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JuLy 25, 2016

Chemoradiation improves OS, PFS in older patients with glioblastomaPatients with MGMT–methylated tumors experienced greatest benefit

Pembrolizumab improves long-term outcomes in advanced melanomaPatients derived benefit regardless of prior treatment with ipilimumab

Trastuzumab biosimilar safe, effective for advanced breast cancerBiosimilar has potential as “affordable treatment option” for HER-2–positive breast cancer

Chimeric antigen receptor T cells exhibit efficacy in advanced lymphoma Anti–CD19 CAR T cells may become “important part of lymphoma therapy”

PERSPECTIVES FROM ASCO AnnuAl MeeTing

A HemOnc TOday Special Report

3 | July 25, 2016 | Healio.com/HemOnc

| september 25, 2014 | Healio.com/HemOnc

Originally published in HemOnc Today | Date TBD, 2016

head1

The CSC model may help explain tumor recurrenceThe CSC model is a radical departure from the clonal evolution model. In the clonal evolution model, all cells within a malignant tumor have similar tumorigenic activity.5 By contrast, in the CSC model only a subset of tumor cells, CSCs, have tumor-initiating capability.2 Cancers are organized in a cellular hierarchy, with the CSCs at their apex having tumor-initiating capability.5 One important clinical implication of the CSC model is that it may help to explain why early tumor shrinkage is often poorly predictive of overall survival.6,7 While conventional therapies kill the bulk of non-stem cancer cells, resulting in tumor shrinkage, CSCs may remain viable and later reestablish the tumor, leading to relapse.8 Tumors with increased expression of genes associated with CSCs have also been correlated with lower overall survival in breast and lung cancers.9

Stemness of CSCs may lead to tumorigenicityThe heterogeneous high tumorigenicity of CSCs may be a direct result of their stemness. In both normal stem cells and CSCs, stemness is defined by the characteristics of self-renewal and differentiation.8 Unlike normal stem cells, which differentiate into healthy, mature, cell types, CSCs differentiate into cancer cells. The stemness of CSCs is maintained by several signaling pathways that are overexpressed and overactivated, including JAK-STAT, Wnt/β-catenin, Hedgehog, Nanog, Notch, TGF-β, Hippo-YAP/TAZ, and PI3K/Akt.10-14 These stemness pathways maintain stemness and promote tumorigenicity. This makes CSCs phenotypically different from non-stem cancer cells and confers therapy resistance.4

Epithelial-mesenchymal transition (EMT) of CSCs may lead to metastasis CSCs are also able to transform to a mesenchymal state by the process of EMT. In this state, CSCs become highly migratory and invasive and therefore prone to metastasis.13,15 After spreading to a distant site, they can undergo mesenchymal-epithelial transition and become tumorigenic, colonizing the new site.15 This is a potential mechanism for how CSCs contribute to metastasis and recurrence. Some evidence suggests that EMT and stemness may be coupled, as they are mediated by many of the same factors.16

CSCs are highly resistant to conventional cancer therapiesAlthough current chemotherapies and radiotherapy can kill most non-stem cancer cells, CSCs remain highly resistant.17,18 Further, conventional therapies have been shown to increase the percentage of CSCs within malignant residual tumors.19,20 Many mechanisms that mediate the therapy resistance of CSCs have been identified, including overactivated stemness signaling.10

A key implication of the CSC model for cancer treatment is that both CSCs and non-stem cancer cells should be targeted to reduce tumor recurrence and metastasis.19,21 Several approaches to targeting CSCs are being studied, including stemness-associated signaling pathways that may mediate tumorigenesis, metastasis, and resistance.1,22 The next generation of cancer therapeutics is in development with investigational agents designed to inhibit stemness pathways.1

TARGETING CANCER STEM CELL PATHWAYS AND STEMNESS

Not all cells within a tumor are equalDespite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 A potential new approach to address this is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). CSCs are highly tumorigenic, unlike bulk tumor cells.2 Molecular surface markers for CSCs have been demonstrated within multiple solid and hematologic tumor types, supporting the notion that not all cells within a tumor are equal.3,4 This is the basis of the CSC model.2

References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol. 2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S, ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. wClin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341-1347. 8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90(8):615-621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679. 20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844. 21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267.

EDU-NPS-0108 6/2016 ©2016 Boston Biomedical

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stemness pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

Learn more at www.bostonbiomedical.com

EDU-NPS-0108_R01_BBI_ROB_Ad_HemOncToday.indd 1 6/23/16 2:43 PM

The ASCO Annual Meeting, held in Chicago from June 3-7 under the theme “Collective wisdom: The future of patient-centered care and research,” brought

together hematologists and oncologists from around the world for 5 days of late-breaking clinical trials and re-search updates.

Key areas of focus included breast cancer, glioblastoma and melanoma. Numerous presentations also demon-strated the benefits of immunotherapy in multiple cancer subtypes. An address by Vice President Joe Biden on the

national cancer moonshot initiative focused on collabora-tion and “a lot more openness” among clinicians and re-searchers.

This HemOnc Today supplement provides readers with an overview of the most noteworthy – and potentially prac-tice-changing – findings presented at the ASCO Annual Meeting. Perspectives from physicians in the hematology/oncology communities provide further insight into the im-pact these findings may have in everyday practice.— The Publishers of HemOnc Today

© Copyright 2016, SLACK Incorporated. All rights reserved. No part of this publication may be reproduced without written permission. The ideas and opinions expressed in this HemOnc TOday® supplement do not necessarily reflect those of the editor, the editorial board or the publisher, and in no way imply endorsement by the editor, the editorial board or the publisher.

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Web Watch

Visit Healio.com/Hematology-Oncology for more in-depth coverage of the findings in immuno-oncology presented at the meeting in the Discoveries from ASCO: Immuno-oncology resource center. The resource center provides exclusive video perspectives from key opinion leaders regarding late-breaking clinical trials and other recent research in immuno-oncology to be presented at the ASCO Annual Meeting.

ASCO Annual Meeting highlights late-breaking clinical trials, research updates

Video coVerage

Visit Healio.com/Hematology-Oncology to hear more from Brian Bolwell, MD, chairman of the Taussig Cancer Institute at Cleveland Clinic, about studies on the affordability of higher, escalating drug prices for cancer treatments in the United States and other countries.

“Figuring out how to work with pharma to try to moderate … drug pricing is utterly imperative both for the health care economy, as well as for our citizens.”

— BRIAN BOLWELL, MD

54 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc

Originally published in HemOnc Today | June 25, 2016

Chemoradiation improves OS, PFS in older patients with glioblastoma

The addition of concomitant and adjuvant temozolomide to hyper-fractionated radiation therapy sig-

nificantly prolonged PFS and OS among older patients with newly diagnosed glioblastoma, according to phase 3 study results presented during the plenary ses-sion of the ASCO Annual Meeting.

Patients with MGMT–methylated tumors derived the greatest benefit from temozolomide.

Although glioblastoma occurs pri-marily in older adults, no clear guide-lines for treatment have been defined.

“The peak age of incidence of glio-blastoma is 64 years, and the incidence appears to be increasing with our ag-ing population,” James R. Perry, MD, FRCPC, Crolla family endowed chair in brain tumor research at Odette Can-cer Centre and Sunnybrook Health Sci-ences Centre in Toronto, said during a press conference. “The current best practice is surgical resection, followed by radiotherapy combined with che-motherapy.”

A trial conducted by the EORTC suggested a survival benefit could be gained through the addition of temo-zolomide to radiation therapy in newly diagnosed patients; however, the re-searchers observed a trend of decreas-ing benefit with increasing age, and the potential OS benefit of the combina-tion in older patients remained un-known.

“The studies that we have in older pa-tients over 65 years have only compared radiation schedules head-to-head, or radiation alone vs. temozolomide alone,” Perry said. “There has never been a trial of combined chemotherapy with radiation in elderly patients.”

Perry and colleagues conducted a global randomized clinical trial of 562 older patients (median age, 73 years;

range, 65-90; 61% men).Researchers randomly assigned

patients to 40 Gy radiation therapy in 15 fractions, with or without 3 weeks of concomitant temozolomide and monthly adjuvant temozolomide (n = 281 for both). Patients assigned adjuvant temozolomide received treat-ment for up to 12 cycles or until pro-gression.

Patients assigned temozolomide

achieved longer median OS (9.3 months vs. 7.6 months; HR = 0.67; 95% CI, 0.56-0.8) and longer me-dian PFS (5.3 months vs. 3.9 months; HR = 0.5; 95% CI, 0.41-0.6) than those assigned radiation alone.

A total of 462 patients provided an adequate tissue sample for MGMT analysis, which has been conducted in 354 patients to date.

Originally published in HemOnc Today | July 10, 2016

Age, complications influence death after colon cancer surgery

Perioperative complications in-creased the 1-year risk for death after colon cancer surgery among

patients of all ages, according to study results.

The elevated risk extended beyond the 30-day postoperative period, and nearly one-quarter of patients aged older than 65 years died of cardiovas-cular disease.

Few studies have focused on age-re-lated differences in the rate and cause of death beyond the postoperative pe-riod among patients undergoing colec-tomy.

“Most of the previous studies look-ing at long-term outcomes have fo-cused on oncologic endpoints, such as RFS, to analyze the effects of differ-ent treatment regimens,” Christopher Thomas Aquina, MD, MPH, surgi-cal resident at University of Rochester Medical Center and research fellow at Surgical Health Outcomes & Re-search Enterprise, told HemOnc To-day. “This research has been critical in improving outcomes for patients, but it has not traditionally accounted for other factors influencing OS.”

Aquina and colleagues accessed the New York State Cancer Registry and Statewide Planning and Research Cooperative System to identify 26,420 patients who underwent colectomy for stage I to stage III colon adenocarci-noma between 2004 and 2011.

The researchers categorized pa-

tients by age group — younger than 65 years, 65 years to 74 years, and 75 years or older — and by occurrence of major complications. They then compared age groups with cause of death 1 year after surgery.

Overall, 3.3% of patients died with-in 30 days of surgery, and 11.6% died within 1 year. Mortality varied by age group (< 65 years, 3.8%; 65-74 years,

8.3%; ≥ 75 years, 18.8%).A greater percentage of older pa-

tients experienced a major complica-tion (< 65 years, 23.3%; 65-74 years, 29.9%; ≥ 75 years, 38.2%). Postop-

erative complications significantly increased the risk for death at 1 year across all age groups: aged older than 65 years (6.4% vs. 1.9%); 65 to 74 years (12.8% vs. 3.8%); 75 years or older (22.4% vs. 9.2%; P < .0001 for all).

Although colon cancer was the leading cause of death in all cohorts, a greater proportion of younger patients died of the disease than older patients (< 65 years, 58%; ≥ 75 years, 43.9%).

However, the risk for death caused by cardiovascular disease increased with age. More than one-quarter (27.8%; n = 429) of patients aged 75 years or older died of cardiovascular disease, compared with 9.3% (n = 21) of patients aged younger than 65 years and 20.7% (n = 83) of patients aged 65 years to 74 years.

“The major focus following sur-gery typically involves preventing cancer recurrence through close on-

“Traditionally, there has not been as much focus placed on the management of the patient’s other comorbidities, which may be driving the higher rates of death from cardiovascular disease.”— ChRIsTOphER ThOMAs AquINA, MD, Mph

PERSPECTIVE

This study adds to the landscape of knowledge in terms of postoperative outcomes in older adults who undergo sur-gery for colon cancer. This study highlights the importance of integrating geriatric oncology practices. As patients aged, the overall risk for postoperative complications increased, re-sulting in higher rates of 1-year mortality.

Two individuals with the same chronological age do not nec-essarily have the same functional or physiological age. The study of the use of geriatric oncology principles, such as a comprehensive geriatric assessment, is already underway

in terms of preoperative assessment for older adults getting ready for surgery. This is important because doctors can identify potential vulnerabilities that a surgeon might not be able to anticipate through a standard history or physical exam. As a result of that, we can research potential interventions for vulnerabilities detected through the geriatric assessment to improve overall surgical outcomes.

This study identifies age as a risk factor for long-term mortality, and it really empha-sizes the need for geriatric oncology principles and comprehensive geriatric assess-ment in the preoperative and perioperative settings.

— Daneng Li, MDCity of Hope

Disclosure: Li reports no relevant financial disclosures.

Daneng Li

PERSPECTIVE

The take-home message of this trial is that, regardless of the age of the adult patient, it is now becoming the standard of care to give radiotherapy plus temozolomide to patients with newly diagnosed glioblastoma. The second important takeaway is that the benefit of temozolomide was most pro-nounced among those with glioblastomas that demonstrated methylation of the promoter for a gene called MGMT. How-ever, there also was a benefit regardless of MGMT methylation.

The context for why this is important is twofold. One, the prior practice-changing trial that led to our current standard of care of radiotherapy and temozolomide in patients with

glioblastoma excluded patients aged older than 70 years. In addition, that prior trial suggested the benefit of temozolomide decreased with age. Therefore, it was un-clear whether temozolomide prolonged survival when combined with radiotherapy in patients aged older than 70 years.

The other important aspect of this study was the length of the radiotherapy course. In this trial it was 3 weeks, whereas it was 6 weeks in the prior landmark trial by Stupp and colleagues. Six weeks of radiotherapy can be a rough treatment in older patients, and there had been previous studies demonstrating that a shortened course, using a technique called hypofractionation, was not inferior to a 6-week course in older patients.

What remains unclear is whether radiotherapy itself can be omitted in elderly pa-tients with MGMT–methylated tumors. This trial included two arms, both of which had radiation. The question was whether adding temozolomide to radiation was beneficial, and the answer was yes. The flip question of randomly assigning patients to get temozolomide alone or with radiotherapy remains unanswered.

References:Roa W, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.06.082.Stupp R, et al. N Engl J Med. 2005;10;352:987-996.

— Andrew B. Lassman, MDNewYork-Presbyterian

Columbia university Medical CenterDisclosure: Lassman reports no relevant financial disclosures.

Andrew B. Lassman

Chemoradiation continues on page 7

Age continues on page 7

76 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc

Originally published in HemOnc Today | June 25, 2016

Chimeric antigen receptor T cells exhibit efficacy in advanced lymphoma

Treatment with T cells genetically modified to express chimeric an-tigen receptors that target CD19

induced remission in patients with advanced B-cell lymphoma when ad-ministered with low-dose chemother-apy, according to study results.

The use of chimeric antigen receptor (CAR) T cells may become a standard of care for advanced lym-phoma in the near future, according to James N. Kochenderfer, MD, in-vestigator in the experimental trans-plantation and immunology branch of the NCI’s Center for Cancer Re-search.

“T cells that are genetically modi-fied to express CARs targeting CD19 have significant activity against B-cell malignancies,” Kochenderfer said during his presentation. “In almost all clinical trials of anti–CD19 CAR T cells, the T-cell infusions are preceded by chemotherapy, because depletion of the recipient leukocytes has been shown to enhance the activity of adoptively transferred T cells.”

Kochenderfer and colleagues pre-viously reported data from patients treated with CAR T cells and high-dose chemotherapy.

In the current analysis, researchers assigned 22 patients with advanced lymphoma to low-dose condition-ing chemotherapy, followed by anti–CD19 CAR T-cell infusion.

Nineteen patients had diffuse large B-cell lymphoma (DLBCL). Two pa-tients had follicular lymphoma and one had mantle cell lymphoma.

Eighteen patients received dai-ly cyclophosphamide (300 mg/m2 per day) for 3 days; the remain-ing four patients received a dose of 500 mg/m2 on the same schedule. All patients received fludarabine

(30 mg/m2) on the same schedule.Patients received a single dose of

CAR T cells 2 days after completion of chemotherapy. After that, research-ers analyzed blood CAR T cells and serum cytokines.

The overall response rate for the en-tire cohort was 73%, with an ORR of

68% in the DLBCL patient population.Eight patients with DLBCL

achieved complete response, as did all patients with follicular lymphoma and mantle cell lymphoma.

Five patients with DLBCL achieved a partial response, with two patients achieving stable disease. Four patients

PERSPECTIVE

This abstract provides additional data on chimeric antigen receptor (CAR) T cells for the treatment of aggressive lym-phomas. CAR T cells are very exciting, receiving much at-tention, and there are a lot of data coming out about their use in lymphoid malignancies. One of the challenges is to take them forward in a way that definitively demonstrates their value compared with other treatments. This study in-cluded data from 22 patients and showed that a regimen of fludarabine or cyclophosphamide in a nonmyeloablative fashion, in addition to CAR T cells, could induce meaningful remissions in patients with diffuse large B-cell lymphoma

(DLBCL). A few other aggressive subtypes were included, but most of the patients in this report had DLBCL. A majority of patients in this study had a response. This is exciting because it shows we can observe a high response rate when patients are treated with CAR T cells. Further, the chemotherapy regimen used was attenuated in dose, so we can attribute the effect primarily to the CAR T cells and less so to the chemotherapy.

These additional data show this regimen has potential in the treatment of patients with resistant, aggressive lymphoma. As far as follow-up is concerned, we need additional studies with larger groups of patients, with longer follow-up periods, to see if these responses are going to be durable. That is going to be quite important to see in much larger patient populations. We also need to address the critical fact that there is an inherent selection bias in CAR T-cell therapy. There are patients who are not candidates for this type of treatment because of their age and comorbidity burden, or because they have rapidly aggressive or growing disease. Because there is an inherent delay of a few weeks required to get a patient enrolled and get them CAR T cells — and sometimes longer to even be able to be considered for a spot on a trial — some patients with aggressive lymphoma are left out because they cannot wait that long for therapy. So, there is an inherent bias toward patients who are healthy, and those who have more favorable (ie, less rapidly growing or symp-tomatic) disease, allowing them to wait a little longer for treatment.

That said, the lymphoma community remains excited, and it is safe to say there is a good chance this treatment will be more widely used in the future.

— John P. Leonard, MDWeill Cornell Medicine

NewYork-Presbyterian HospitalDisclosure: Leonard reports a prior consultant role with Kite Pharma.

John P. Leonard

experienced progressive disease.Ten patients’ responses remained

ongoing at the time of reporting, with response durations ranging from 1 month to 20 months.

All but four patients had chemo-therapy-refractory lymphoma or re-lapsed lymphoma after autologous stem cell transplantation.

All patients developed fevers, and 55% (n = 12) experienced grade 3 or grade 4 neurological toxicities. How-ever, all toxicities resolved, typically

in less than 2 weeks, Kochenderfer said.

Patients had a median CAR–posi-tive cell level of 47 μL (range, 4-1,217). Those who achieved complete or par-tial responses had higher peak blood CAR–positive cell levels than those with stable or progressive disease.

“Anti–CD19 CAR T cells are now involved in multicenter trials,” Ko-chenderfer said. “They will prob-ably become an important part of lymphoma therapy in the future,

particularly to salvage the patients who are refractory to chemotherapy and have very few other options.” – by Cameron Kelsall n

Reference:Kochenderfer J, et al. Abstract LBA3010. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: The NIH funded this study. Ko-chenderfer reports institutional research fund-ing from Bluebird Bio and Kite Pharma, as well as a patent agreement with Bluebird Bio. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Among the 165 patients with MGMT–methylated tumors, those as-signed temozolomide achieved longer median OS than those assigned radia-tion alone (13.5 months vs. 7.7 months; HR = 0.53; 95% CI, 0.38-0.73).

Unmethylated patients assigned the combination had a median OS of 10 months, compared with 7.9 months for those assigned radiation (HR = 0.75; 95% CI, 0.56-1.01).

A quality-of-life analysis showed no differences in physical, cognitive, emo-tional or social functioning between arms. Patients assigned temozolomide

reported more nausea, vomiting and constipation than those assigned ra-diation alone.

The researchers reported high pa-tient adherence to therapy, with more than 97% of patients completing 3 weeks of chemoradiation.

“This is quite important, because the elderly often have difficulties with mobility, or with distance from treat-ment centers,” Perry said. “They some-times don’t have a caregiver who is able to bring them back and forth to treat-ment, so the shorter radiation schedule is an advantage.”

Thirty-nine percent of patients as-signed temozolomide and 41% of patients assigned radiation alone re-

ceived systemic therapy after progres-sion.

“Oncologists now have evidence to consider radiotherapy with temozolo-mide in all newly diagnosed elderly patients with glioblastoma,” Perry said. – by Cameron Kelsall n

Reference:Perry JR, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: This study received funding from the Canadian Cancer Society Research Insti-tute, as well as from an unrestricted grant from Schering-Plough/Merck. Perry reports stock and ownership interests in DelMar Pharma-ceuticals and VBL Therapeutics. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Chemoradiationcontinued from page 4

cologic follow-up and appropriate use of chemotherapy,” Aquina said. “Tra-ditionally, there has not been as much focus placed on the management of the patient’s other comorbidities, which may be driving the higher rates of death from cardiovascular disease. Older patients are more likely to have higher rates of cardiovascular disease and a higher overall level of comor-

bidity burden compared with younger patients.”

Aquina told HemOnc Today that he hopes these data will lead to stron-ger collaborations between surgeons and medical oncologists.

“We hope that this work empha-sizes the need for greater collabora-tion with our colleagues in geriatric oncology to allow for a more nuanced preoperative assessment, including a comprehensive geriatric assessment when appropriate,” Aquina said. “We

feel that multidisciplinary support will help improve the delivery of care to older patients with colon cancer.” – by Cameron Kelsall n

Reference:Aquina CT, et al. Abstract 10012. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: Aquina reports no relevant fi-nancial disclosures. Other researchers report consultant roles with Seattle Genetics and upToDate.

Agecontinued from page 5

Learn more at www.bostonbiomedical.com

The CSC model may help explain tumor recurrenceThe CSC model is a radical departure from the clonal evolution model. In the clonal evolution model, all cells within a malignant tumor have similar tumorigenic activity.5 By contrast, in the CSC model only a subset of tumor cells, CSCs, have tumor-initiating capability.2 Cancers are organized in a cellular hierarchy, with the CSCs at their apex having tumor-initiating capability.5 One important clinical implication of the CSC model is that it may help to explain why early tumor shrinkage is often poorly predictive of overall survival.6,7 While conventional therapies kill the bulk of non-stem cancer cells, resulting in tumor shrinkage, CSCs may remain viable and later reestablish the tumor, leading to relapse.8 Tumors with increased expression of genes associated with CSCs have also been correlated with lower overall survival in breast and lung cancers.9

Stemness of CSCs may lead to tumorigenicityThe heterogeneous high tumorigenicity of CSCs may be a direct result of their stemness. In both normal stem cells and CSCs, stemness is defined by the characteristics of self-renewal and differentiation.8

Unlike normal stem cells, which differentiate into healthy, mature, cell types, CSCs differentiate into cancer cells. The stemness of CSCs is maintained by several signaling pathways that are overexpressed and overactivated, including JAK-STAT, Wnt/β-catenin, Hedgehog, Nanog, Notch, TGF-β, Hippo-YAP/TAZ, and PI3K/Akt.10-14 These stemness pathways maintain stemness and promote tumorigenicity. This makes CSCs phenotypically different from non-stem cancer cells and confers therapy resistance.4

Epithelial-mesenchymal transition (EMT) of CSCs may lead to metastasis CSCs are also able to transform to a mesenchymal state by the process of EMT. In this state, CSCs become highly migratory and invasive and therefore prone to

metastasis.13,15 After spreading to a distant site, they can undergo mesenchymal-epithelial transition and become tumorigenic, colonizing the new site.15 This is a potential mechanism for how CSCs contribute to metastasis and recurrence. Some evidence suggests that EMT and stemness may be coupled, as they are mediated by many of the same factors.16

CSCs are highly resistant to conventional cancer therapiesAlthough current chemotherapies and radiotherapy can kill most non-stem cancer cells, CSCs remain highly resistant.17,18 Further, conventional therapies have been shown to increase the percentage of CSCs within malignant residual tumors.19,20 Many mechanisms that mediate the therapy resistance of CSCs have been identified, including overactivated stemness signaling.10

A key implication of the CSC model for cancer treatment is that both CSCs and non-stem cancer cells should be targeted to reduce tumor recurrence and metastasis.19,21 Several approaches to targeting CSCs are being studied, including stemness-associated signaling pathways that may mediate tumorigenesis, metastasis, and resistance.1,22 The next generation of cancer therapeutics is in development with investigational agents designed to inhibit stemness pathways.1

TARGETING CANCER STEM

CELL PATHWAYS AND STEMNESS

Not all cells within a tumor are equalDespite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 A potential new approach to address this is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). CSCs are highly tumorigenic, unlike bulk tumor cells.2 Molecular surface markers for CSCs have been demonstrated within multiple solid and hematologic tumor types, supporting the notion that not all cells within a tumor are equal.3,4 This is the basis of the CSC model.2

References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol. 2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S, ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341-1347. 8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90(8):615-621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679. 20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844. 21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267.

EDU-NPS-0108 6/2016 ©2016 Boston Biomedical

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stemness pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

EDU-NPS-0108_R01_BBI_ROB_Ad_IslandSpread.indd All Pages 6/24/16 12:05 PM

1110 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc

Originally published in HemOnc Today | June 25, 2016

Upfront autologous HSCT superior to novel therapies for multiple myeloma

First-line treatment with autolo-gous hematopoietic stem cell transplantation prolonged PFS

compared with bortezomib-contain-ing chemotherapy in younger pa-tients with newly diagnosed multiple myeloma, according to results of a randomized phase 3 study.

Thus, autologous HSCT should remain the preferred first-line treat-ment option over novel therapies for younger patients with newly diag-nosed multiple myeloma, according to the researchers.

“For more than 2 decades, che-motherapy at the doses requiring the support of autologous stem cells has been considered the gold stan-dard for younger and fit patients with newly diagnosed multiple my-eloma,” Michele Cavo, MD, head of the Seràgnoli Institute of Hematology at University of Bologna, said dur-ing a press briefing. “Over the past 10 to 15 years, therapies with novel, nongenotoxic drugs have dramati-cally increased the response rate and significantly [extended] survival in previously untreated myeloma pa-tients. Remarkable activity of novel therapies has recently put into ques-tion the role of upfront autologous stem cell transplantation in multiple myeloma.”

Cavo and colleagues compared the efficacy of the VMP chemotherapy regimen — which consists of bortezo-mib (Velcade; Takeda/Millennium), melphalan and prednisone — with autologous HSCT in 1,266 patients aged 65 years or younger with newly diagnosed multiple myeloma.

All patients received induction therapy with bortezomib, cyclophos-phamide and dexamethasone. They then were randomly assigned to four

cycles of VMP (n = 512) or one to two courses of high-dose melphalan with single autologous HSCT (n = 754).

Patients treated in centers with a tandem HSCT policy were randomly assigned to receive VMP or single or double autologous HSCT.

Patients then underwent a second randomization to consolidation ther-apy with bortezomib, lenalidomide (Revlimid, Celgene) and dexameth-asone or no consolidation therapy, followed by lenalidomide mainte-

PERSPECTIVE

With the arrival of noncytotoxic agents in the early 2000s, the role and timing of high-dose melphalan was evaluated in several randomized phase 3 studies. Palumbo and col-leagues with the European Myeloma Network conducted two randomized phase 3 trials evaluating lenalidomide (Rev-limid, Celgene) and low-dose dexamethasone induction fol-lowed by conventional chemotherapy — melphalan, predni-sone and lenalidomide in one trial, and cyclophosphamide, prednisone and lenalidomide in the other — or high-dose melphalan with autologous stem cell transplant (HDM–ASCT, single or tandem). Both trials showed PFS and OS benefits

with HDM–ASCT but were criticized for not having proteasome inhibitors in induc-tion treatment.

Attal and colleagues then presented the Intergroupe Francophone du Myelome (IFM) 2009 data — which compared early vs. late HDM–ASCT — at the ASH Annual Meeting and Exposition in 2015. Results showed a PFS benefit in favor of early HDM–ASCT. All patients on the IFM 2009 trial received lenalidomide, bortezomib (Velcade, Takeda/Millennium) and dexamethasone induction and lenalidomide maintenance, thus quelling concerns about suboptimal induction.

Now, Cavo and colleagues have presented another clinical trial in which bortezomib, cyclophosphamide and dexamethasone induction was followed by either bortezo-mib, melphalan and prednisone consolidation or HDM–ASCT (single or tandem). Data from the study follow the same theme: HDM–ASCT conferred superior PFS. The PFS benefit was seen in patients with standard- and high-risk cytogenetics and was more pronounced in the tandem HDM–ASCT arm.

If we are compelled to use best available evidence and data to treat our patients, then upfront/early HDM–ASCT should remain the standard of care for transplant-eligible patients with multiple myeloma.

References:Attal M, et al. Abstract 391. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Florida.Gay F, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00389-7.Palumbo A, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1402888.

— Saad Z. Usmani, MD, FACPHemOnc TOday Editorial Board member

Levine Cancer Institute, Carolinas HealthCare SystemDisclosure: usmani reports no relevant financial disclosures.

Saad Z. usmani

Originally published in HemOnc Today | June 10, 2016

Pembrolizumab improves long-term outcomes in advanced melanoma

Forty percent of patients with ad-vanced melanoma achieved 3-year OS with pembrolizumab, accord-

ing to long-term follow-up of the KEY-NOTE-001 study.

Patients derived benefit from pem-brolizumab (Keytruda, Merck) regard-less of prior treatment with ipilimumab (Yervoy, Bristol-Myers Squibb).

“These data confirm that pembro-lizumab provides a long-term survival benefit for patients with advanced mel-anoma,” Caroline Robert, MD, PhD, head of the dermatology unit at Insti-tute Gustave-Roussy in Paris, said in a press briefing. “The response rate con-trasts with past results from patients with this disease. The data show dura-ble responses in one-third of patients, with complete durable responses that are visible after stopping treatment.”

Pembrolizumab received accel-erated approval for advanced mela-noma in September 2014 based on data from KEYNOTE-001. Data from KEYNOTE-002 also has shown that pembrolizumab prolongs PFS com-pared with chemotherapy, and in KEYNOTE-006, pembrolizumab ex-tended OS and PFS compared with ipilimumab for patients with advanced melanoma.

Prior to the approval of ipilimumab in 2011, median survival for advanced melanoma had been less than 1 year, Robert said.

Robert and colleagues conduct-ed long-term follow-up of patients treated in the KEYNOTE-001 study to determine 3-year OS. The analy-sis included 655 patients — enrolled into ipilimumab-naive and -treat-ed cohorts — assigned 2-mg/kg or 10-mg/kg doses of pembrolizumab every 3 weeks or 10 mg/kg every 2 weeks until intolerable toxicity, disease

progression or investigator decision to stop treatment. Seventy-five percent of patients had received one or more pre-vious therapies and 52% had received ipilimumab.

Following pembrolizumab discon-tinuation, researchers followed up with patients every 3 months to assess OS.

Median follow-up was 32 months (range, 24-46); all patients were fol-lowed for a minimum of 2 years.

Mean treatment duration was 11.3 months and 21% of patients continued pembrolizumab beyond the data cutoff date of Sept. 18, 2015.

Overall, 358 patients died. The 3-year OS rate was 40% and median OS was 23.8 months (95% CI, 20.2-29).

OS rates appeared similar across

treatment regimens, with the highest median OS being 25.9 months (95% CI, 18.9-41.8) in the cohort that re-ceived 10 mg/kg every 2 weeks.

The rate of 3-year OS was 41% both in cohorts who had and had not previ-ously received ipilimumab. However, 3-year OS was higher in treatment-na-ive patients (45%), for whom median OS was 32 months (95% CI, 27.1-not reached).

Ninety-five patients achieved a complete response, 61 of whom stopped treatment as a result. Response duration ranged from 17+ months to 43+ months.

Two patients experienced disease progression after stopping treatment,

PERSPECTIVE

This abstract reports on long-term survival outcomes in pa-tients with advanced melanoma treated with pembrolizum-ab (Keytruda, Merck) in the KEYNOTE-001 trial. Researchers report a 40% 3-year OS rate with a median survival of nearly 2 years and a “tail-of-the-curve” phenomenon consistent with long-term survival benefit with this agent.

These data mirror the long-term outcomes with nivolumab (Opdivo, Bristol-Myers Squibb) reported this year by Hodi and colleagues at the American Association for Cancer Re-search Annual Meeting. Their results demonstrated a 42% 3-year OS rate and a 34% 5-year OS rate.

Taken together, these studies demonstrate the remarkable clinical benefit achieved with PD-1–based immunotherapeutics in patients with advanced melanoma. Ad-ditional work is needed to enable us to better select those patients who are best treated with single-agent anti–PD-1 therapy as opposed to those who may require combined immunological checkpoint blockade with regimens such as ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab.

Reference:Hodi FS, et al. Abstract CT001. Presented at: AACR Annual Meeting; April 16-20, 2016; New Orleans.

— Richard D. Carvajal, MDNewYork-Presbyterian

Columbia university Medical CenterDisclosure: Carvajal reports a consultant role with Merck.

Richard D. Carvajal

Pembrolizumab continues on page 13

Upfront continues on page 15

1312 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc

Originally published in HemOnc Today | July 10, 2016

Trastuzumab biosimilar safe, effective for advanced breast cancer

Women with HER-2–posi-tive advanced breast cancer treated with MYL-1401O,

a biosimilar trastuzumab antibody, achieved outcomes comparable to those of women treated with the bio-

similar’s FDA–ap-proved reference product, accord-ing to results of a randomized phase 3 study.

The addition of trastuzumab (Herceptin, Ge-

nentech) — a biologic agent approved by the FDA in 1998 and now indicated for women with early- or late-stage breast cancer — to chemotherapy has resulted in a 5- to 8-month survival improvement for women with late-stage disease. The addition of 1 year of trastuzumab to chemotherapy has been shown to reduce the risk for recurrence by 10% and improve survival by about 9% in women with early-stage disease.

“Biologic agents are usually targeted therapies and are costly, limiting access across the globe,” Hope S. Rugo, MD, professor of medicine at University of California, San Francisco, said dur-ing a press conference. “Many biologic agents are losing patent protection soon or have already lost patent pro-tection in other countries. Biosimilars have the potential to significantly im-prove access to expensive agents.”

Regulatory agencies have estab-lished requirements for biosimilar ap-proval. They include a demonstration of structural and functional similarity to the reference product; a demonstra-tion of similar pharmacokinetics and pharmacodynamics; and confirmation of similar safety, efficacy and immuno-genicity.

Rugo and colleagues evaluated the safety, efficacy and immunogenicity of MYL-1401O (Mylan Inc.) compared with trastuzumab.

The analysis included data from 458 women treated at 95 sites worldwide. All women had HER-2–positive meta-static breast cancer, and they had not received prior chemotherapy or trastu-zumab for metastatic disease. Forty-four percent of women had hormone receptor–positive disease.

Researchers randomly assigned patients to MYL-1401O (n = 230) or trastuzumab (n = 228) with docetaxel or paclitaxel every 3 weeks for at least eight cycles. Patients with stable disease beyond the eighth cycle could continue to receive the antibody therapy alone until disease progression or unaccept-able toxicity.

Overall response rate at week 24 served as the study’s primary endpoint. The FDA also asked researchers to cal-culate ORR ratio as an endpoint, and the European Medicines Agency asked for the difference in ORR between the biosimilar and trastuzumab. Secondary endpoints included PFS, OS and safety.

At week 24, the ORR was 69.6% for MYL-1401O and 64% for trastuzumab. Researchers calculated an ORR ratio of 1.09 (90% CI, 0.97-1.21; and 95% CI, 0.95-1.23), meeting the predefined equivalency margin. The difference in ORR was 5.5 (90% CI, –1.7 to 12.69; and 95% CI, –3.08 to 14.04), which also fell within the required equivalency range.

Based on 41 events in the biosimi-lar arm and 48 in the reference prod-uct arm, median PFS had not yet been reached.

The overall antidrug antibody rate was 2.4% with MYL-1401O and 2.8% with trastuzumab, consistent with pub-

lished data, Rugo said. The dose-nor-malized maximum concentration and area under the curve also were similar between the two agents.

Safety appeared comparable be-tween study groups, and no significant changes in cardiac function occurred in either cohort.

Serious adverse events — which were primarily hematologic and related to taxane therapy — occurred in 38.1% of those assigned the biosimilar and 36.2% of those assigned the reference product.

Common adverse events included neutropenia (biosimilar, 27.5%; refer-ence product, 25.2%), febrile neutrope-nia (4.5% vs. 4.1%), leukopenia (1.6% vs. 4.9%) and pneumonia (1.6% vs. 2%).

Four fatal events occurred in each study arm.

“This proposed biosimilar has the potential to meet the need for an af-fordable treatment option for patients with HER-2–positive cancers,” Rugo said. “This is one of the first trials of biosimilars in oncology to dem-onstrate these similar results. On-going trials with other biosimilars should further improve access world-wide to these lifesaving therapies.” – by Alexandra Todak n

Reference:Rugo HS, et al. Abstract LBA503. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: The study was funded in part by Mylan. Rugo reports a speakers bureau role with and honoraria from Genomic Health; travel expenses from Mylan, Nektar, Novartis, OBI Pharma and Roche/Genentech; and insti-tutional research funding from Celsion, Eisai, Genentech, MacroGenics, Merck, Nektar, No-vartis, OBI Pharma, Pfizer and Plexxikon. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Hope S. Rugo

PERSPECTIVE

We expect that the area of biosimilars is going to have a bigger cost impact than maybe some of the oral drugs when they go generic. Many of these biologic drugs are now just coming off patent, so the whole field of biosimi-lars is new. We do not know exactly how it is going to play out, but, of course, the cost is expected to go down significantly.

Trastuzumab (Herceptin, Genentech) is no longer one of the most expensive bio-logic drugs, although it used to be when it first was approved. It can cost anywhere

from $3,000 to $4,000 a month, whereas some of the newer bio-logic drugs are four times that price. Still, we expect the price will come down — we hope by at least half.

For some patients, the price will not make a difference because insurance covers most infused medications. However, there are patients who have copays, and it will make a difference for them. In many parts of the world, where these drugs are simply not available because of the cost, the availability of a biosimilar would make a huge difference.

The FDA requires a certain degree of testing to prove the efficacy and safety of a biosimilar. First, the methods for manufacturing must be very clearly laid out. Second, the product must have the same chemical composition and physical and functional proper-ties as the parent drug. Third — and most importantly — the bio-logical effects on patients and on the tumor must be similar, the pharmacokinetics must be well worked out and, ultimately, the safety and efficacy must be proven to be similar.

In the randomized, double-blind phase 3 trial, the overall response rate for MYL-1401O (Mylan) given with a taxane in the first line was about 70%, compared with 64% for trastuzumab. This was statisti-cally similar and met the threshold that is set for eventual approval of the drug. In addition, mean serum concentrations over time were similar, as were fatal adverse events (1.6% in each group). However, the number of patients who had to discontinue early due to subclinical or clinical cardiomyopathy was not reported.

For aromatase inhibitors, the level of comfort in prescribing a ge-neric is pretty high. Still, there are some differences between the

generics and branded drugs. I have had some patients have reac-tions to the packaging, like the capsule and its coloring. However, this is uncommon. For the most part, when it comes down to a single, simple chemical, people feel confident.

However, antibodies are different. They are complicated and you cannot make an antibody identical to another. Antibodies are not only encoded proteins from a gene, but they also are folded and glycosylated, and they undergo many other posttranslational changes that affect their function. Even though you may show similar responses in a trial, it does not prove that it is identical be-yond a shadow of a doubt. There will be no perfect trial to prove these agents are 100% identical, and there will always be a small amount of uncertainty.

How do physicians perceive that level of uncertainty, and how willing are they to convince their patient, who also may be reluc-tant? Sometimes reluctance comes more from the patient, who may consider the biosimilar to be a fake or knockoff. We shouldn’t think of it that way, but rather as a biosimilar even though we can-not prove it is fully equivalent.

Based on the design of the study, if the confidence intervals are set narrowly enough — as specified by FDA and other regulatory agencies — I would generally feel confident. I say that not only as a scientist and as a clinician, but also as a member of society. We all have to make sure that, together, we can be a healthy society by equitable distribution of health care. It is not just about one in-dividual person; it is about making sure that societal health is cov-ered. With runaway drug prices and health care costs — especially when they do not make a difference in relevant patient outcomes — we have to make sure we are doing what we can to make medi-cal care available and affordable to everyone.

Biosimilars are an important step in that direction, but we do have to maintain our vigilance over time that we are doing everything we can to make sure they are truly biosimilar.

— Debu Tripathy, MDHemOnc TOday Editorial Board member

The university of Texas MD Anderson Cancer CenterDisclosure: Tripathy reports service on the steering committee for a regis-

try study for Genentech/Roche, the manufacturer of Herceptin.

Debu Tripathy

one of whom restarted treatment with pembrolizumab.

The safety profile of pembrolizum-ab appeared comparable to data from other studies. The most common ad-verse events included fatigue (40%), itchiness (28%) and rash (23%). Eight

percent of patients discontinued treat-ment due to adverse events.

“Advanced melanoma is still a very challenging cancer, which is why it is so remarkable that such a large pro-portion of patients see a long-term survival benefit from this therapy,” Robert said in a press release. “The results of this study further demon-strate the potential for long-term ben-

efit with pembrolizumab.” – by Nick Andrews n

Reference:Robert C, et al. Abstract 9503. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: The study was funded by Merck. Robert reports consultant/advisory roles with Amgen, Bristol-Myers Squibb, GlaxoSmith-Kline, Merck, Novartis and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Pembrolizumabcontinued from page 10

1514 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc

Originally published in HemOnc Today | July 10, 2016

Off-label therapies benefit patients with advanced, mutated cancers

Patients with nine different tumor types benefited from targeted therapies administered outside

of current drug indications, accord-ing to the results of a basket study pre-sented at the ASCO Annual Meeting.

The researchers intend to expand cohorts of patients with HER-2–am-plified colorectal cancer, bladder cancer and biliary cancer, as well as BRAF–mutated lung cancer, based on the observed outcomes.

“An increasing number of targeted agents for advanced cancer are ap-proved now based on the presence of molecular abnormalities in the cancers,” John D. Hainsworth, MD, senior investigator at Sarah Cannon Research Institute in Nashville, Ten-

nessee, said during a press conference. “Major successes in this area include HER-2–targeted treatment for HER-2–positive breast cancer and BRAF–

targeted treatment for melanoma. We have known, though, that the same mutations are found in a wide variety of other cancers, although at a lower incidence. It is difficult to test how ef-ficient these same treatments are, due

to the difficulty of identifying the pa-tient population.”

The MyPathway study included data from 129 patients with advanced

solid tumors and no available cura-tive therapy. Patients’ tumors har-bored the following alterations:

l HER-2 amplification (n = 53), mutation (n = 23), both (n = 5) or RBMS-NRG1 fusion (n = 1);

“This trial design is feasible, with patients selected based on molecular abnormalities in their cancers rather than on their primary tumor type or primary site.”— JOhN D. hAINsWORTh, MD

PERSPECTIVE

The MyPathway study is both a basket trial and an umbrella trial. Basket trials look at genomic alterations across dif-ferent histologies. For instance, in this study, if you have a BRAF mutation, it does not matter if you have breast, lung or colon cancer — it all goes in the basket. yet, it also is an umbrella trial, because it includes four different baskets. We are, therefore, getting a lot of mileage out of this one trial.

It is much more efficient to have one trial with four different baskets rather than having four basket trials.

The most interesting part of this trial is the HER-2 basket. Patients with a variety of different tumor types — includ-ing colorectal cancers and biliary tumors — are having re-ally nice responses, and this is going to be very important. It is remarkable that we are seeing responses in diseases like colorectal cancer from giving a drug that would usually be given to patients with breast cancer or gastric cancer.

In the future, we will see more basket trials, because they make a lot of sense. However, organizations and institutions will need to have a system in place to be able to do them.

It would be really difficult to perform a genomically based basket trial if genomic sequencing is not part of the practice, because these alterations are rare, and only very small sub-sets will have the alterations. For colorectal cancer, it may only be 2% or 3% that have HER-2 alterations. If you are not regularly checking for it, you are not going to be able to ac-crue patients. It is really difficult to have to put 100 patients on a trial in order to find one who is eligible, so you have to be doing sequencing regularly.

Further, a lot of academic centers that do clinical trials are very siloed. Colorectal cancer researchers do not work to-gether with the head and neck cancer researchers. They are all in their own territories. For a trial like this, you have to have a system that allows you to work across diseases.

These barriers will not be hard to overcome, but I do not know that all centers are ready to work with a trial like this one.

— Razelle Kurzrock, MDCenter for Personalized Cancer Therapy

university of California, San DiegoDisclosure: Kurzrock reports research funding from Foundation

Medicine.

Razelle Kurzrocknance until progression or toxicity.

PFS from the time of the first ran-domization served as the study’s pri-mary endpoint.

Cavo presented data from an inter-im analysis performed in January after 33% of required events had occurred.

Median follow-up from the time of the first randomization was 23.9 months.

Although median PFS had not yet been reached, patients assigned high-dose melphalan and autologous HSCT were less likely than those assigned VMP to experience disease progres-

sion (HR = 0.76; 95% CI, 0.61-0.94).This benefit persisted across pa-

tient subgroups, including among patients with revised International Staging System stage III disease (HR = 0.52; 95% CI, 0.32-0.84) and high-risk cytogenetics (HR = 0.72; 95% CI, 0.54-0.97).

A greater proportion of patients assigned transplant achieved at least a very good partial response (84% vs. 74%; OR = 1.9; 95% CI, 1.42-2.54).

Cox regression analysis re-sults showed randomization to the transplantation arm inde-pendently predicted longer PFS (HR = 0.61; 95% CI, 0.45-0.82).

“These preliminary results do

support the conclusion that upfront high-dose chemotherapy and autolo-gous transplant continues to be the best treatment option for fit patients with newly diagnosed myeloma, even in the novel-agent era,” Cavo said. – by Alexandra Todak n

Reference:Cavo M, et al. Abstract 8000. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: The study was funded by the Haemato Oncology Foundation for Adults in the Netherlands. Cavo reports honoraria and travel expenses from and consultant/advi-sory roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Please see the abstract for a list of all other researchers’ rel-evant financial disclosures.

l BRAF V600E (n = 18) or other (n = 15);

l Hedgehog (Hh) PTCH1 (n =7) or SMO (n = 1); or

l EGFR (n = 6).Patients enrolled in the trial had

received a median of three (range, 0-10) prior lines of therapy.

The researchers evaluated the use of therapies targeting these altera-tions, including trastuzumab (Her-ceptin, Genentech) and pertuzumab (Perjeta, Genentech) for patients with HER-2 amplification; vemurafenib (Zelboraf, Genentech) for patients with BRAF alterations; vismodegib (Erivedge, Genentech) for patients with Hh alterations; and erlotinib (Tarceva; Genentech, Astellas) for pa-tients with EGFR mutations.

Investigator-assessed response rate within the tumor-pathway cohort served as the study’s primary endpoint.

Eleven patients had insufficient follow-up data and were not included in the analysis.

Twenty-nine patients achieved a partial response or complete re-sponse, including one complete re-sponse achieved by a patient with HER-2–amplified colorectal cancer.

Researchers also observed respons-es in three patients with HER-2–am-plified bladder cancer and three with HER-2–amplified biliary cancer (lung cancer, n = 2; salivary gland cancer, n = 1); three patients with BRAF–mu-tated lung cancer; one case each of BRAF–mutated ovarian cancer, can-cer of unknown primary origin, colon cancer, pancreatic cancer, and head and neck cancer; and two patients with Hh alterations (squamous cell carcinoma, n = 1; cancer of unknown primary origin, n = 1).

Three patients with BRAF–mu-tated lung cancer achieved objective responses, and two achieved stable disease. The researchers will expand this cohort based on these data.

Responses continued up to 11 months. Fourteen responding pa-

tients progressed, at a median of 6 months (range, 3-14) after treatment.

The study design allows for the ac-crual of up to 500 patients, with ex-pansions for groups that demonstrate benefit. The researchers intend to in-corporate new agents that target ad-ditional molecular alterations.

“This trial design is feasible, with patients selected based on molecular abnormalities in their cancers rather than on their primary tumor type or primary site,” Hainsworth said. “It offers opportunities for patients with these molecular abnormalities.” – by Cameron Kelsall n

Reference:Hainsworth JD, et al. Abstract LBA11511.Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: Genentech funded this study. Hainsworth reports institutional research funding from Astellas, AstraZeneca, Cel-gene, Genentech, Johnson & Johnson, Eli Lilly and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Upfrontcontinued from page 11

The CSC model may help explain tumor recurrenceThe CSC model is a radical departure from the clonal evolution model. In the clonal evolution model, all cells within a malignant tumor have similar tumorigenic activity.5 By contrast, in the CSC model only a subset of tumor cells, CSCs, have tumor-initiating capability.2 Cancers are organized in a cellular hierarchy, with the CSCs at their apex having tumor-initiating capability.5 One important clinical implication of the CSC model is that it may help to explain why early tumor shrinkage is often poorly predictive of overall survival.6,7 While conventional therapies kill the bulk of non-stem cancer cells, resulting in tumor shrinkage, CSCs may remain viable and later reestablish the tumor, leading to relapse.8 Tumors with increased expression of genes associated with CSCs have also been correlated with lower overall survival in breast and lung cancers.9

Stemness of CSCs may lead to tumorigenicityThe heterogeneous high tumorigenicity of CSCs may be a direct result of their stemness. In both normal stem cells and CSCs, stemness is defined by the characteristics of self-renewal and differentiation.8 Unlike normal stem cells, which differentiate into healthy, mature, cell types, CSCs differentiate into cancer cells. The stemness of CSCs is maintained by several signaling pathways that are overexpressed and overactivated, including JAK-STAT, Wnt/β-catenin, Hedgehog, Nanog, Notch, TGF-β, Hippo-YAP/TAZ, and PI3K/Akt.10-14 These stemness pathways maintain stemness and promote tumorigenicity. This makes CSCs phenotypically different from non-stem cancer cells and confers therapy resistance.4

Epithelial-mesenchymal transition (EMT) of CSCs may lead to metastasis CSCs are also able to transform to a mesenchymal state by the process of EMT. In this state, CSCs become highly migratory and invasive and therefore prone to metastasis.13,15 After spreading to a distant site, they can undergo mesenchymal-epithelial transition and become tumorigenic, colonizing the new site.15 This is a potential mechanism for how CSCs contribute to metastasis and recurrence. Some evidence suggests that EMT and stemness may be coupled, as they are mediated by many of the same factors.16

CSCs are highly resistant to conventional cancer therapiesAlthough current chemotherapies and radiotherapy can kill most non-stem cancer cells, CSCs remain highly resistant.17,18 Further, conventional therapies have been shown to increase the percentage of CSCs within malignant residual tumors.19,20 Many mechanisms that mediate the therapy resistance of CSCs have been identified, including overactivated stemness signaling.10

A key implication of the CSC model for cancer treatment is that both CSCs and non-stem cancer cells should be targeted to reduce tumor recurrence and metastasis.19,21 Several approaches to targeting CSCs are being studied, including stemness-associated signaling pathways that may mediate tumorigenesis, metastasis, and resistance.1,22 The next generation of cancer therapeutics is in development with investigational agents designed to inhibit stemness pathways.1

TARGETING CANCER STEM CELL PATHWAYS AND STEMNESS

Not all cells within a tumor are equalDespite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 A potential new approach to address this is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). CSCs are highly tumorigenic, unlike bulk tumor cells.2 Molecular surface markers for CSCs have been demonstrated within multiple solid and hematologic tumor types, supporting the notion that not all cells within a tumor are equal.3,4 This is the basis of the CSC model.2

References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol. 2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S, ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. wClin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341-1347. 8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90(8):615-621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679. 20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844. 21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267.

EDU-NPS-0108 6/2016 ©2016 Boston Biomedical

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stemness pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

Learn more at www.bostonbiomedical.com

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