Community Oncologists Perception and Adaptability to Emerging Chimeric Antigen T-cell (CAR-T) Therapy

research report Community Oncologists Perception and Adaptability to Emerging Chimeric Antigen T-cell (CAR-T) Therapy Chadi Nabhan, MD, MBA, FACP; Yolaine Jeune-Smith, PhD; Peter Klinefelter, BA; Jennifer Fillman, MBA; Bruce A. Feinberg, DO The Oncologic Drugs Advisory Committee recently voted 10-0 recommending to the Food and Drug Administration (FDA) the approval of CTL-019, the first chimeric antigen receptor T (CAR-T) therapy. The approval of CTL-019 for the treatment of children and young adults with advanced leukemia represents a major milestone in how immunotherapy targets malignancies. The expected formal approval by the FDA will herald the first CAR-T approved in the United States. A second CAR-T therapy directed at diffuse large B cell lymphoma (DLBCL) is expected shortly. The potential impact of these therapies should not be underestimated, nor should their complexity, which is why a broader understanding of stakeholder knowledge and perception may be critical to their adoption and use. Genetically engineered T cells are emerging as a new treatment modality that harnesses a patient s own immune system to fight against various malignancies. 1 T cells, an essential component of cellular adaptive immunotherapy, identify cancer cells through antigen recognition, mediated by T-cell receptors linked to peptides presented by the major histocompatibility complex. 2 When the receptor binds to the antigen complex, T cells are activated and the immune system is stimulated. This new therapeutic approach requires T cells to be harvested from the host, modified by linking the extracellular antigen recogniaffiliations: Cardinal Health Specialty Solutions, Cardinal Health, Dublin, OH address correspondence to: Chadi Nabhan, MD, MBA, FACP Vice President and Chief Medical Officer Cardinal Health Specialty Solutions Dublin, OH Phone: (312) 927-3327 Email: chadi.nabhan@cardinalhealth.com abstract: The Oncologic Drugs Advisory Committee recently voted 10-0 recommending to the Food and Drug Administration (FDA) the approval of the first chimeric antigen receptor T (CAR-T) therapy. We sought to better understand the challenges that might hinder community oncologists use and referral for CAR-T therapy once regulatory approval is granted. A total of 379 US-based community oncologists/hematologists and practice administrators were surveyed during 6 live meetings conducted between November 2016 and June 2017 to assess their insights of CAR-T therapy and perceived barriers to its adoption. When queried on how their prescribing habits might evolve should CAR-T therapies become FDA approved for indications studied in ongoing and completed clinical trials; only 22% suggested they are unlikely to prescribe CAR-T therapy. Importantly, most prescribers (46%) plan on referring their patients to large academic centers, while one-third would rather treat some of their patients locally while referring others to academic sites. Cost did not appear to be a hindrance to prescribing. key words: chimeric antigen receptor T therapy, clinical pathways, community oncology, cost-effectiveness, pediatric oncology citation: Journal of Clinical Pathways. 2017;3(7):31-35. Received August 13, 2017; accepted September 25, 2017 disclosures: The authors report no relevant financial relationships. acknowledgements: Portions of this research were presented as a poster at the 22nd Annual International Society for Pharmacoeconomics and Outcomes Research Meeting in Boston, MA. Since the original submission of this paper, CTL-019 has been approved by the Food and Drug Administration for acute lymphoblastic leukemia in children and young adults. www.jcponline.com October 2017 Journal of Clinical Pathways 31 jcp1017rr_nabhan.indd 31

Table 1. Baseline Knowledge and Perception of CAR-T Therapy How familiar are you with the current data (efficacy and toxicity) on CAR-T therapy? (279 respondents) Very familiar 10% Moderately familiar 10% Somewhat familiar 38% Not very familiar 19% Not at all familiar 23% How would you best describe CAR-T cell therapy? (158 respondents) A new treatment option 24% A potentially game-changing approach to treatment 44% A last-line approach for seriously ill patients 3% Another immuno-oncology option, like PD-1 inhibitors 24% Not sure 5% Have you referred any patients to CAR-T cell therapy in the past 12 months? (291 respondents) Yes 20% No 80% tion domain from a monoclonal antibody fragment to the T cells intracellular signaling domain, then expanded prior to infusion. These newly modified T cells are designated as chimeric antigen receptor T cells. 3 Emerging data have clearly shown significant CAR-T activity in relapsed/refractory DLBCL, 4 primary mediastinal B-cell lymphoma, 5 chronic lymphocytic leukemia, 6,7 and acute lymphoblastic leukemia. 8,9 Despite these results, the significant toxicity of these therapies, the complexity of its administration, and the logistics surrounding its operation might hinder the commercial uptake and market success of CAR-T therapy. To address these issues, CAR-T manufacturers have assured the FDA that treatment will be limited to highly specialized centers with stem cell transplantation capabilities. Most cancer patients are seen in the community setting, 10 thereby community oncologists will play an instrumental role in patient referral and likely determine the initial adoption of this treatment. To this end, understating barriers to community oncology providers perceptions of CAR-T therapy efficacy, toxicity, and rela- Table 2. Prescribing and Site of Therapy for CAR-T Upon Approval If approved today, how likely are you to prescribe CAR-T therapy to any patient in your practice in the next 12 months? (210 respondents) Very likely 27% Moderately likely 21% Somewhat likely 31% Not very likely 14% Not at all likely 8% If approved, how do you plan on utilizing CAR-T therapy based on the information you have today? (338 respondents) I plan on referring all my eligible patients to academic centers. 46% I plan on referring some of my eligible patients to academic centers. 34% I plan on treating my eligible patients at my local hospital. 16% I don t plan on prescribing or recommending CAR-T therapy to my patients. 4% Given what you currently know about CAR-T therapy and if it were priced at parity with allogeneic stem cell transplantation, how cost-effective do you believe CAR-T therapy would be? (155 respondents) Very cost-effective 7% Moderately cost-effective 25% Somewhat cost-effective 36% Not very cost-effective 25% Not at all cost-effective 8% 32 Journal of Clinical Pathways October 2017 www.jcponline.com jcp1017rr_nabhan.indd 32

Table 3. Providers Perceptions About Toxicity and Management of CAR-T Therapy Based on the toxicity profile, how long do you think patients should be hospitalized for observation following CAR-T infusion? (122 respondents) It should be an outpatient procedure. 24% 1 week 36% 2 weeks 25% 3 weeks 9% 4 weeks 6% > 4 weeks 1% Based on my current and past experience, I believe the management of CAR-T associated toxicities is. (113 respondents) Very difficult 20% Difficult 67% Neutral 11% Easy 3% Very easy 0% Given the toxicity profile of CAR-T therapy, which of the following best describes your opinion on toxicity management for patients treated with this therapy? Please select all that apply. (69 respondents) AE management will be difficult at first, but management may improve with continued experience. Like allogenic stem cell transplant, AE management will continue to be a challenge even with experience. 38% 45% The toxicity profile may deter me from prescribing CAR-T therapy. 33% We have inpatient facilities, so I do not foresee AE management as an issue. 9% Given the toxicity profile of CAR-T therapy, who do you think will be the primary person responsible for managing the toxicity? (72 respondents) Oncologist 69% Board-certified oncology pharmacist 3% Advanced practitioner 4% Nurse 1% Pulmonologist/Intensive care specialist 22% Abbreviation: AE, adverse event. tive cost to value is essential to drive strategies for market uptake. We sought to better understand the challenges that might hinder community oncologists use and referral for CAR-T therapy once regulatory approval is granted. methods A total of 379 US-based community oncologists/hematologists and practice administrators were surveyed during six live meetings conducted between November 2016 and June 2017 to assess their insights of CAR-T therapy and perceived barriers to its adoption. Respondents represented a variety of practice types: 16% large sized (>10 physicians), 15% medium sized (6-10 physicians), 20% small sized (2-5 physicians), 15% solo practice, 16% hospital-owned community practices, 6% community-based hospitals, and 11% university-owned hospitals. Participants represented all geographic areas in the United States (37% South, 24% Midwest, 20% Northeast, and 19% West). The survey was composed of multiple choice answers to specific questions. Audience response system devices were used to capture participants responses and allowed more than one answer selection when appropriate. results When asked about published information from clinical trials, almost half of the participants were not familiar with the efficacy and toxicity data on CAR-T therapy. Despite most respondents labeling CAR-T therapy as a potentially game-changing approach, only 20% had ever referred a patient to a CAR-T clinical trial (Table 1). When queried on how their prescribing habits might evolve should CAR-T therapies become FDA approved for indications studied in ongoing and completed clinical trials; only 22% suggested they are unlikely to prescribe CAR-T therapy. Importantly, most prescribers (46%) plan on referring their patients to large academic centers, while onethird would rather treat some of their patients locally while referring others to academic sites (Table 2). Cost did not www.jcponline.com October 2017 Journal of Clinical Pathways 33 jcp1017rr_nabhan.indd 33

I do not know enough about CAR T-cell therapy to prescribe 19% Cost of therapy 29% Logistics of administering and following patients are cumbersome 64% Patients treated on clinical trials are not representative of the real-world patient population 19% Toxicity is high 46% Efficacy data is marginal 9% 0% 20% 40% 60% 80% Percentage of Respondents Figure 1. Barriers to successful implementation, according to respondents. appear to be a hindrance to prescribing, as most believed CAR-T would be cost-effective if priced at parity with allogeneic stem cell transplantation. Questions about toxicity centered on how optimal management should be delivered. Over 60% suggested that patients should be monitored for 1 to 2 weeks after administration. Notably, one-third stated that toxicity might hinder their prescribing of CAR-T therapy. While the majority believed that medical oncologists should oversee the management of CAR-T-treated patients, 22% believed that engaging critical care physicians will be essential for optimal care (Table 3). Lastly, we inquired about barriers to successful CAR-T implementation; the logistics of administration was the most common barrier, followed by the known and perceived toxicities (Figure 1). discussion While regulatory approval is expected for CAR-T therapy, this by itself is not a guarantee for commercial success and patients access when indicated. Prescribing patterns of physicians to new market entrants can be influenced by many factors, 11 and studying these factors is critical to ensure proper adoption of this approach where appropriate. Our study highlights several findings that are critical to all stakeholders. First and foremost, lack of familiarity with published data might be predictable since studies were conducted in refractory diseases that are commonly treated at academic sites. Overcoming this educational barrier can be achieved through data dissemination, webinars, regional symposia, and other venues. Whether this explains the low referral rates in the preceding 12 to 18 months for ongoing CAR-T studies is unknown. Physicians appear receptive to prescribing CAR-T therapy once regulatory approval is granted, but there was no consensus as to their desire on where treatment should be delivered. While almost half of the respondents suggested that all eligible CAR-T patients should be referred to academic centers, one-third stated that they will refer some but not all of their CAR- T eligible patients. Fewer physicians voiced their willingness to treat these patients locally if allowed by payers and manufacturers. This might be problematic as CAR-T therapy requires highly specialized centers with allogeneic stem cell transplantation capabilities given the uniqueness of observed toxicities. 12 While it is unlikely that CAR-T therapy will be given at community sites at launch, this might change in the future. To this end, investing in resources that facilitate safe and effective CAR-T therapy in nonacademic entities is an essential strategy for payers and manufacturers to ensure that eligible patients receive this therapy. Travel to academic sites is not always feasible and certainly represents a logistical barrier for any specialized therapy or procedure. 13 Timely referral and having proper channels between community and academic sites is critical given the seriousness of illnesses that CAR-T are indicated to treat. Additional logistical challenges were suggested as major hurdles for CAR-T therapy adoption. Community oncologists voiced their concerns about the operational complexity and the fact that successful CAR-T admin- 34 Journal of Clinical Pathways October 2017 www.jcponline.com jcp1017rr_nabhan.indd 34

istration requires harmonized collaboration between the treating facility, manufacturers, and the transportation system. Aligning these stakeholders to assure timely apheresis, collection, transportation, T-cell expansion, and reinfusion might be challenging, especially as eligible patients are often sick, with active disease, and receiving lymphodepleting chemotherapy prior to the infusion. Legitimate concerns about toxicities were voiced by most community oncologists. While this might not be surprising for a novel treatment approach, the fact that these toxicities might hinder prescribing and referral patterns underscores the present educational gap and the importance of teaching community oncologists how these toxicities are treated effectively. Notably, while most respondents agreed that the medical oncologist should oversee the management of CAR-T therapy recipients, one quarter identified engaging intensive care specialists as essential for optimal outcomes given the potential complications. Lastly, cost did not appear to be a barrier. While pricing will not be determined until regulatory approval is granted and payers decide how reimbursement will take place, community oncologists view CAR-T therapy as cost-effective based on publicly available data if priced at parity with allogeneic stem cell transplantation. Assuring proper patient access to novel, effective, and potentially lifesaving therapies is essential when a new entrant offers these attributes. Our aim was to better understand barriers to CAR-T therapy adoption in the community setting and how this new therapy is perceived among general oncologists. Better understanding of these hurdles and barriers allows better process for clinical pathways positioning of a promising new entrant to the health care market. We found that toxicity and logistics are the major concerns. We propose that investing in educational platforms to disseminate clinical trial efficacy data, toxicity management algorithms, and operational phases is a critical initial step to assure patients access to CAR-T therapy moving forward. Longer follow up after regulatory approval is needed to measure future success. References 1. Feinberg BA, Fillman J, Simoncini J, Nabhan C. CAR-T cells: the next era in immunooncology. Am J Manag Care. 2017;23(2 Spec No.):SP48-SP52. 2. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327(5963):291-295. 3. Almasbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602. 4. Neelapu S, Locke F, Bartlett N, et al. Kte-C19 (anti-cd19 CAR T cells) induces complete remissions in patients with refractory diffuse large B-cell lymphoma (DLBCL): results from the pivotal phase 2 ZUMA-1. Blood. 2016;126. 5. Locke F, Neelapu S, Bartlett N, et al. A phase 2 multicenter trial of KTE-C19 (anti-cd19 CAR T cells) in patients with chemorefractory primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL): interim results from ZUMA-1. Blood. 2016;126. 6. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139. 7. Turtle C, Berger C, Sommermeyer D, et al. Anti-CD19 chimeric antigen receptormodified T cell therapy for B cell expansion and persistence of CAR-T cells and clinical outcomes. Blood. 2015;126. 8. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517-528. 9. Turtle C, Hanafi L, Berger C, et al. Addition of fludarabine to cyclophosphamide lymphodepletion improves in vivo expansion of CD19 chimeric antigen receptormodified T cells and clinical outcome in adults with B cell acute lymphoblastic leukemia. Blood. 2015;126. 10. American Society of Clinical Oncology. The state of cancer care in America, 2017: A report by the American Society of Clinical Oncology. J Oncol Pract. 2017;13(4):e353-e394. 11. Khullar D, Chokshi DA, Kocher R, et al. Behavioral economics and physician compensation--promise and challenges. N Engl J Med. 2015;372(24):2281-2283. 12. Nabhan C, Parsad S, Feinberg B. Positioning CAR-T therapy into clinical pathways for non-hodgkin B-cell lymphoma and beyond. Journal of Clinical Pathways. 2017;3(2):41-47. www.jcponline.com October 2017 Journal of Clinical Pathways 35 jcp1017rr_nabhan.indd 35