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Supplement to PERSPECTIVES FROM July 25, 2016 ASCO Annual Meeting A HemOnc Today Special Report Chemoradiation improves OS, PFS in older patients with glioblastoma Patients with MGMT–methylated tumors experienced greatest benefit Pembrolizumab improves long-term outcomes in advanced melanoma Patients derived benefit regardless of prior treatment with ipilimumab Trastuzumab biosimilar safe, effective for advanced breast cancer Biosimilar 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” This HemOnc Today supplement is produced by SLACK Incorporated. 3 | July 25, 2016 | Healio.com/HemOnc ASCO Annual Meeting highlights head1 late-breaking clinical trials, research updates Originally published in HemOnc Today | Date TBD, 2016 TARGETING CANCER STEM CELL PATHWAYS AND STEMNESS Not all cells within a tumor are equal Despite 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 The CSC model may help explain tumor recurrence The 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 tumorigenicity The 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 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):13411347. 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 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 T he 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 research updates. Key areas of focus included breast cancer, glioblastoma and melanoma. Numerous presentations also demonstrated the benefits of immunotherapy in multiple cancer subtypes. An address by Vice President Joe Biden on the Web watch CSCs are highly resistant to conventional cancer therapies Although 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 national cancer moonshot initiative focused on collaboration and “a lot more openness” among clinicians and researchers. This HemOnc Today supplement provides readers with an overview of the most noteworthy – and potentially practice-changing – findings presented at the ASCO Annual Meeting. Perspectives from physicians in the hematology/ oncology communities provide further insight into the impact these findings may have in everyday practice. — The Publishers of HemOnc Today Video Coverage 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. 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 Learn more at www.bostonbiomedical.com 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. © 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. Delivering the best in health care information and education worldwide 6900 Grove Road, Thorofare, NJ 08086 USA • phone: 856-848-1000 • Healio.com/HemOnc This HemOnc Today supplement is produced by SLACK Incorporated. 4 | July 25, 2016 | Healio.com/HemOnc 5 | July 25, 2016 | Healio.com/HemOnc Originally published in HemOnc Today | June 25, 2016 Originally published in HemOnc Today | July 10, 2016 Chemoradiation improves OS, PFS in older patients with glioblastoma Age, complications influence death after colon cancer surgery T he addition of concomitant and adjuvant temozolomide to hyperfractionated radiation therapy significantly prolonged PFS and OS among older patients with newly diagnosed glioblastoma, according to phase 3 study results presented during the plenary session of the ASCO Annual Meeting. Patients with MGMT–methylated tumors derived the greatest benefit from temozolomide. Although glioblastoma occurs primarily in older adults, no clear guidelines for treatment have been defined. “The peak age of incidence of glioblastoma is 64 years, and the incidence appears to be increasing with our aging population,” James R. Perry, MD, FRCPC, Crolla family endowed chair in brain tumor research at Odette Cancer Centre and Sunnybrook Health Sciences Centre in Toronto, said during a press conference. “The current best practice is surgical resection, followed by radiotherapy combined with chemotherapy.” A trial conducted by the EORTC suggested a survival benefit could be gained through the addition of temozolomide to radiation therapy in newly diagnosed patients; however, the researchers observed a trend of decreasing benefit with increasing age, and the potential OS benefit of the combination in older patients remained unknown. “The studies that we have in older patients 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 treatment for up to 12 cycles or until progression. 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 median 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. P erioperative complications increased 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 cardiovascular disease. 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 within 30 days of surgery, and 11.6% died within 1 year. Mortality varied by age group (< 65 years, 3.8%; 65-74 years, Chemoradiation continues on page 7 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 pronounced among those with glioblastomas that demonstrated methylation of the promoter for a gene called MGMT. However, 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 unclear whether temozolomide prolonged survival when combined with radiotherapy in patients aged older than 70 years. Andrew B. Lassman 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 patients 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, MD NewYork-Presbyterian Columbia University Medical Center Disclosure: Lassman reports no relevant financial disclosures. “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 Few studies have focused on age-related differences in the rate and cause of death beyond the postoperative period among patients undergoing colectomy. “Most of the previous studies looking at long-term outcomes have focused on oncologic endpoints, such as RFS, to analyze the effects of different treatment regimens,” Christopher Thomas Aquina, MD, MPH, surgical resident at University of Rochester Medical Center and research fellow at Surgical Health Outcomes & Research Enterprise, told HemOnc Today. “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 adenocarcinoma between 2004 and 2011. The researchers categorized pa- 8.3%; ≥ 75 years, 18.8%). A greater percentage of older patients experienced a major complication (< 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 surgery typically involves preventing cancer recurrence through close onAge continues on page 7 PERSPECTIVE This study adds to the landscape of knowledge in terms of postoperative outcomes in older adults who undergo surgery for colon cancer. This study highlights the importance of integrating geriatric oncology practices. As patients aged, the overall risk for postoperative complications increased, resulting in higher rates of 1-year mortality. Two individuals with the same chronological age do not necessarily have the same functional or physiological age. The study of the use of geriatric oncology principles, such as a Daneng Li 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 emphasizes the need for geriatric oncology principles and comprehensive geriatric assessment in the preoperative and perioperative settings. — Daneng Li, MD City of Hope Disclosure: Li reports no relevant financial disclosures. 6 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc 7 Originally published in HemOnc Today | June 25, 2016 Chimeric antigen receptor T cells exhibit efficacy in advanced lymphoma T reatment with T cells genetically modified to express chimeric antigen receptors that target CD19 induced remission in patients with advanced B-cell lymphoma when administered with low-dose chemotherapy, according to study results. The use of chimeric antigen receptor (CAR) T cells may become a standard of care for advanced lymphoma in the near future, according to James N. Kochenderfer, MD, investigator in the experimental transplantation and immunology branch of the NCI’s Center for Cancer Research. “T cells that are genetically modified 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 previously reported data from patients treated with CAR T cells and highdose chemotherapy. In the current analysis, researchers assigned 22 patients with advanced lymphoma to low-dose conditioning chemotherapy, followed by anti– CD19 CAR T-cell infusion. Nineteen patients had diffuse large B-cell lymphoma (DLBCL). Two patients had follicular lymphoma and one had mantle cell lymphoma. Eighteen patients received daily cyclophosphamide (300 mg/m2 per day) for 3 days; the remaining 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, researchers analyzed blood CAR T cells and serum cytokines. The overall response rate for the entire 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 lymphomas. CAR T cells are very exciting, receiving much attention, 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 included 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 John P. Leonard 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 symptomatic) 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, MD Weill Cornell Medicine NewYork-Presbyterian Hospital Disclosure: Leonard reports a prior consultant role with Kite Pharma. 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 chemotherapy-refractory lymphoma or relapsed lymphoma after autologous stem cell transplantation. All patients developed fevers, and 55% (n = 12) experienced grade 3 or grade 4 neurological toxicities. However, all toxicities resolved, typically in less than 2 weeks, Kochenderfer said. Patients had a median CAR–positive cell level of 47 μL (range, 4-1,217). Those who achieved complete or partial 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,” Kochenderfer said. “They will probably 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 Chemoradiation reported more nausea, vomiting and constipation than those assigned radiation alone. The researchers reported high patient 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 treatment centers,” Perry said. “They sometimes don’t have a caregiver who is able to bring them back and forth to treatment, so the shorter radiation schedule is an advantage.” Thirty-nine percent of patients assigned temozolomide and 41% of patients assigned radiation alone re- ceived systemic therapy after progression. “Oncologists now have evidence to consider radiotherapy with temozolomide in all newly diagnosed elderly patients with glioblastoma,” Perry said. – by Cameron Kelsall n bidity burden compared with younger patients.” Aquina told HemOnc Today that he hopes these data will lead to stronger collaborations between surgeons and medical oncologists. “We hope that this work emphasizes the need for greater collaboration 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 continued from page 4 Among the 165 patients with MGMT–methylated tumors, those assigned temozolomide achieved longer median OS than those assigned radiation 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, emotional or social functioning between arms. Patients assigned temozolomide Age continued from page 5 cologic follow-up and appropriate use of chemotherapy,” Aquina said. “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. Older patients are more likely to have higher rates of cardiovascular disease and a higher overall level of comor- Reference: Kochenderfer J, et al. Abstract LBA3010. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago. Disclosure: The NIH funded this study. Kochenderfer reports institutional research funding 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. 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 Institute, as well as from an unrestricted grant from Schering-Plough/Merck. Perry reports stock and ownership interests in DelMar Pharmaceuticals and VBL Therapeutics. Please see the abstract for a list of all other researchers’ relevant financial disclosures. Reference: Aquina CT, et al. Abstract 10012. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago. Disclosure: Aquina reports no relevant financial disclosures. Other researchers report consultant roles with Seattle Genetics and UpToDate. The CSC model may help explain tumor recurrence TARGETING CANCER STEM CELL PATHWAYS AND STEMNESS Not all cells within a tumor are equal Despite 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 The 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 tumorigenicity The 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 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 therapies Although 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 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 Learn more at www.bostonbiomedical.com 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. 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 10 | July 25, 2016 | Healio.com/HemOnc 11 | July 25, 2016 | Healio.com/HemOnc Originally published in HemOnc Today | June 10, 2016 Originally published in HemOnc Today | June 25, 2016 Pembrolizumab improves long-term outcomes in advanced melanoma Upfront autologous HSCT superior to novel therapies for multiple myeloma F orty percent of patients with advanced melanoma achieved 3-year OS with pembrolizumab, according to long-term follow-up of the KEYNOTE-001 study. Patients derived benefit from pembrolizumab (Keytruda, Merck) regardless of prior treatment with ipilimumab (Yervoy, Bristol-Myers Squibb). “These data confirm that pembrolizumab provides a long-term survival benefit for patients with advanced melanoma,” Caroline Robert, MD, PhD, head of the dermatology unit at Institute Gustave-Roussy in Paris, said in a press briefing. “The response rate contrasts with past results from patients with this disease. The data show durable responses in one-third of patients, with complete durable responses that are visible after stopping treatment.” Pembrolizumab received accelerated approval for advanced melanoma in September 2014 based on data from KEYNOTE-001. Data from KEYNOTE-002 also has shown that pembrolizumab prolongs PFS compared with chemotherapy, and in KEYNOTE-006, pembrolizumab extended 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 conducted long-term follow-up of patients treated in the KEYNOTE-001 study to determine 3-year OS. The analysis included 655 patients — enrolled into ipilimumab-naive and -treated 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 previous therapies and 52% had received ipilimumab. Following pembrolizumab discontinuation, researchers followed up with patients every 3 months to assess OS. Median follow-up was 32 months (range, 24-46); all patients were followed 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 received 10 mg/kg every 2 weeks. The rate of 3-year OS was 41% both in cohorts who had and had not previously received ipilimumab. However, 3-year OS was higher in treatment-naive 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, Pembrolizumab continues on page 13 PERSPECTIVE This abstract reports on long-term survival outcomes in patients with advanced melanoma treated with pembrolizumab (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. Richard D. Carvajal 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 Research 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. Additional 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, MD NewYork-Presbyterian Columbia University Medical Center Disclosure: Carvajal reports a consultant role with Merck. F irst-line treatment with autologous hematopoietic stem cell transplantation prolonged PFS compared with bortezomib-containing chemotherapy in younger patients with newly diagnosed multiple myeloma, according to results of a randomized phase 3 study. Thus, autologous HSCT should remain the preferred first-line treatment option over novel therapies for younger patients with newly diagnosed multiple myeloma, according to the researchers. “For more than 2 decades, chemotherapy at the doses requiring the support of autologous stem cells has been considered the gold standard for younger and fit patients with newly diagnosed multiple myeloma,” Michele Cavo, MD, head of the Seràgnoli Institute of Hematology at University of Bologna, said during a press briefing. “Over the past 10 to 15 years, therapies with novel, nongenotoxic drugs have dramatically increased the response rate and significantly [extended] survival in previously untreated myeloma patients. Remarkable activity of novel therapies has recently put into question 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 bortezomib (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, cyclophosphamide 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 therapy with bortezomib, lenalidomide (Revlimid, Celgene) and dexamethasone or no consolidation therapy, followed by lenalidomide mainteUpfront continues on page 15 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 colleagues with the European Myeloma Network conducted two randomized phase 3 trials evaluating lenalidomide (Revlimid, Celgene) and low-dose dexamethasone induction followed by conventional chemotherapy — melphalan, prednisone and lenalidomide in one trial, and cyclophosphamide, prednisone and lenalidomide in the other — or high-dose melphalan with autologous stem cell transplant (HDM–ASCT, Saad Z. Usmani single or tandem). Both trials showed PFS and OS benefits with HDM–ASCT but were criticized for not having proteasome inhibitors in induction 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 bortezomib, 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 transplanteligible 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, FACP HemOnc Today Editorial Board member Levine Cancer Institute, Carolinas HealthCare System Disclosure: Usmani reports no relevant financial disclosures. 12 | July 25, 2016 | Healio.com/HemOnc 13 | July 25, 2016 | Healio.com/HemOnc Originally published in HemOnc Today | July 10, 2016 Trastuzumab biosimilar safe, effective for advanced breast cancer W omen with HER-2–positive advanced breast cancer treated with MYL-1401O, a biosimilar trastuzumab antibody, achieved outcomes comparable to those of women treated with the biosimilar’s FDA–approved reference product, according to results of a randomized phase 3 study. The addition of trastuzumab Hope S. Rugo (Herceptin, Genentech) — 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 latestage 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 during a press conference. “Many biologic agents are losing patent protection soon or have already lost patent protection in other countries. Biosimilars have the potential to significantly improve access to expensive agents.” Regulatory agencies have established requirements for biosimilar approval. They include a demonstration of structural and functional similarity to the reference product; a demonstration of similar pharmacokinetics and pharmacodynamics; and confirmation of similar safety, efficacy and immunogenicity. 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 metastatic breast cancer, and they had not received prior chemotherapy or trastuzumab for metastatic disease. Fortyfour 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 unacceptable toxicity. Overall response rate at week 24 served as the study’s primary endpoint. The FDA also asked researchers to calculate 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 biosimilar arm and 48 in the reference product 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-normalized maximum concentration and area under the curve also were similar between the two agents. Safety appeared comparable between 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%; reference product, 25.2%), febrile neutropenia (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 affordable treatment option for patients with HER-2–positive cancers,” Rugo said. “This is one of the first trials of biosimilars in oncology to demonstrate these similar results. Ongoing trials with other biosimilars should further improve access worldwide 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 institutional research funding from Celsion, Eisai, Genentech, MacroGenics, Merck, Nektar, Novartis, OBI Pharma, Pfizer and Plexxikon. Please see the abstract for a list of all other researchers’ relevant financial disclosures. 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 biosimilars 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 biologic drugs, although it used to be when Debu Tripathy it first was approved. It can cost anywhere from $3,000 to $4,000 a month, whereas some of the newer biologic 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 properties as the parent drug. Third — and most importantly — the biological 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 statistically 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 generic is pretty high. Still, there are some differences between the Pembrolizumab continued from page 10 one of whom restarted treatment with pembrolizumab. The safety profile of pembrolizumab appeared comparable to data from other studies. The most common adverse events included fatigue (40%), itchiness (28%) and rash (23%). Eight generics and branded drugs. I have had some patients have reactions 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 beyond 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 reluctant? 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 cannot 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 individual person; it is about making sure that societal health is covered. 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 medical 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, MD HemOnc Today Editorial Board member The University of Texas MD Anderson Cancer Center Disclosure: Tripathy reports service on the steering committee for a registry study for Genentech/Roche, the manufacturer of Herceptin. percent of patients discontinued treatment due to adverse events. “Advanced melanoma is still a very challenging cancer, which is why it is so remarkable that such a large proportion of patients see a long-term survival benefit from this therapy,” Robert said in a press release. “The results of this study further demonstrate 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, GlaxoSmithKline, Merck, Novartis and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures. 14 | July 25, 2016 | Healio.com/HemOnc | July 25, 2016 | Healio.com/HemOnc 15 Originally published in HemOnc Today | July 10, 2016 Off-label therapies benefit patients with advanced, mutated cancers P atients with nine different tumor types benefited from targeted therapies administered outside of current drug indications, according to the results of a basket study presented at the ASCO Annual Meeting. The researchers intend to expand cohorts of patients with HER-2–amplified 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 approved 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 HER2–positive breast cancer and BRAF– to the difficulty of identifying the patient population.” The MyPathway study included data from 129 patients with advanced “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 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 efficient these same treatments are, due solid tumors and no available curative therapy. Patients’ tumors harbored the following alterations: lHER-2 amplification (n = 53), mutation (n = 23), both (n = 5) or RBMS-NRG1 fusion (n = 1); PERSPECTIVE Razelle Kurzrock The MyPathway study is both a basket trial and an umbrella trial. Basket trials look at genomic alterations across different 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 — including colorectal cancers and biliary tumors — are having really 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 subsets 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 accrue 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 together 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, MD Center for Personalized Cancer Therapy University of California, San Diego Disclosure: Kurzrock reports research funding from Foundation Medicine. l BRAF V600E (n = 18) or other (n = 15); lHedgehog (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 alterations, including trastuzumab (Herceptin, 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 patients 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 response, including one complete response achieved by a patient with HER-2–amplified colorectal cancer. Researchers also observed responses in three patients with HER-2–amplified bladder cancer and three with HER-2–amplified biliary cancer (lung cancer, n = 2; salivary gland cancer, n = 1); three patients with BRAF–mutated lung cancer; one case each of BRAF–mutated ovarian cancer, cancer 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–mutated 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 accrual of up to 500 patients, with expansions for groups that demonstrate benefit. The researchers intend to incorporate new agents that target additional 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 Upfront sion (HR = 0.76; 95% CI, 0.61-0.94). This benefit persisted across patient subgroups, including among patients with revised International Staging System stage III disease (HR = 0.52; 95% CI, 0.32-0.84) and highrisk 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 results showed randomization to the transplantation arm independently 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 autologous 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 continued from page 11 nance until progression or toxicity. PFS from the time of the first randomization served as the study’s primary endpoint. Cavo presented data from an interim 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 highdose melphalan and autologous HSCT were less likely than those assigned VMP to experience disease progres- 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, Celgene, Genentech, Johnson & Johnson, Eli Lilly and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures. 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/advisory roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures. TARGETING CANCER STEM CELL PATHWAYS AND STEMNESS Not all cells within a tumor are equal Despite 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 The CSC model may help explain tumor recurrence The 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 tumorigenicity The 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 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):13411347. 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 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 therapies Although 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 Learn more at www.bostonbiomedical.com 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.