely will, and perhaps substantially, impact that outcome. Additionally, despite objections of some academic and regulatory purists, in many settings it is ethically mandated that patients be permitted to cross over at the time of documented disease progression from the control arm (eg, placebo or inferior standard-of-care strategy) to a demonstrated highly clinically active investigative approach. In addition to the issue of an inability to actually measure the effect of therapy on OS in conditions whose natural histories increasingly suggest they should be considered very serious, but more chronic, disease processes, one must also

recognize that there are other goals that are highly relevant to cancer patients in addition to survival. In fact, in the opinion of this commentator, it would be difficult to argue against the proposition that there is almost certainly genuine value associated with improvement in a clinically relevant symptom (eg, pain) that favorably affects the quality of life of an individual cancer patient. Of course, in this discussion of value, it is important to be able to measure this improvement, even if the outcome is principally subjective in nature (eg, using a validated symptom assessment instrument). An example of such an analysis is the recently reported Phase III trial that compared chemotherapy alone versus chemotherapy plus bevacizumab in the management of platinum-resistant ovarian cancer, in which the addition of the antiangiogenic agent was shown to rather substantially reduce pain.4 Furthermore, as completely anticipated, the study failed to reveal a superior OS outcome with the addition of the antiangiogenic agent to chemotherapy but demonstrated an improvement in progression-free survival with this management approach. Does this mean the objectively measured improvement in a serious cancerrelated symptom and its likely highly favorable impact on quality of life is not of clinical value? Although one cannot be certain of the response that would be provided to this question by the author of the previously noted commentary,2 it would almost certainly not be difficult to appreciate how patients and their families would view such an outcome.5 Finally, we come to the fundamental issue of the patient perspective regarding the actual clinical utility of a given approach. Do we really understand what is truly important to patients and the relative value they would place on avoiding

certain specific side effects of therapy? Or what they consider to be the value of reducing a wide range of specific cancer-related symptoms, perhaps even in the absence of measurable decreases in tumor masses (eg, RECIST criteria)? The point to be made here is that in the mathematical calculation of value (cost divided by a defined measured outcome), which in the future may be used to determine whether a particular antineoplastic agent is acceptable/permitted to be used in a given clinical setting, the patient’s voice must be strongly considered in the process used to define the relevant parameters to be included in the denominator of this equation.5

References 1. Stump TK, Eghan N, Egleston BL, et al. Cost concerns of patients with cancer. J Oncol Pract. 2013;9(5):251-257, PMID: 23943901. 2. Bach PB. Indication-specific pricing for cancer drugs. JAMA. 2014;312(16):16291630, PMID: 25279433. 3. Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst. 2009;101(23):1642-1649, PMID: 19903805. 4. Pujade-Lauraine E, Hilpert F, Wever B, et al. Bevacizumab combined with chemotherapy for platinum-resistant ovarian cancer. The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308, PMID: 24637997. 5. Frey MK, Phillips SR, Jeffries J, et al. A qualitative study of ovarian cancer survivors’ perceptions of endpoints and goals of care. Gynecol Oncol. 2014;135:261-265, PMID: 25230215.

Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Sarah Tilyou at

smtilyou@mcmahonmed.com

LOOK AHEAD

Next month’s issue of Clinical Oncology News will feature: • Continued coverage of the 2014 San Antonio Breast Cancer Symposium and the American Society of Hematology Annual Meeting • First reports from the American Society of Clinical Oncology’s 2014 Gastrointestinal Cancers Symposium

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Fusion of Palliative Care Into Rounds Yields Benefits Boston—A fully integrated, inpatient rounding partnership between palliative care specialists and medical oncologists resulted in significant reductions in hospital lengths of stay and both seven- and 30-day readmission rates, according to a study presented at the 2014 Palliative Care in Oncology Symposium. Richard Riedel, MD, an associate professor of medicine and the medical director of the Inpatient Solid Tumor

Service at Duke University Medical Center, in Durham, N.C., reported the study’s results during the symposium (abstract 03). “This model,” Dr. Riedel said, “resulted universally in improved nursing and physician satisfaction, with very favorable impressions of the benefits added by our palliative care colleagues. There was value added in incorporating our palliatricians into the daily management of patients on our inpatient oncology ward.” According to Dr. Riedel, the concept of optimizing cancer care through the early integration of palliative care is becoming increasingly recognized and widely endorsed. Early integration of palliative care allows physicians to address quality-of-life issues and symptom management throughout the trajectory of a patient’s disease. However, although current data support the benefit of palliative care integration in the outpatient and consultative realms, Dr. Riedel noted that the benefits of fully integrating palliative

care to the daily activities on an inpatient oncology ward remained largely unknown. “To our knowledge, this model appears to be the first of its kind,” he said. Before the study, the traditional inpatient rounding service at Duke University Medical Center consisted of one medical oncology attending, one fellow, two internal medicine residents, advanced practice providers and other

each specialty. What we’ve tried to stress to our colleagues is that this still remains one rounding team, with the added benefit of two attendings with complementary skill sets.” The study retrospectively analyzed patients admitted to the solid tumor inpatient service, before the integration of palliative care (September 2009 through June 2010) and after implementation (September 2011 through

‘The integration of palliative care into oncology is the definition of good cancer care. This novel paradigm of co-rounding certainly has impressive results.’ —Jyoti Patel, MD ancillary services, who together would care for the inpatient census. In the new model, patients are assigned primarily to the medical oncology or the palliative care attending, based, in part, on symptom burden and reason for admission. Both attendings share the house staff and advanced practice providers and work together to care for the admitted patients. Dr. Riedel also stressed the new model’s emphasis on open communication and collaboration. “There are standardized touch points throughout the day, where the entire team will physically meet,” he said, “with both the medical oncologist and palliative care specialist in attendance. Each patient is discussed, so there can be input from

June 2012), assessing 731 pre-intervention patients, with 1,170 pre-intervention admission encounters and 783 post-intervention patients, with 1,183 post-intervention encounters. The patients admitted during the post-intervention cohort period experienced a decrease in mean hospital length of stay from 4.5 to approximately 4.1 days ((P=0.02). “More impressively,” said Dr. Riedel, “we saw statistically significant reductions in our readmission rates, with a relative 23% reduction in our sevenday readmission rate [P [ <0.0001] and a 12% reduction in our 30-day readmission rate [[P<0.048].” Dr. Riedel also pointed to a 15%

reduction in the number of patients transferred to the ICU during their inpatient stay and a 17% increase in hospice referrals in the post-intervention cohort. Although the drop in ICU transfer rates and the increase in hospice referrals were not deemed statistically significant, Dr. Riedel raised the possibility that there was more efficient resource utilization as a result of these improvements.

“These results speak to the skill set of our palliative care colleagues,” concluded Dr. Riedel, “and the clear value that they bring to our inpatient oncology ward.” When asked by Clinical Oncology News what the specific skills are that palliative care physicians bring to the table, Dr. Riedel said, “We don’t exactly know what is in the palliative care ‘syringe.’ Our palliative care providers have a unique and finely tuned skill set in managing complex symptom burden as well as the ability to facilitate timely goals of care conversations. One can hypothesize that more aggressive symptom management may result in decreased readmission rates, but we don’t know for sure.” Commenting on the Duke study results, symposium moderator Jyoti Patel, MD, said, “The integration of palliative care into oncology is the definition of good cancer care. This novel paradigm of co-rounding certainly has impressive results.” —Chase Doyle

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

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Venous Thromboembolism Prophylaxis

Rivaroxaban Shows Advantage Over Warfarin in Ca Patients Madrid—Rivaroxaban was found to be as effective as sequential use of enoxaparin and warfarin for the prevention of recurrent venous thromboembolism (VTE) but safer, in two Phase III studies. Administered in a fixed dose, rivaroxaban, unlike enoxaparin and warfarin, does not require monitoring and dose adjustments based on prothrombin time. The two similarly designed Phase III studies—conducted under the EINSTEIN trials program—randomized 8,282 patients with recurrent VTE to receive the factor Xa inhibitor rivaroxaban (Xarelto, Janssen), or five days of the low-molecular-weight heparin (LMWH) enoxaparin followed by warfarin. The noninferiority trials enrolled patients with active cancer (diagnosis or treatment within the previous six months) or a history of cancer. Rivaroxaban was given in a dose of 15 mg twice daily for 21 days followed by a dose of 20 mg once daily. The doses of enoxaparin and then warfarin were adjusted to maintain an international normalized ratio between 2 and 3. Prophylaxis was continued from three to 12 months depending on risk assessment. There were 655 recurrent VTE events in patients with active cancer and 469 in those with a history of cancer. The relative efficacy of the two treatment strategies was evaluated separately for those two groups. Presenting the pooled data from the trials during the 2014 Congress of the European Society for Medical Oncology (ESMO; abstract LBA48), Martin H.

The data ‘are interesting’ but do not yet supersede current guidelines from ESMO and the American Society of Clinical Oncology. —Florian Scotté, MD, PhD Prins, MD, PhD, a professor of clinical epidemiology at Maastricht University, in the Netherlands, characterized the relative protection against VTE with the two strategies as “similar.” He reported that for the patients experiencing recurrent VTE, there was a numerical but not statistically significant advantage for rivaroxaban relative to enoxaparin-warfarin in the active cancer group (4.5% vs. 6.6%), whereas the rates in those with a history of cancer were identical (2.1%). The rates of major bleeding were lower with rivaroxaban than with enoxaparin-warfarin among patients with active cancer (2.3% vs. 5.0%) and those with a history of cancer (0.4% vs. 1.7%); however, a low number of bleeding events in the latter group may explain why the difference, despite resulting in a hazard ratio (HR) of 0.23, did not reach statistical significance. The 95% confidence interval for this HR was wide

(0.03-2.06). The HR for active cancer patients of 0.42, signifying a nearly 60% lower risk, did produce an upper boundary for the confidence interval (0.18-0.99) within the range of statistical significance. Mortality rates, which were also presented, did not differ with statistical significance. The absolute mortality rates in the active cancer group were 16.4% and 17.6% for rivaroxaban and enoxaparinwarfarin, respectively. The respective mortality rates in those with a history of cancer were 2.1% and 1.7%.

In his assessment of these data, the ESMO-appointed discussant, Florian Scotté, MD, PhD, a medical oncologist at the Georges Pompidou European Hospital, in Paris, suggested that the data “are interesting” but do not yet supersede current guidelines from ESMO and the American Society of Clinical Oncology. Both recommend LMWH therapies as first-line, long-term prophylaxis against VTE recurrence. He noted, for example, that the rivaroxaban prescribing information suggests a relative contraindication for patients with severe renal insufficiency. “Impaired renal function is very common during cancer treatment,” observed Dr. Scotté, indicating why the EINSTEIN trial results may not have uniform application in clinical practice. He suggested that a trial directly comparing rivaroxaban to an LMWH alone would be more useful for understanding the relative utility of this option. Such results are needed to change practice, he added, suggesting that the “take-home message may be that rivaroxaban is not yet recommended in cancer patients but may be in the future.” —Ted Bosworth Dr. Prins reported financial relationships with Bayer, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Leo Pharma, Pfizer, Sanofi and ThromboGenics. Dr. Scotté reported financial relationships with Johnson & Johnson, Leo Pharma, Merck, Roche, Sandoz, Sanofi and Vifor Pharma.

FDA Committee Recommends Approval of First U.S. Biosimilar

he FDA Oncologic Drugs Advisory Committee (ODAC) unanimously recommended the approval of the first U.S. biosimilar, filgrastim (EP2006, Sandoz) for all five indications that the company sought, in a meeting on January 7th. The review of the studies show that “EP2006 is highly similar to U.S.-licensed Neupogen,” said Albert Deisseroth, MD, PhD, a medical officer team leader in the FDA’s Division of Hematology Products. EP2006 is distributed under the name Zarzio outside the United States. No word is available yet on what its name will be if it is approved for use in the United States. This is the first U.S. biosimilar to be considered under the FDA’s new biosimilar approval pathway, and the advisory committee recommended that the FDA approve the product for five indications, the same indications as U.S.-licensed Neupogen [Amgen]: • To decrease the incidence of infections as manifested by febrile neutropenia in

•

patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; To reduce the time to neutrophil recovery and the duration of fever after induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia (AML); To reduce the duration of neutropenia and neutropenia-related clinical sequelae, such as febrile neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation For the mobilization of hematopoietic progenitor cells in the peripheral blood for collection by leukapheresis; and For chronic administration to reduce the incidence and duration of sequelae of neutropenia, such as fever,

infections, oropharyngeal ulcers, in symptomatic patients with congenital neutropenia, cyclic neutropenia or idiopathic neutropenia. The recommendation was made after the presentation of a comprehensive package of nonclinical, clinical and postmarketing pharmacovigilance data, which demonstrated that the biosimilar filgrastim is highly similar to the reference product, Neupogen. The pivotal clinical package included a pharmacokinetics and pharmacodynamics (PK/PD) study in healthy volunteers, which established bioequivalence, and a clinical efficacy and safety study in breast cancer patients, which demonstrated the same clinical performance and safety as the reference product. The clinical package also is supported by a global program that includes five randomized, double-blind, single- and multiple-dose PK/PD studies in healthy volunteers, assessing the PK and PD equivalence of biosimilar filgrastim and

Neupogen, as well as a European noncomparative clinical safety and efficacy study and postmarketing pharmacovigilance data from countries where the product is approved. Committee members reported that they were impressed that Zarzio has generated nearly 7.5 million patientexposure days of experience outside the United States. ODAC chairperson Deborah K. Armstrong, MD, called the data “more detailed analytic analysis than we are used to seeing at ODAC.” Before the vote, the committee heard from many organizations and speakers who overwhelmingly endorsed the approval, many citing the hope that biosimilars will lower the cost of biological drug treatment for many Americans. Although the FDA does not have to follow the recommendations of its advisory panels, it usually does. —Marie Rosenthal

CURRENT PRACTICE

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The Growth of Complex Cancer Care Integrative programs tailor mainstream and complementary interven ntions to a patient’s disease severity and needs

hen we get sick, it’s natural to hope for a cure, no matter how farfetched. Increasingly over the past few decades, patients are looking for answers outside of conventional medicine. This desire, however, can lead some vulnerable patients to abandon mainstream treatments for alternative therapies. Although very few patients actually do so—less than 4%, by some estimates ((Ann Oncol 2005;16[4]:655663, PMID: 15699021)—those who choose this path put their health in further jeopardy and present clinical and ethical challenges for physicians. A 2006 study in the American Journal of Surgery found that breast cancer patients who refused or delayed conventional therapy—surgery, chemotherapy and/or radiation therapy—and opted for an alternative treatment significantly increased their risk for a cancer recurrence and for dying of the disease (192[4]:471-473, PMID: 16978951). Of 11 patients who declined surgery, 10 developed more advanced disease. An additional nine out of 10 patients who refused chemotherapy or radiation therapy increased their estimated 10-year mortality rate by almost 50% (from 17% to 25%); two developed local recurrences and two died of cancer. Although alternative medicine and complementary medicine often are lumped together, there is an important distinction. Complementary interventions are not touted as cancer treatments; instead, they are meant to accompany mainstream care, offering patients a variety of ways to relieve pain, nausea, fatigue and anxiety. “Alternative medicine is harmful,” said Steven Novella, MD, an assistant professor of neurology at Yale University School of Medicine, in New Haven, Conn., and the executive editor of the blog Science-Based Medicine. “If such alternatives were evidence-based at all, they would be considered medicine, not alternative medicine, and would be adopted into mainstream

care.” In contrast, he said, “complementary interventions are designed to make patients feel better and improve quality of life, not replace conventional medicine.”

there is a different way of treating their cancer to make sure they’ve explored all options,” Dr. Deng said. “I lay out the science of what cancer is, how it arises, what the main treatments are

Patients appear increasingly interested in integrating complementary modalities—such as meditation, acupuncture, massage, and a range of diets, nutritional supplements and exercise regimens—into their mainstream treatments. Patients appear increasingly interested in integrating complementary modalities—such as meditation, acupuncture, massage, and a range of diets, nutritional supplements and exercise regimens—into their mainstream treatments. To meet patient demands for more comprehensive care, integrative programs have been cropping up at leading cancer centers across the United States, including Memorial Sloan-Kettering Cancer Center, in New York City; the University of Texas MD Anderson Cancer Center, in Houston; and Dana-Farber Cancer Institute, in Boston. These integrative oncology programs pair mainstream care with complementary interventions, with the goal of creating a comprehensive care package tailored to each patient’s disease severity and needs. “Some patients have strong convictions and want to do more, so it’s important for oncologists to understand each patient’s psychosocial background and find out what concerns lie beneath the surface,” said Gary Deng, MD, PhD, the interim chief of Integrative Medicine at Memorial Sloan-Kettering Cancer Center. “By delving deeper, oncologists can foster trust with their patients and, hopefully, dissuade them from trying complementary or alternative interventions that may be harmful.” According to Dr. Deng, newly diagnosed patients may be the most susceptible to alternative therapies. “Newly diagnosed patients often ask whether

and why they work or sometimes don’t work. I try to explain this in a way that makes patients feel comfortable that they’re not missing out on any alternative options.” Other patients, however, may be more interested in reducing their symptoms while undergoing mainstream treatment or diminishing their chances of a recurrence while in remission. Such patients may want to explore complementary interventions and are usually beyond wanting to try something alternative, Dr. Deng said. For these patients, Dr. Deng proposes a package of lifestyle changes that may help improve their overall health. Getting patients to exercise, for example, is particularly important. There is extensive research showing that exercise may protect people from developing cancer and increase survival in those already diagnosed with a range of tumors, including breast, colorectal and prostate. (Oncology 2013;27[6]:580-585, PMID: 23909073; JAMA 2005;25;293[20]:24792486, PMID: 15914748; J Clin Oncol 2006;24[22]:3527-3534, PMID: 16822844; Arch Intern Med d 2005;165[9]:1005-1010, PMID: 15883238). In fact, the evidence is so robust that many experts now consider exercise a part of mainstream care, not complementary care. But for most modalities, the evidence is murky. Many studies exploring the benefits of interventions,

such as acupuncture, conflict or are inconclusive (Support Care Cancer 2012;20[6]:1147-1158, PMID: 22447366; Support Care Cancer 2013;21[6]:17351741, PMID: 23334562), whereas others reveal that an intervention may hurt more than it helps. Take, for instance, the use of antioxidant supplements, which actually appear to increase cancer mortality ((Lancet 2004;364[9441]:12191228, PMID: 15464182). According to Harriet Hall, MD, a retired family physician and U.S. Air Force flight surgeon who writes the SkepDoc column in Skeptic magazine, “The field of CAM [complementary and alternative medicine] is vast: It includes methods that may work but have not been tested and methods that have been tested but have not generated sufficient evidence to have become part of conventional medicine. It also includes methods that have been tested and proven ineffective but that promoters still believe in because of personal experience, anecdotal evidence, rejection of scientific method, or misguided thinking.” The vastness of CAM often means that the limited or specific benefits of an intervention may lead people to a dangerous extreme. For instance, vitamins may be beneficial for patients with specific vitamin deficiencies but harmful when taken in large doses, and meditation may help reduce stress and possibly depression, but there is no evidence that it increases survival in patients with cancer. However, when complementary interventions are low risk and given in an appropriate context—namely, to reduce symptoms and promote overall health— they can serve an important purpose: improving quality of life. “Being happy counts for something,” said Dr. Deng. “There is no data that happier patients do better in terms of survival, but if an intervention is low risk and makes a patient’s day-to-day life better, then there is very little downside.” —Victoria Stern

TREATMENTS COMPLEMENTARY

Meditation

Acupuncture

Nutrition

CONVENTIONAL

Exercise

Massage

Surgery

Targeted Therapy

Chemotherapy

Radiation

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

One Unit Better Than Two for Cord Blood Transplant in Kids T

he risk for graft-versus-host disease (GVHD) appears to be lower in pediatric patients undergoing transplantation for hematologic cancer who receive one rather than two units of cord blood, according to results of a randomized trial. There was no difference in survival, the primary end point, but the data suggested that a single unit may be sufficient and perhaps preferable in children, although most adults require two units to reach an adequate cell dose. The trial was prompted by promising results of two-unit cord blood transplantations in adults. It was conducted in children, however, because of the difficulty in achieving an adequate cell dose, defined as at least 2.5 × 107 nucleated cells per kilogram, with single units in larger patients. The expectation of the trial ((N Engl J Med 2014;371[18]:1685-1694, PMID: 25354103) was a better outcome with the larger dose, but there was no significant difference in the primary end point of survival at one year (73% vs. 65%; P=0.17 for single- and double-unit transplants, respectively).

does not typically yield a dose of cells considered adequate for hematologic transplantation. Although this requires partially HLA-matched cord blood from two donors, outcomes appeared similar to or better than those observed previously in studies with single units. For example, survival was better in several series than those observed in the COBLT (Cord Blood Transplantation) study, which used single units and helped establish cord blood as a

viable option for hematopoietic stem cell engraftment for cancer treatment. Although many variables, such as differences in conditioning regimens, complicated efforts to judge the relative benefits of more recent experience with two-unit cord blood transplantation relative to COBLT, in children at least, one-unit transplantation appears preferable. “This is helpful news for physicians considering the best treatment

options for their patients,” said investigator Joanne Kurtzberg, MD, the codirector of the Stem Cell Laboratory at Duke University Medical Center, in Durham, N.C. Based on these results Dr. Kurtzberg concluded, “a single unit is sufficient and perhaps preferable in children.” —Ted Bosworth Dr. Kurtzberg reported no relevant financial relationships.

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014 Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD

Nevertheless, several other outcomes evaluated over the course of follow-up favored the single-unit dose. In particular, grade III or IV acute GVHD was lower in children who received the single unit (13% vs. 23%; P=0.02) and platelet recovery appeared to occur more quickly (58 vs. 84 days). The rate of neutrophil recovery was almost identical (88% vs. 89%). Other outcomes provided additional support for the adequacy of single units in children. For example, disease-free survival at one year was 70% among those receiving a single unit and 64% in those receiving two units ( =0.11). The rates of relapse at one (P year (12% vs. 14%) and treatment-related death (19% vs. 22%) were also similar for the one- and two-unit doses, respectively. In adults, two units have been used because cord blood from a single donor

Expiration Date: November 11, 2015

Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their signiﬁcance in treatment. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Clinical Conundrums Updates in Malignant Hematology from NEJM, Blood, JCO, Lancet Oncologyy and the FDA Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

QUESTIONS

1. True or False? Multiple studies

published in The New England Journal of Medicine ((NEJM M) demonstrated that the presence of 3 recurrent molecular aberrations in otherwise healthy individuals could signal subsequent development of myeloid neoplasms.

2. True

or False? On December 3, 2014, the FDA granted accelerated approval for blinatumomab

ANSWERS

1. True. The 2 studies analyzed data

from whole-exome sequencing of DNA from peripheral blood cells unselected for cancer or hematologic phenotypes. Clonal hematopoiesis with somatic mutations was rare in people younger than age 40 years but rose appreciably in frequency with older age. Detectable clonal expansions most commonly involved somatic mutations in 3 genes, DNMT3A, ASXL1, and TET2. Clonal hematopoiesis was a strong risk factor for subsequent myeloid cancers in both studies. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477-2487, PMID: 25426838. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498, PMID: 25426837.

2. True. In Protocol MT103-211, 32%

(95% confidence interval [CI], 26%40%) of patients with R/R ALL achieved complete remission (CR) with 2 cycles of treatment, and the response was durable (median, 6.7 mo; range, 0.46-16.5 mo). Furthermore, 31% (95% CI, 25%-39%) of the patients in the study had a CR with or without complete hematologic recovery but with reduction in minimal residual disease to <10-4. Blinatumomab is administered by continuous infusion for

Primum non nocere. (First, do no harm.)

(Blincyto, Amgen) for the treatment of Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R Ph-negative- ALL).

compared with corticosteroids alone.

5. True or False? In a study pub-

lished in NEJM, substantial therapeutic activity of nivolumab (Opdivo, BristolMyers Squibb) was observed in patients with heavily treated relapsed or refractory Hodgkin lymphoma (R/R HL).

6. True or False? In a study pub-

lished in NEJM, lenalidomide (Revlimid, Celgene) and dexamethasone was associated with progression-free survival (PFS) that was similar to that found with carfilzomib (Kyprolis, Onyx), lenalidomide, and dexamethasone in patients with relapsed multiple myeloma (MM).

for the diagnosis of MM in Lancet Oncology. According to these new criteria, all of the following patients have MM except: a. A 45-year-old woman with endorgan damage of multiple osteolytic bone lesions and 30% clonal plasma cells on bone marrow (BM) biopsy. b. A 45-year-old man with end-organ damage of multiple osteolytic bone lesions, hypercalcemia, and 15% clonal plasma cells on BM biopsy. c. A 45-year-old man without endorgan damage with 15% clonal plasma cells on BM biopsy. d. A 45-year-old woman without endorgan damage with 65% clonal plasma cells on BM biopsy.

True or False? In a study published 3. True or False? Blinatumomab is a 7. in JCO, patients with relapsed or refractobispecific T-cell engager (BiTE) mono- ry aggressive lymphomas fare better with 10. The IMWG released new criteclonal antibody directed at both CD19 on precursor B-cell ALL cells and CD4 on cytotoxic T cells.

DHAP (dexamethasone, cytarabine, and cisplatin) than with GDP (gemcitabine, dexamethasone, and cisplatin).

4. True or False? Blood and Mar- 8. True

row Transplant Clinical Trials Network (BMT CTN) 0802, a Phase III, multicenter, randomized doubleblinded trial, concluded that the addition of mycophenolate mofetil (MMF) to corticosteroids as initial therapy for acute graft-versus-host disease (GVHD) improves GVHD-free survival

4 weeks of a 6-week cycle. For patients weighing at least 45 kg, the recommended dose and schedule for blinatumomab is 9 mcg per day on days 1 to 7 and 28 mcg per day on days 8 to 28 of the first 42-day cycle, and 28 mcg per day on days 1 to 28 in later cycles. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm425597.htm. Accessed December 27, 2014.

3. False. Blinatumomab is a bispecif-

ic CD19-directed CD3 T-cell engager that activates endogenous T cells when bound to the CD19-expressing target cell. Activation of the immune system results in release of inflammatory cytokines. Cytokine release syndrome (CRS), including life-threatening or fatal events, was reported in 11% of the patients. A boxed warning regarding CRS and neurologic toxicities is included in the product labeling. In addition, the FDA approved blinatumomab with a Risk Evaluation and Mitigation Strategy that consists of a communication plan to inform health care providers about serious risks and the potential for preparation and administration errors with the drug. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm425597.htm. Accessed December 27, 2014.

4. False. The addition of MMF to cor-

ticosteroids as initial therapy for acute GVHD does not improve GVHD-free

or False? Ibrutinib (Imbruvica, Pharmacyclics) and idelalisib (Zydelig, Gilead), B-cell receptor signal inhibitors (BCRi) produce high response rates and prolong PFS, but complete remissions are rare with these agents.

9. The International Myeloma Work-

ing Group (IMWG) released new criteria

survival compared with corticosteroids alone. This trial asked the question whether MMF plus corticosteroids was superior to corticosteroids alone as initial therapy for acute GVHD. The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy. A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled (116 MMF, 119 placebo). Treatment results were similar for GVHD-free survival at day 56; cumulative incidence of chronic GVHD at 12 mo; overall survival (OS); incidence of Epstein-Barr virus reactivation; incidence of severe, life-threatening infections; relapse at 12 months; and quality of life. Bolaños-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014;124(22):32213227, PMID: 25170121.

5. True. Nivolumab, a PD-1–block-

ing antibody, can inhibit tumor immune evasion in patients with R/R HL. In this ongoing study, patients with R/R HL who had already been heavily treated received nivolumab at a dose of 3 mg/kg every 2 weeks until they had a CR, tumor progression, or excessive toxic effects. Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous hematopoietic cell

ria for the diagnosis of smoldering MM (SMM) in Lancet Oncology. According to these new criteria, all of the following patients have SMM except: a. A 45-year-old man without endorgan damage with 15% clonal plasma cells on BM biopsy. b. A 55-year-old man without endorgan damage with 55% clonal plasma cells on BM biopsy. c. A 55-year-old man without endorgan damage with 63% clonal plasma cells on BM biopsy.

transplantation (auto-HCT) and 78% after a relapse following administration of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a CR and 70% with a partial response; the remaining 3 patients (13%) had stable disease. PFS at 24 weeks was 86%; 11 patients were continuing to participate in the study. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s Lymphoma. N Engl J Med. 2014; Dec 6 [Epub ahead of print], PMID: 5482239.

6. False.

In ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma), the addition of carfilzomib to lenalidomide and dexamethasone led to significantly improved outcomes in patients with relapsed MM: a clinically relevant 31% decrease in the risk of disease progression or death and an increase of 8.7 months in the median PFS (26.3 mo in the carfilzomib group vs 17.6 mo in the control group treated with lenalidomide and dexamethasone). According to the investigators, no other regimens have been associated with an equivalent duration of median PFS in the absence of transplantation (see story on page 25).

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

Trend for Survival Benefit With Carfilzomib in Relapsed MM San Francisco—Adding carfilzomib to lenalidomide and dexamethasone in patients with relapsed multiple myeloma (MM) significantly improves progression-free survival (PFS), with a trend for improvement in overall survival (OS), according to interim results from a multicenter Phase III study. Moreover, health-related quality of life (HRQoL) was significantly better in the arm receiving the additional agent. “Based on the results of this Phase III trial, I think it is fair to say that [this regimen] could represent a new standard of care in relapsed multiple myeloma,” reported principal investigator A. Keith Stewart, MB, ChB, the Polak Professor for Clinical Research at Mayo Clinic in Scottsdale, Ariz. In this study, called ASPIRE and presented at the 2014 annual meeting of the American Society of Hematology (abstract 79), the advantage of the experimental regimen extended to both standard- and high-risk patients. The open-label ASPIRE trial randomized 792 patients with relapsed MM to receive lenalidomide (Revlimid, Celgene) and weekly dexamethasone (Rd) or Rd plus carfilzomib (Kyprolis, Onyx) (KRd). Most patients had good performance status, although about one-third had neuropathy at baseline. Nearly 60%

had relapsed after previous transplant. Almost all had been exposed to bortezomib (Velcade, Millennium), lenalidomide, or both, but only 15% were refractory to their previous bortezomib treatment. In the 50% of patients whose cytogenetic risk status was classified by fluorescence in situ hybridization, about onefourth were considered high risk and the remainder had a standard-risk profile. The median PFS was 26.3 months in the arm receiving carfilzomib and 17.6 months in the arm without carfilzomib, producing a hazard ratio (HR) of 0.69 ((P<0.0001). When patients were stratified by cytogenetic risk group, the relative advantage of KRd over Rd was similar in the standard-risk group (29.6 vs. 19.5 months; P=0.004) and in the high-risk group (23.1 vs. 13.8 months; P=0.083). Low numbers may explain why the statistical difference in the high-risk group was only a trend. In the interim analysis of OS, which is a secondary end point, KRd also was

favored after a median follow-up of 32 months (HR, 0.70; P=0.018). This difference, although conventionally significant, did not meet the prespecified level of significance for stopping the trial, according to Dr. Stewart. The group that received carfilzomib had higher objective response rates (87.1% vs. 66.7%; P<0.0001) and complete response rates (31.8% vs. 9.3; P<0.0001). These advantages were achieved with a low cost in adverse events (AEs). Treatment discontinuation due to AEs was less frequent with KRd than with Rd (15.3% vs. 17.7%), although the median duration of treatment was longer (83 vs. 57 weeks). The shorter mean treatment duration in the Rd group was primarily due to early treatment discontinuation, which occurred more frequently in this arm of the study (39.8% vs. 50.1%). The AEs most commonly elevated with KRd relative to Rd were primarily hematologic. There was no difference between groups in rates of

Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2014; Dec 6 [Epub ahead of print], PMID: 25482145.

and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014;32(31):3490-3496, PMID: 25267740.

treatment era: stem cell transplantation or novel agents? Blood. 2014;124(26):3841-3849, PMID: 25301705.

7. False.

8. True.

The randomized NCICCTG LY.12 trial showed that in patients with relapsed or refractory diffuse large B-cell lymphoma, compared with DHAP, GDP was associated with a noninferior response rate; similar transplantation, event-free survival, and OS rates; less toxicity and hospitalization; and superior quality of life. Patients with B-cell lymphoma also received rituximab (Rituxan, Genentech). Responding patients proceeded to hematopoietic cell collection and auto-HCT. Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine,

‘Based on the results of this Phase III trial, I think it is fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.’ —A. Keith Stewart, MB, ChB

Although BCRi produce durable responses, CRs are limited in the relapsed setting. Moreover, patients with 17p– still have inferior outcomes with BCRi compared with patients who do not harbor this mutation. It is worth mentioning that survival plateaus after allogeneic hematopoietic cell transplantation and morbidity decrease with time; the long-term prognosis of patients responsive to BCRi is unknown. Jaglowski SM. Transplant for CLL: still an option? Blood. 2014;124(26):3835-3836, PMID: 25525078. Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new

O’Brien SM, Furman RR, CoutreSE, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. ASCO Meeting Abstracts. 2014;32(15 suppl):7014.

9. c. The patient described in choice

C has SMM. According to new MM criteria, patients with a clonal BM plasma cell percentage of at least 60%, an involved:uninvolved serum free light chain ratio of at least 100 (involved free light chain must be ≥100 mg/L), and more than 1 focal lesion (>5 mm) on magnetic resonance imaging studies should be considered to have MM. Rajkumar SV, Dimopoulos MA, Palumbo A, et al.

peripheral neuropathy (17.1% vs. 17%). In the context of its greater efficacy, the tolerability of KRd was reflected in a consistent and progressive improvement in HRQoL observed over the course of the 18 cycles. A comparable improvement was not observed in those who remained on Rd alone. Calling the median 26.3-month median PFS “unprecedented” in a relapsed MM population, Dr. Stewart concluded that these results suggest KRd is the most active and perhaps the preferred therapy for this population. This perspective was reinforced by Brad S. Kahl, MD, the clinical research director for hematologic malignancies at the University of Wisconsin School of Medicine, in Madison. Although Dr. Kahl suggested that it would be useful to see a clearer demonstration of an OS advantage with longer follow-up, he agreed that this therapy offers activity that is superior to that seen with currently available regimens and may become a new standard for treatment. —Ted Bosworth Dr. Stewart reported financial relationships with Array BioPharma, Bristol-Myers Squibb, Celgene, Millennium and Novartis. Dr. Kahl reported a financial relationship with Infinity.

International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548, PMID: 25439696.

10.

c. SMM is defined according to a serum monoclonal protein (immunoglobulin [Ig]G or IgA) level of at least 30 g/L or urinary monoclonal protein of at least 500 mg/24 h and/or clonal BM plasma cells of 10% to 60%, and d the absence of myeloma-defining events or amyloidosis. Choice c describes a patient with MM according to the new IMWG criteria for the diagnosis of MM. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548, PMID: 25439696.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

New Therapy Offers Survival Benefit in Phase III AML Study San Francisco—The — combination of the investigational agent vosaroxin and cytarabine was associated with an overall survival (OS) benefit in patients with relapsed or refractory acute myeloid leukemia (AML) during the Phase III VALOR trial. The absolute improvement was modest but significant, providing a potential toehold for progress in this disease. “These data support the use of vosaroxin and cytarabine as a new option for salvage therapy in older patients with relapsed disease,” reported Farhad Ravandi, MD, the chief of the section of developmental therapeutics in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, in Houston. Presenting the trial data at the 2014 annual meeting of the American Society of Hematology (abstract LB6), Dr. Ravandi noted that the last approval for a new drug in AML took place in 2000. Vosaroxin is a topoisomerase II inhibitor that is a first-in-class anticancer quinolone derivative being developed by Sunesis. Unlike most other drugs that are active in AML, such as daunorubicin, vosaroxin is minimally metabolized and has activity independent of p53. High response rates in Phase II trials, including one conducted in older, previously untreated highrisk AML patients that was presented at the 2014 annual meeting of the American Society of Clinical Oncology, supported

BRENTUXIMAB continued from page 1

aggressive lymphomas demonstrated a clinically significant improvement in outcome after auto-HCT. This magnitude of advantage “has never been seen before in patients with relapsed/refractory lymphoma, let alone with Hodgkin lymphoma,” said Dr. Moskowitz, the clinical director of the Division of Hematologic Oncology at Memorial SloanKettering Cancer Center (MSKCC), in New York City. “I think that once this study is published, this therapy will be the standard of care.” Presenting the data at the 2014 annual meeting of the American Society of Hematology (ASH; abstract 673), Dr. Moskowitz described the AETHERA trial as the only randomized, placebocontrolled study ever performed in HL. During the study, 329 patients were enrolled at 78 sites in North America

‘Expectation cannot be ... high in refractory AML. We should not discount small but significant steps.’ —Farhad Ravandi, MD Phase III development. In the newly completed, placebo-controlled multinational trial, 711 patients with refractory or relapsed AML were enrolled. Refractory AML was defined as failure to achieve or sustain a complete remission (CR) for more than 90 days with previous therapy. Relapsed AML was defined as a recurrence within 24 months after CR with a prior therapy. Patients were excluded if they were on active immunosuppressive therapy for graft-versus-host disease or had undergone a hematopoietic cell transplant (HCT) within the previous 90 days. All patients received cytarabine, with randomization to vosaroxin or placebo. On an intent-to-treat analysis, the median OS, which was the primary endpoint, fell just short of statistical significance (7.5 vs. 6.1 months; P=0.06), but the difference climbed to significance in preplanned censoring for baseline

stratification factors, such as age or HCT ((P=0.02). For example, when data was censored for HCT, vosaroxin was associated with about a 6-week median OS improvement relative to placebo (6.7 vs. 5.3 months; P=0.02). Objective response rate, a secondary end point, also associated vosaroxin with a significant CR advantage ((P<0.0001). The greater rates of objective response were consistent when patients were subdivided by age and reason for study entry (relapse vs. refractory to previous therapy). Overall, vosaroxin was well tolerated. Although myelosuppression was greater in those who received vosaroxin than in those who did not, there were no significant differences in nonhematologic toxicities, leading Dr. Ravandi to characterize this regimen as well tolerated. However, quality-of-life data were not presented. Asked whether a median six-week survival is an important clinical advantage,

This magnitude of advantage ‘has never been seen before in patients with relapsed/refractory lymphoma, let alone with Hodgkin lymphoma.’ —Craig H. Moskowitz, MD and Europe. Most of the study population had multiple adverse prognostic risk factors, such as failure to achieve remission with front-line therapy. They were randomized to receive 16 cycles of brentuximab (Adcetris, Seattle Genetics)—an antibody-drug conjugate directed at the surface CD30 protein expressed on HL tumor cells—or placebo, administered over one year. The median PFS, which was the primary end point of the trial, was 43 months for those receiving brentuximab and 24 months for those receiving placebo, producing a hazard ratio of 0.57 ( =0.001). At two years, the PFS rate was (P 65% in the experimental therapy group

versus 45% in the control group. This difference in relative PFS at two years is particularly important because relapses after remissions of this duration in the past have been rare, Dr. Moskowitz said. The therapy was relatively well tolerated. Brentuximab was associated with a far greater rate of peripheral neuropathy (56% vs. 16%), but Dr. Moskowitz reported that most of these events were grade 2 or lower. There were no grade 4 events of any kind in either arm of the study, and adverse events associated with brentuximab, including peripheral neuropathy, resolved when therapy was discontinued. There was no overall survival

Dr. Ravandi made an analogy between refractory AML and metastatic lung cancer. Both are aggressive diseases that are widely disseminated in a variety of tissues and associated with a short OS. Treatment options for both remain limited. He cautioned, “Expectation cannot be ... high in refractory AML,” and added, “We should not discount small but significant steps.” Offering his opinion, David Steensma, MD, an attending physician in hematologic oncology at Dana-Farber Cancer Institute, in Boston, agreed that “the benefit is clearly statistically significant,” but he acknowledged that “the magnitude of benefit in this trial was not great” and he cautioned that “it is difficult to know just where this drug will fit,” given other options, such as participating in a treatment trial. He noted that he would personally have been more enthusiastic about a broader role for this combination if a five- to eight-month median OS improvement had been observed, but he agreed that “progress is often incremental like this.” —Ted Bosworth Dr. Ravandi reported a financial relationship with Sunesis. Dr. Steensma reported financial relationships with Amgen, Ariad, Celgene and Novartis.

advantage observed or expected because of a trial design that permitted placebo patients to receive brentuximab at progression, according to Dr. Moskowitz. He noted that 85% of placebo patients crossed over. Dr. Moskowitz concluded that these data will change practice, and Brad S. Kahl, MD, the clinical research director for hematologic malignancies at the University of Wisconsin School of Medicine, in Madison, who was invited by ASH to comment on the study, agreed. He noted that AETHERA is “the first study to show a benefit for any post-transplant therapy” in HL, providing an opportunity to improve outcome, particularly in high-risk populations. —Ted Bosworth Dr. Moskowitz reported financial relationships with Genentech, Merck and Seattle Genetics. Dr. Kahl reported a financial relationship with Infinity.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2015 • CLINICALONCOLOGY.COM

In Refractory MM, Trial Confirms Pomalidomide as Standard San Francisco—In patients with multiple myeloma (MM) who have become refractory to most therapeutic options, oral pomalidomide significantly extends overall (OS) and progression-free survival (PFS), according to data from the largest study ever conducted in this population. Objective response rates to the regimen, which was well tolerated, were substantial even though the heavily pretreated patients were generally refractory to other novel agents. “These data confirm that pomalidomide plus low-dose dexamethasone is a standard of care for refractory multiple myeloma patients who have failed lenalidomide and bortezomib,” said Meletios A. Dimopoulos, MD, the chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, in Greece. He presented the results of this study, called STRATUS, at the 2014 annual meeting of the American Society of Hematology (abstract 80). The Phase IIIb STRATUS study reinforces the results of MM-003, a previously published multinational openlabel Phase III trial (Lancet ( Oncol 2013;14[11]:1055-1066, PMID: 24007748). In that study, 302 patients were assigned in a 2-to-1 ratio to pomalidomide (Pomalyst, Celgene) plus low-dose dexamethasone (POM/LoDex) or to highdose dexamethasone in 28-day cycles. Compared with high-dose dexamethasone (40 mg per day on days 1-4, 9-12 and 17-20), POM/LoDex (pomalidomide 4 mg on days 1-21; dexamethasone 40 mg on days 1, 8, 15 and 22) doubled median PFS (4 vs. 1.9 months; P<0.0001). In the single-arm STRATUS trial, the same regimen of POM/LoDex was evaluated in 452 heavily pretreated patients with MM enrolled at 85 treatment sites. The average number of prior therapies was five. All of the patients had failed lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium) or both, all had progressive disease within 60 days of their last therapy, and 78% were refractory to both bortezomib and lenalidomide.

MM-003 established POM/LoDex as a treatment option, and STRATUS confirms that pomalidomide can provide clinically important inhibition of MM in patients previously exposed to lenalidomide and is a viable standard of care in patients who have exhausted other treatment options. —Meletios A. Dimopoulos, MD

‘Although pomalidomide may be in the same class as the other [immunomodulatory drugs] thalidomide and lenalidomide, pomalidomide clearly offers benefits even when those same in-class agents have failed.’ —Sagar Lonial, MD After a median follow-up of 6.8 months and four cycles of POM/LoDex, the median PFS was 4.3 months, matching that observed in MM-003, and the median OS was 10.9 months, which is one of the longest durations of median OS reported in patients with this degree of previous treatment exposure. For

patients refractory to lenalidomide as well as those refractory to both lenalidomide and bortezomib, the PFS and OS rates were similar to those reported for the study population overall. These improvements in outcome, which were consistent with an objective response rate of 35%, were achieved

with relatively low rates of nonhematologic grade 3 or 4 adverse events (AEs). The only nonhematologic grade 3 or 4 AE occurring in more than 10% of patients was pneumonia (11%). The next most common was fatigue (5%). Grade 3 or higher peripheral neuropathy occurred in less than 1%. Grade 3 hematologic AEs included neutropenia (39%), anemia (27%) and thrombocytopenia (19%). Dose reductions due to AEs were recorded in 28% of patients, but only 9% discontinued therapy. “STRATUS confirms that that improvement in outcome with POM/ LoDex previously observed in MM-003 is achieved with an acceptable safety profile,” Dr. Dimopoulos reported. MM-003 established POM/LoDex as a treatment option, and STRATUS confirms that pomalidomide can provide clinically important inhibition of MM in patients previously exposed to lenalidomide and is a viable standard of care in patients who have exhausted other treatment options, he said. The results of STRATUS are clinically meaningful, according to Sagar Lonial, MD, a professor in the Department of Hematology and Medical Oncology at Emory University’s Winship Cancer Institute, in Atlanta. Dr. Lonial characterized the findings “as an important step” for patients with refractory MM, “particularly those with high-risk genetics.” Moreover, he suggested that the data demonstrate that chemically related immunomodulatory drugs are not interchangeable. “Although pomalidomide may be in the same class as the other [immunomodulatory drugs] thalidomide and lenalidomide,” Dr. Lonial said, “pomalidomide clearly offers benefits even when those same in-class agents have failed.” —Ted Bosworth Dr. Dimopoulos reported financial relationships with Celgene. Dr. Lonial reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis and Onyx.

SOLID TUMORS

PROSTATE continued from page 11

the study, according to the ESMO-invited discussant, Bernard Tombal, MD, the chairman of the Division of Urology at Cliniques Universitaire, Saint-Luc, in Brussels, Belgium. Emphasizing the substantial proportion of patients in the control arm who crossed over to abiraterone, Dr. Tombal suggested that the

OS data are less important for confirming that abiraterone is effective than for demonstrating that early abiraterone is better than late abiraterone. Furthermore, the newly reported OS advantage from abiraterone “may help provide access to this drug,” by showing a convincing benefit to third-party payors who were previously unwilling to reimburse for this therapy, Dr. Tombal suggested.

The COU-AA-302 trial demonstrated that early suppression of androgen activity improves outcome in mCRPC, but there is now interest in evaluating the relative efficacy and timing of abiraterone relative to enzalutamide, which also recently showed significant PFS and OS benefits when compared with placebo for treatment of mCRPC before chemotherapy (N ( Engl J Med 2014;371[5]:424-433, PMID: 24881730).

At ESMO, preliminary evidence presented suggested that use of one of these androgen-suppressing agents does not preclude benefit from the other (abstract 788P), but data are needed to determine if there is an optimal sequence. —Ted Bosworth Dr. Tombal reported no relevant financial relationships. Dr. Ryan reported a financial relationship with Janssen.

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