Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers

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The Centers for Medicare & Medicaid Services (CMS) covers autologous treatment for cancer with T-cells expressing at least one chimeric antigen receptor (CAR) when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) and used for a medically accepted indication as defined at Social Security Act section 1861(t)(2) i.e., is used for either an FDA-approved indication (according to the FDA-approved label for that product), or for other uses when the product has been FDA-approved and the use is supported in one or more CMS-approved compendia. The use of non-FDA-approved autologous T-cells expressing at least one CAR is non-covered. Autologous treatment for cancer with T-cells expressing at least one CAR is non-covered when the requirements in Section A are not met. This policy continues coverage for routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meet the requirements listed in NCD 310.1. See Appendix B for the language representative of Medicare's national coverage determination (NCD) for implementation purposes only.

Decision Memo: TO: Administrative File: CAG-00451N FROM: Tamara Syrek Jensen, JD Director, Coverage and Analysis Group Joseph Chin, MD, MS Deputy Director, Coverage and Analysis Group Lori M. Ashby, MA Director, Division of Policy and Evidence Review Rosemarie Hakim, PhD Acting Director, Evidence Development Division Lori A. Paserchia, MD Lead Medical Officer Katherine B. Szarama, PhD Lead Analyst SUBJECT: National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers DATE: August 7, 2019 I. Decision The Centers for Medicare & Medicaid Services (CMS) covers autologous treatment for cancer with T-cells expressing at least one chimeric antigen receptor (CAR) when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) and used for a medically accepted indication as defined at Social Security Act section 1861(t)(2) i.e., is used for either an FDA-approved indication (according to the FDA-approved label for that product), or for other uses when the product has been FDA-approved and the use is supported in one or more CMS-approved compendia. The use of non-FDA-approved autologous T-cells expressing at least one CAR is non-covered. Autologous treatment for cancer with T-cells expressing at least one CAR is non-covered when the requirements in Section A are not met. This policy continues coverage for routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meet the requirements listed in NCD 310.1. See Appendix B for the language representative of Medicare's national coverage determination (NCD) for implementation purposes only. II. Background Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations. Please find below a list of these acronyms and corresponding full terminology: AATB - American Association of Tissue Banks ACT - Adoptive Cell Therapy AEs - adverse events AIDS - Acquired immune deficiency syndrome ALL - Acute Lymphoblastic Leukemia AHRQ - Agency for Healthcare Research and Quality ARC - American Red Cross ASBMT - American Society for Blood and Marrow Transplantation ASCT - Autologous stem cell transplantation ASFA - American Society for Apheresis AYA - adolescent and young adult BCMA - B-cell maturation antigen BLA - Biologics Licensing Application BOMC - Mini-Cog, Blessed Orientation-Memory-Concentration CAP - College of American Pathologists CAR - Chimeric Antigen Receptor CAR-T - Chimeric Antigen Receptor T-cells CARG - Cancer and Aging Research Group score CD-19 - Cluster of Differentiation 19 CED - Coverage with Evidence Development CHOP - Children's Hospital of Philadelphia CIBMTR - Center for International Blood and Marrow Transplant Research CMS - Centers for Medicare & Medicaid Services CNS - central nervous system CRASH - Chemotherapy Risk Assessment Scale for High-Age Patients CR - complete response CRi - complete response with incomplete hematologic/blood count recovery CRS - cytokine release syndrome DLBCL - diffuse large B-cell lymphoma DLT - dose-limiting toxicity DOR - duration of response ECOG-PS - Eastern Cooperative Oncology Group Performance Status ETASU - Elements To Assure Safe Use FACT - Foundation for the Accreditation of Cellular Therapy FDA - Food and Drug Administration FL - Follicular Lymphoma G8 - Geriatric-8 GA - geriatric assessment GDS - Geriatric Depression Scale HCT - allogeneic hematopoietic cell transplantation HIV - human immunodeficiency virus IADL - Instrumental activities of daily living ICER - Institute for Clinical and Economic Review ICU - Intensive Care Unit ISCT - International Society for Cellular Therapy MA - Medicare Advantage MAC - Medicare Administrative Contractor MEDCAC - Medicare Evidence Development and Coverage Advisory Committee NCA - National Coverage Analysis NCCN - National Comprehensive Cancer Network NCD - National Coverage Determination NCI - National Cancer Institute NHL - Non-Hodgkin's Lymphoma NMDP - National Marrow Donor Program NOS - not otherwise specified ORR - overall response/remission rate OS - overall survival PFS - progression-free survival Ph - Philadelphia PMR - postmarketing requirements PR - partial response PRO - Patient-Reported Outcome REMS - Risk Evaluation and Mitigation Strategies R/R - relapsed/refractory SBRA - Summary Basis for Regulatory Action SEER - Surveillance, Epidemiology, and End Results Program TA - technology assessment US - United States VES-13 - Vulnerable Elders Survey-13 Background on Cancer What is cancer? Cancer is a collection of related diseases of dividing cells that can start almost anywhere in or on the body, evade the immune system, and invade nearby tissues. Categories of cancer are typically organized by the location in the body and specific type of cell. These categories may include carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, melanoma, and brain and spinal cord tumors. There are also changes to these cells that are not considered cancer. These changes include hyperplasia - when a cell divides faster than normal - and dysplasia - a buildup of extra cells with abnormal shape and disorganization. Lymphomas are cancers of lymphocytes (B cells or T cells) and consist of two main types. Hodgkin lymphoma arises usually from B cells and Non-Hodgkin lymphoma (NHL) can form from B cells or T cells. According to the American Cancer Society (2018), Hodgkin lymphoma is most common in early adulthood, with an average age of 39 at diagnosis, while NHL accounts for about four percent of all cancers in the U.S. with an estimate that about 74,680 adult and children (41,730 males and 32,950 females) will be diagnosed with NHL and about 19,910 people will die from NHL (11,510 males and 8,400 females) during 2018. The most common sub-type of NHL is diffuse large B cell lymphoma (DLBCL) representing 30-40% of all cases worldwide and has a number of different cell subtypes of origin to divide cases into germinal centre B cell like subtypes and activated B cell like subtypes (Li et al., 2018). Additionally, follicular lymphoma, which arises from B cells, affects people over 50 years old, and comprises nearly 20-30% of NHL. While NHL can occur at any age, the risk increases with age; more than half of patients are 65 or older at the time of diagnosis (American Cancer Society, 2018). In its 2018 guideline, The National Comprehensive Cancer Network (NCCN) noted that the incidence of NHL increased significantly between 1970 and 1995 but has moderated since the mid-1990s. While the increase was attributed partly to the human immunodeficiency virus (HIV) epidemic and the development of AIDS-related NHL, much of the increase in incidence has been observed in patients in their sixth and seventh decades. As a result, patients with NHL may also have significant comorbidities. Leukemias are cancers that arise from blood-lineages of the bone marrow. The type of leukemia depends of the type of cell and cell growth. Acute lymphoblastic leukemia (ALL) is also a cancer of B-cell origin that is associated with immature B-cells in the bone marrow, blood, and other organs. The NCCN (2018a) notes that "the age-adjusted incidence rate of ALL in the U.S. is 1.58 per 100,000 individuals per year" (National Cancer Institute (NCI), 2016a), with approximately 5,970 new cases and 1,440 deaths estimated in 2017 (Swerdlow et al., 2008). The median age at diagnosis for ALL is 15 years (NCI, 2016b) with 57.2% of patients diagnosed at younger than 20 years of age (NCI, 2016c). In contrast, 26.8% of cases are diagnosed at 45 years or older and only approximately 11% of patients are diagnosed at 65 years or older (NCI, 2016c). ALL represents 75% to 80% of acute leukemias among children, making it the most common form of childhood leukemia; by contrast, ALL represents approximately 20% of all leukemias among adults (Jabbour et al., 2005; Esparza et al.,2005). Chronic lymphoblastic leukemia (CLL) is a more slowly progressing type. Multiple myeloma begins in a different type of cell, the plasma cell. According to the Surveillance, Epidemiology, and End Results (SEER) Program Cancer Statistics Review (Noone et al., 2018) there were an estimated 124,733 people living with myeloma in the US and the lifetime risk of developing this cancer at some point is approximately 0.8 percent. Additionally, the number of new cases per year is 6.7 per 100,000 with 3.3 deaths per 100,000. In general, plasma cell neoplasms are most common in people who are at middle age or older. Treatment can be based on the stage of cancer, which is the result of a determination of combination of factors including the amount of cancer in the body and biomarkers such as albumin in the blood. What are the treatment options for cancer patients? Cancer has many treatments available, with some seen as the standard of care and others only available in the context of a clinical trial. For some patients, participation in a clinical trial may be the best process to access a new potential treatment. Surgery may be performed to remove certain cancerous tumors. Radiation therapy can be delivered externally or internally to disrupt cell division and keep cells from growing. Drugs, such as chemotherapy, stop cancer cell growth and division depending on the type and stage of cancer being treated. Targeted therapy works to attack a subset of cells by leveraging specific cellular processes, such as protein synthesis and degradation. Immunotherapy is a type of cancer treatment that involves strengthening a patient's own immune system. Different types of immunotherapy for cancer include biologicals such as monoclonal antibodies and cytokines, and drugs such as immune checkpoint inhibitors, and cancer vaccines. As one example, monoclonal antibodies identify and attach to substances on the cell surface to kill or keep cancer cells from spreading. Another method of rapidly-emerging immunotherapy is called adoptive cell transfer (ACT), which consists of the collection, alteration and then re-administration of a patient's immune cells to attack the patient's cancer. For example, in the case of stem cell transplantation, blood can be taken from the patient or a healthy donor, and these infused stem cells can restore the patient's normal immune system. Each treatment has specific and sometimes distinct side effects and the population receiving a given treatment could be at risk for serious side effects or adverse events as a result. Schuster et al. (2017), states that DLBCL "is successfully treated in about two thirds of patients with rituximab-based immunochemotherapy (Feugier et al., 2005; Pfreundschuh et al., 2006). When current frontline immunochemotherapy fails, high-dose chemotherapy with autologous stem-cell transplantation can lead to long-term disease-free survival (Gisselbrecht et al., 2010)." For patients with follicular lymphoma, there is "an excellent prognosis after receiving frontline rituximab- based therapies; however, in 20% of patients with follicular lymphoma, relapse occurs within 2 years after initial immunochemotherapy (Tan et al., 2013; Casulo et al., 2015). Among patients with relapsed follicular lymphoma that is refractory to rituximab and to alkylating-agent‐based therapy, treatment with idelalisib or copanlisib, the only agents that have been approved by the Food and Drug Administration (FDA) for such patients, is associated with a median response duration of 10.8 and 12.2 months, respectively (Salles et al., 2017; Whippany et al., 2017)." (Schuster, 2017) Crump et al. 2017 reported on the results of a large, international, multi-cohort, retrospective study of patient's with NHL called SCHOLAR-1. The authors noted that "Published analyses of large-scale outcome data from patients with refractory DLBCL are limited" therefore the goal of the SCHOLAR-1 study was to evaluate the outcomes of currently available therapies for patients with refractory DLBCL in order to serve as a benchmark for future studies. The authors defined refractory DLBCL as "progressive disease (received ≥ 4 cycles of first-line therapy) or stable disease (received 2 cycles of later line therapy) as best response to chemotherapy or relapse ≤ 12 months after ASCT." Objective response rate, complete response rate and overall survival were estimated from the time of initiation of salvage therapy for refractory disease. The authors found "the objective response rate was 26% (complete response rate, 7%) to the next line of therapy, and the median overall survival was 6.3 months. Twenty percent of patients were alive at 2 years. Outcomes were consistently poor across patient subgroups and study cohorts." Survival Rates from Cancer Expected 5-year relative survival rates from 2008-2014 are derived from tables by socio-economic status, geography and race developed by the SEER program (Noone et al., 2018) and are available at https://seer.cancer.gov/csr/1975_2015/results_merged/topic_survival.pdf . The rates inclusive of both sexes and all races are reported here, while noticeable disparities are described in our analysis (see section VIII.). Survival rate in myeloma was 50.7%. Rates in lymphoma differed between Hodgkin (86.6%) and NHL (71.4%) as did rates in leukemia subsets between acute lymphocytic (68.1%) and chronic lymphocytic (84.2%). According to the NCCN (2018a), the "The cure rates and survival outcomes for patients with ALL have improved dramatically over the past several decades, primarily among children (Ma et al., 2014). Improvements are largely owed to advances in the understanding of the molecular genetics and pathogenesis of the disease, the incorporation of risk-adapted therapy, the advent of new targeted agents, and the use of allogeneic hematopoietic cell transplantation (HCT). Data from the SEER database have shown a 5- year overall survival (OS) of 86% to 89% for children (Kenderian et al., 2013; Ma et al., 2014); however, AYA patients were reported to have a 5-year OS between 42% to 63% depending on the age range. Adults have the poorest 5-year OS rate of 24.1% for patients between the ages of 40 and 59 and an even lower rate of 17.7% for patients between the ages of 60 and 69 (Pulte et al., 2014). Although the exact OS percentage can vary based on how the age range is defined for pediatric, AYA, and adult patients, the trend is nonetheless clear that OS decreases substantially with increased age. The exception is infants younger than age one, which is an age group that has not seen any improvement in survival over the last 30 years (Jabbour et al., 2005). The 5-year OS in this population is 55.8% (Ma et al., 2014). Cure rates for AYAs with ALL remain suboptimal compared with those for children, although substantial improvements have been seen with the recent adoption of pediatric treatment regimens (Stock et al., 2010). AYA patients represent a unique population, because they may receive treatment based on either a pediatric or an adult protocol, depending on local referral patterns and institutional practices." Schuster et al (2017) notes that "for most patients treated since the introduction of rituximab, the expected rate of 3-year event-free survival after autologous stem-cell transplantation is only approximately 20% (Gisselbrecht et al., 2010)." "These patients with early relapse have a poor prognosis, with a rate of 5-year overall survival of only 50% when they are treated with currently available therapies (Tan et al., 2013; Casulo et al., 2015)." Background on Chimeric Antigen Receptor T-cell Therapy A person's immune system contains cells to help fight substances that are foreign to the body, such as bacterial and viral infections. These cells are called white blood cells, most of which are lymphocytes. The two main types of lymphocytes are B lymphocytes (B-cells) and T lymphocytes (T-cells). B-cells generate and release antibodies to fight infection, especially bacterial infections, while T-cells employ a number of other mechanisms to fight abnormal cells such as cancer. As previously described, one type of therapy that leverages the immune systemimmunotherapyis CAR T-cell therapy. What is CAR T-cell therapy? Chimeric Antigen Receptor T-cells (CAR T-cells) are T-cells that have been genetically altered in order to improve the ability of the T-cells to fight cancer. The genetic modification creates a new and special receptor on the surface of the T-cell. This special receptor is called a CAR and there are many CARs on the surface of the T-cell. CAR enhances the ability of the T-cell to recognize and attach to a specific protein, called an antigen, on the surface of a cancer cell. Currently there are two FDA-approved CAR T-cell products: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). These two CAR T-cell products have a CAR that recognizes a specific antigen on the surface of certain cells, called CD-19. What are the toxicities associated with CAR T-cell therapy? As with the administration of other types of cancer chemotherapy agents, administration of CAR T-cell therapy has associated toxicities. First, as a result of their normal duties, T-cells release cytokines in order to stimulate and direct an immune response. During administration of a CAR T-cell therapy, this significantly large number of T-cells present can lead to a massive release of cytokines, which leads to cytokine release syndrome (CRS)a potentially life-threatening toxicity that produces a systemic inflammatory disorder mainly characterized by fever, rapid pulse (tachycardia) and low blood pressure (hypotension). The severity of CRS has been correlated with the patient's cancer burden (Baruch et al. 2017) and has been managed with an FDA-approved drug called tocilizumab. Another prominent toxicity associated with CAR T-cell therapy is neurotoxicity, which can include confusion or seizure-like activity. According to the NCI (2017d), "in nearly all patients the problem is short lived and reversible." Finally, a significant toxicity of some CAR T-cell therapy is B-cell aplasia, which is a mass die off of B-cells. Since a functional target of recently approved CAR T-cell products is also found on the surface of normal B-cells, this CAR T-cell therapy also destroys the normal B-cells, which leads to the decreased production of antibodies. To compensate, immunoglobulin therapy is administered in order to provide the patient with antibodies to fight off infections. III. History of Medicare Coverage CMS does not currently have an NCD on CAR T-cell therapy. A. Current Request CMS received a complete, formal request for a national coverage determination from Efrem Castillo, MD, Medicare & Retirement Chief Medical Officer, UnitedHealthcare. The formal request letter can be viewed via the tracking sheet for this NCA on the CMS website at https://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx? NCAId=291 . CMS initiated this national coverage determination (NCD) to consider coverage under the Medicare Program for CAR T-cell therapy, a rapidly emerging adoptive cell transfer immunotherapy for select patients with relapsed or refractory cancers. Treatment protocols vary, but may be summarized in five steps: lymphocyte harvesting from the patient with cancer; creation of cancer-targeting lymphocytes in vitro using various immune modulators; selection of lymphocytes with reactivity to cancer antigens using enzyme-linked immuno-assay; depletion of the patient's remaining lymphocytes using immunosuppressive agents; transfusion of the cancer-targeting lymphocytes back into the patient with cancer-this transfusion represents one treatment. The scope of this review is limited to autologous transplant of T-cells expressing at least one CAR for treatment of patients with cancer. B. Benefit Category Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act (the Act). CAR T-cell therapy falls under the benefit categories set forth in section § 1861(b) "inpatient hospital services", § 1861(s)(2)(B) "hospital services," and § 1861(t) "drugs and biologicals". This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Action May 16, 2018 CMS opens an NCA for Initial 30-day public comment period begins. June 15, 2018 First public comment period ends. CMS receives 53 comments. August 22, 2018 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting to discuss CAR T-cell therapy and patient-reported outcomes. February 15, 2019 Proposed Decision Memorandum posted. 30-day public comment period begins. March 17, 2019 Second public comment period ends. CMS receives 93 comments. V. Food and Drug Administration (FDA) Status The existing CAR T-cell therapies on the market were approved as biologics and, therefore, provisions of the Medicare statute for biologicals apply. To date, two CAR T-cell products have been approved by the FDA. The first CAR T-cell product, tisagenlecleucel, received FDA approval on August 30, 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. A second FDA indication for tisagenlecleucel was granted on May 1, 2018 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. The second CAR T-cell product, axicabtagene ciloleucel received FDA approval on October 18, 2017 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL, not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Additional information about the FDA approval of tisagenlecleucel, including the Risk Evaluation Mitigation Strategy (REMS) program, is found at https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm . Additional information about the FDA approval of axicabtagene ciloleucel, including the REMS program, is found at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel . VI. General Methodological Principles When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will be redacted or will not be made available to the public. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination. VII. Evidence A. Introduction This section provides a summary of the evidence we considered during our review. The evidence reviewed to date includes the published medical literature on pertinent clinical trials of autologous transplant of T-cells expressing at least one CAR for treatment of patients with cancer. For this NCD, CMS searched for and determined whether the current evidence on CAR T-cell therapy is adequate to draw conclusions about health outcomes, as well as whether the body of evidence is generalizable to the Medicare population. This NCA summarizes the clinical evidence relating to the administration of the two FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, in patients with FDA indications. The evidence CMS examines has as its focus health outcomes, i.e., the benefits and harms of a particular treatment. Independently assessed, validated instruments were most heavily weighted. Study endpoints should be clearly defined a priori to both improve the quality of clinical research and so as to allow comparison between clinical trials. In addition, we present evidence on non-FDA-approved uses, NCCN compendia recommendations, as well as evidence of promising Phase I/II clinical trials developing additional CAR T-cell products earlier in the product lifecycle. Key outcomes of interest to CMS in the treatment of cancer were long-term overall survival (OS, at least one year), progression-free survival (PFS), objective response rate (ORR) including complete response (CR) and partial response (PR), duration of response to specify days to disease progression and/or days to disease recurrence, peri-administration and long- term risk of AEs (especially any and all life-threatening AEs such as CRS), 30-day hospitalization rate, as well as health- related quality of life and function after the administration of CAR T-cell therapy in Medicare beneficiaries. B. Discussion of Evidence 1. Question(s) Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with relapsed or refractory large B-cell lymphoma? Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with relapsed or refractory B-cell precursor acute lymphoblastic leukemia? Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with other types of cancer? If the answer to any of the questions above is positive, is the available evidence adequate to identify the characteristics of the patient, practitioner or facility that predict which beneficiaries are more likely to experience overall benefit or harm from CAR T-cell therapy? 2. External Technology Assessments CMS did not commission an external technology assessment (TA) on this topic. An English language TA was identified during our review and is summarized below. On February 15, 2018, the Institute for Clinical and Economic Review (ICER), a self-proclaimed "independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs," published a TA titled Chimeric Antigen Receptor T-Cell Therapy for B-Cell Cancers: Effectiveness and Value. As of this date, the TA is found at https://icer-review.org/material/car-t-final-report/ . In September, 2017, ICER performed a search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials from September 25 - 27, 2017. ICER noted that they "sought out head-to-head studies for these interventions, but none were identified. Recognizing the current state of the evidence base for CAR T-cell therapy, we included single-arm trials and compared outcomes with historical control data." ICER also held discussions with patients and patient groups. The ICER analysis was reported by FDA indication. Acute Lymphoblastic Leukemia The ICER analysis included the results from three single-arm clinical trials for tisagenlecleucel for patients with relapsed or refractory ALL. Information for two of the trials (B2101J and B2205J), which were Phase I/II trials that had yet to be published in the clinical literature, was obtained from the Novartis FDA Advisory Committee Briefing Document (2017). Information for the remaining trial, the Phase II ELIANA trial, was obtained from Maude et al. (2017). The primary clinical endpoint selected was cure of the cancer, for which ICER noted there is "no accepted definition of a cure, as relapses can rarely occur more than 10 years after remission. A recent proposal is that children in remission four years after the completion of treatment could be considered cured ( < 1% chance of relapse; Hunger and Mullighan, 2015; Pui et al., 2014). Thus, four-year event-free survival would be an ideal outcome." ICER found the three clinical trials "to be of lower quality because they lack comparators. Furthermore, the studies are small and have short median follow-up, which adds to the uncertainty about long term outcomes with CAR-T therapy for pediatric B-cell ALL." With regards to the primary clinical endpoint, four-year event-free survival, ICER noted that "none of the trials of CAR-T therapy have followed patients for that long. The reported overall remission rates for tisagenlecleucel in the three trials (from 69% to 95%) represents an optimistic presentation of the results that violates the intention to treat principle because they exclude patients who did not receive the therapy because of manufacturing failures, death prior to infusion, or adverse events (AEs). Table ES2 estimates the overall remission rates in the trials based on the number of patients enrolled in each trial (i.e., on an intention to treat basis)." Table ES2 is reproduced in its entirety. Table ES2. Overall Remission Rates in Therapies for Relapsed or Refractory Childhood B-ALL Trial Therapy Overall Remission* B2101J18 Tisagenlecleucel 52/71 = 73% (61% to 83%) B2205J18 Tisagenlecleucel 20/35 = 57% (39% to 74%) B2202 / ELIANA1 Tisagenlecleucel 61/92 = 66% (56% to 76%) Jeha 2006 Clofarabine 12/61 = 20% (11% to 32%) Hijiya 2011 Clofarabine/etoposide/ cyclophosphamide 11/25 = 44% (24% to 65%) Von Stackelberg 2016 Blinatumomab 27/70 = 39% (27% to 51%) Locatelli 2017 Blinatumomab 25/40 = 63% (46% to 77%) *Based on the number enrolled, not the number receiving the infusion with CAR-T cells ICER also noted that while "this presentation suggests more modest benefits, the overall remission rates are higher with tisagenlecleucel than with the other therapies. Table ES3 below estimates the overall event-free survival in the trials based on the number of patients enrolled." Table ES3 is reproduced in its entirety. Table ES3. Estimated Event-Free Survival at Six Months in Therapies for Relapsed or Refractory Childhood B-ALL Trial Therapy Event-free Survival at 6 Months* Overall Survival at 12 Months B2101J18 Tisagenlecleucel 58% 81% B2205J18 Tisagenlecleucel 46% 62% B2202 / ELIANA1 Tisagenlecleucel 60% 62% Jeha 2006 Clofarabine 11% 20% Hijiya 2011 Clofarabine/etoposide/cyclophosphamide 35% 35% Von Stackelberg 2016 Blinatumomab 16% 38% Locatelli 2017 Blinatumomab NR NR *Based on the number enrolled, not the number receiving the infusion with CAR-T cells or the number responding to treatment With regards to toxicity, ICER stated that the "key AEs experienced by the first 68 patients who received an infusion of tisagenlecleucel in the ELIANA trial were reported in the package insert and are summarized in Table ES4 below." Table ES4 is reproduced in its entirety. Table ES4. Key Adverse Events in the ELIANA trial (n=68)27 Adverse Reaction All Grades Grade 3 or Higher Cytokine Release Syndrome 79% 49% Neurologic Toxicities 65% 18% Fever 50% 15% Encephalopathy 34% 10% Headache 37% 3% Acute Kidney Injury 22% 13% Hypotension 31% 22% Hypoxia 24% 18% Infections/Pathogens/Unknown 41% 16% Viral Infections 26% 18% Bacterial Infections 19% 13% Fungal Infections 13% 7% ICER noted that "Additional important grade three or higher adverse events include disseminated intravascular coagulation (9%), histiolymphocytic hemophagocytosis (7%), heart failure (7%), cardiac arrest (4%), seizures (3%), and intracranial hemorrhage (1%). There were 11 deaths: 7 from disease progression, 3 from infections, and one from intracranial hemorrhage. An additional important toxicity is hypogammaglobulinemia due to B-cell aplasia. B-cells are the target of tisagenlecleucel in order to keep the leukemia in remission. Patients without the immunoglobulins produced by B-cells are at risk for infections and are typically treated with monthly intravenous infusions of pooled immunoglobulins (IVIG). The Novartis briefing document for the FDA Advisory Committee states that "responding patients experienced continued B-cell aplasia indicating the long-term effect of tisagenlecleucel" and notes "B-cell aplasia ongoing for > 3 years (FDA Advisory Committee, 2017)." For those who require IVIG, the typical duration of use is unknown." The authors summarized that for the ALL indication, the "ELIANA trial demonstrated CR rates for tisagenlecleucel that were substantially higher than those observed in recent trials of other drug therapies for heavily pre-treated pediatric patients with B-cell ALL. In addition, the disease-free survival and OS were also greater than those observed with other therapies, particularly in the earlier Phase I trials that have longer follow-up. There are important harms that occur commonly with tisagenlecleucel therapy (CRS, neurotoxicity, B-cell aplasia), but they are manageable and perceived by clinicians as arguably no worse than the serious AEs associated with chemotherapy in this patient population. Thus, the estimated net health benefit is substantial ("B+" rating)." The "B+" rating indicates "Moderate certainty of a small or substantial net health benefit, with high certainty of at least a small net health benefit." B-Cell Lymphoma For the FDA indication of B-cell lymphoma, ICER analyzed four clinical trials including a Phase I/II trial (Kochenderfer et al., 2017) and the Phase II ZUMA-1 trial (Neelapu et al., 2017) for axicabtagene ciloleucel as well as a Phase I/II trial (Schuster et al., 2017) and the Phase II JULIET trial (Schuster et al., 2017b, abstract only) for tisagenlecleucel. All four trials studied adults. All four were single-arm. Therefore, ICER selected the SCHOLAR-1 study (Crump et al., 2017), which was an international, multi-cohort retrospective non-Hodgkin's lymphoma research study that retrospectively evaluated outcomes in patients with refractory DLBCL, as a comparator for their analysis. In SCHOLAR-1, Crump et al., 2017, included patients with refractory DLBCL that was defined as "progressive disease or stable disease as best response at any point during chemotherapy ( > 4 cycles of first-line or 2 cycles of later-line therapy) or relapsed at ≥ 12 months from autologous stem cell transplantation. SCHOLAR-1 pooled data from 2 phase 3 clinical trials (Lymphoma Academic Research Organization-CORAL and Canadian Cancer Trials Group LY.12) and two observational cohorts (MD Anderson Cancer Center and University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence)." ICER noted that the SCHOLAR-1 trial used the same inclusion and exclusion criteria as the ZUMA-1 trial to select a subset of patients with aggressive DLBCL. With regards to the primary clinical endpoint, ICER selected event-free survival two years after the completion of treatment as "a reasonable surrogate outcome" based on the work published by Maurer et al. (2014). ICER noted that the "The ZUMA-1 and JULIET studies as well as the two single site studies were considered to be of lower quality because they lack comparators. Furthermore, the studies were small and of short median follow-up, which adds to the uncertainty about long term outcomes with CAR-T therapy for adult aggressive B-cell lymphoma." In addition, both "the ZUMA-1 and JULIET studies of CAR-T therapies for lymphoma followed patients for less than a median of two years, which limits conclusions about long term impact. Complete remission is a marker for long-term survival, but the majority of patients with B-cell lymphoma who have failed prior therapy usually relapse even after achieving subsequent remission." Axicabtagene ciloleucel For axicabtagene ciloleucel, results of the ICER analysis showed: "Table ES6. Objective Response Rates Reported for Axicabtagene Ciloleucel for Relapsed or Refractory Adult B-cell Lymphoma Compared with SCHOLAR-1 Trial Therapy ORR CR ZUMA-1 Axicabtagene ciloleucel 82% 54% NCT00924326 Axicabtagene ciloleucel 73% 55% SCHOLAR-1 Mix of salvage therapies 26% 7% CR: complete remission, ORR: objective response rate The complete remission rate for axicabtagene ciloleucel in ZUMA-1 (54%) shown in Table ES6 represents an optimistic presentation of the results that violates the intention to treat principle because it is based on patients who received the infusion of CAR T-cells and does not include the patients who enrolled in the trials but did not receive the therapy because of manufacturing failures, death prior to infusion, or AEs. Table ES7 below estimates the complete remission rate based on the number of patients enrolled in the trial." Table ES7 is reproduced in its entirety. Table ES7. Estimated Complete Remission Rates for Axicabtagene Ciloleucel for Relapsed or Refractory Adult B-cell Lymphoma Compared with SCHOLAR-1s Trial Therapy Complete Remission Rate* ZUMA-1 Axicabtagene ciloleucel 52/111 = 47% (37% to 57%) NCT00924326 Axicabtagene ciloleucel 12/NR = NR SCHOLAR-1 Mix of salvage therapies 7% (3% to 15%) *Based on the number enrolled, not the number receiving the infusion with CAR-T cells NR: Not reported ICER noted that "Even with this change, the complete remission rate is much higher with axicabtagene ciloleucel than with the other therapies. In SCHOLAR-1, the median overall survival was 6.3 months and the Kaplan-Meier estimates for one and two-year survival rates were 28% and 20% respectively. At six months, the Kaplan-Meier estimates for overall survival were 80% in ZUMA-1 and 55% in SCHOLAR-1. Neelapu and colleagues presented a propensity-score-matched analysis comparing the outcomes of ZUMA-1 to those of SCHOLAR-1 at American Society of Hematology (ASH) in December 2017 (Neelapu et al., 2017a). They reported that after matching, the ORR was 83% in ZUMA-1 and 33% in SCHOLAR-1 (treatment difference 49%, 95% CI 33% to 63%). Similarly, the estimated CR was 57% in ZUMA-1 and 12% in SCHOLAR-1 (treatment difference 46%, 95% CI 26% to 59%). The estimated HR for overall survival was 0.28 (95% CI 0.15 to 0.40) with 18-month OS estimated to be 47% in ZUMA-1 and 23% in SCHOLAR-1." With regards to the toxicity of axicabtagene ciloleucel, ICER presented the following table: "Table ES9. Key Adverse Events in the ZUMA-1 Trial (n=101) Adverse Reaction All Grades Grade 3 or Higher Cytokine Release Syndrome 94% 13% Neurologic Toxicities 87% 31% Fever 86% 16% Encephalopathy 57% 29% Headache 45% 1% Renal Insufficiency 12% 5% Hypotension 57% 15% Hypoxia 32% 11% Infections - Pathogens Unknown 26% 16% Viral Infections 16% 4% Bacterial Infections 13% 9% Fungal Infections 5% NR Additional important grade 3 or higher adverse events include histiolymphocytic hemophagocytosis (1%), heart failure (6%), cardiac arrest (4%), seizures (4%) and pulmonary edema (9%). There were 44 deaths: 37 from disease progression, two from CRS, one from a pulmonary embolus, and four in patients with disease progression who were on subsequent therapies." Tisagenlecleucel The results of the ICER analysis of tisagenlecleucel for relapsed or refractory adult B-cell lymphoma showed: "Table ES8. Objective Response Rates Reported for Tisagenlecleucel for Relapsed or Refractory Adult B-Cell Lymphoma Compared with SCHOLAR-1 Trial Therapy ORR CR JULIET Tisagenlecleucel 53% 40% NCT00924326 Tisagenlecleucel 64% 57% SCHOLAR-1 Mix of salvage therapies 26% 7% CR: complete remission, ORR: objective response rate The complete remission rate for tisagenlecleucel in JULIET (40%) represents an optimistic presentation of the results that violates the intention to treat principle because it is based on patients who received the infusion of CAR-T cells and does not include the patients who enrolled in the trials but did not receive the therapy because of manufacturing failures, death prior to infusion, or AEs, nor does it include patients treated with tisagenlecleucel who had less than three months follow-up at the time of analysis. It was not possible to estimate a complete remission rate using an intent-to-treat analysis based on the data available from the public presentations. The reported CR and ORR in the JULIET trial (40% and 53% respectively) were slightly lower compared to the CR and ORR of the subset of patients with DLBCL in the ZUMA-1 trial (n=77) who were treated with axicabtagene ciloleucel (49% and 82%, respectively; Locke et al., 2017). However, the confidence intervals overlap extensively, and selection bias may also explain part of the differences. For example, the JULIET trial recruited patients from 10 different countries on 4 continents, while 21/22 sites for the ZUMA-1 trial were in the US (one in Israel). The complete remission rate (43%) among patients who received tisagenlecleucel was markedly higher than that observed in the SCHOLAR-1 trial (7%), which predominantly included adults with DLBCL (87% DLBCL). Given the paucity of the currently reported results for the ongoing JULIET trial, we were unable to project long-term outcomes for comparison with axicabtagene ciloleucel or the salvage regimens included in the SCHOLAR-1 study." Below is a table showing the toxicity of tisagenlecleucel, as presented by ICER, as well as commentary by ICER: "Table ES10. Key Adverse Events in the JULIET Trial (n=99) Adverse Reaction All Grades Grade 3 or Higher Cytokine Release Syndrome 58% 23% Neurologic Toxicities 21% 12% Infections 34% 20% Cytopenias Not Resolved by Day 28 36% 27% Febrile Neutropenia 13% 13% Tumor Lysis Syndrome 1% 1% There were no deaths or reported cases of cerebral edema. Finally, there are theoretical concerns about mutagenesis from the insertion of the transgene into the patient's T-cells for both CAR-T therapies. The risk is likely to be quite low, but is an important long-term concern for further study." For the B-cell lymphoma indication, the authors summarize that the "ZUMA-1 trial demonstrated CR rates for axicabtagene ciloleucel that were substantially higher than those observed in recent trials of other drug therapies for heavily pre-treated adults with B-cell lymphoma as reported in the SCHOLAR-1 study. In addition, the disease-free survival and OS appear to be greater than those observed with other therapies, but follow-up in the ZUMA-1 trial is short (median 15.4 months). There are important harms that occur commonly with axicabtagene ciloleucel therapy (CRS, neurotoxicity, B-cell aplasia), but they are manageable and perceived by clinicians as arguably no worse than the serious AEs associated with chemotherapy in this patient population. Thus, the estimated net health benefit is substantial ("B+" rating). There are no head to head trials of axicabtagene ciloleucel and tisagenlecleucel for patients with relapsed/refractory B-cell lymphomas. The ORR and CR with axicabtagene ciloleucel are somewhat higher than those for tisagenlecleucel, but could easily reflect differences in the patient populations or chance. Patients treated with axicabtagene ciloleucel appeared to have fewer grade 3/4 CRS events, but more grade 3/4 neurologic events. Again, this may represent real differences in the two CAR-T therapies because of differences in their co-stimulatory domains, selection bias, or chance. The lack of head-to-head randomized trials and the small number of patients studied render such judgements premature. Given the level of uncertainty, the evidence is insufficient to judge whether one of the CAR-T therapies is superior to the other ("I" rating)." The "I" rating equals a rating of "Insufficient" and indicates "Any situation in which the level of certainty in the evidence is low." ICER Summary: CAR T-cell Therapy In summary, for both tisagenlecleucel and axicabtagene ciloleucel and for both FDA indications, ICER noted a number of uncertainties with regards to the results of the above clinical trials including that "the studies of CAR-T therapies are all single-arm trials. Given the possibility of selection bias in these trials, it is impossible to compare outcomes from these trials to those of other trials without considerable uncertainty." In addition, "the trials themselves are small and have short follow- up. The sample sizes with outcomes in the trials are less than 100 participants, and the median follow-up in the trials is less than two years. Thus, estimates of outcomes from the trials have wide confidence intervals; as such, both the benefits and duration of and long-term relapse-free survival is unknown at this point. A related uncertainty is the long-term harms of therapy. In the intermediate term, there is insufficient data to estimate how many patients will continue to have clinically important hypogammaglobulinemia from B-cell aplasia. There are also theoretical concerns about complications from the viral vectors used in the manufacturing process and of secondary malignancies related to mutations in the T-cells due to the manufacturing process. Finally, there may be unanticipated harms that arise as larger numbers of patients are followed for several years." 3. Internal Technology Assessment Literature Search Methods On June 20, 2018, CMS searched PubMed for clinical trials that focused on tisagenlecleucel or axicabtagene ciloleucel and were published in peer-reviewed journals. The literature search was limited by language (English), study population (human), article type (clinical trial) and timeframe (last ten years). Search terms included "chimeric antigen receptor," "CAR T," "T-cell," "CAR-T," "CART-19," "leukemia," and "lymphoma." Abstracts for the resultant citations were visually reviewed to find the clinical studies that focused on tisagenlecleucel or axicabtagene ciloleucel. From the PubMed search results, we found four relevant articles for lymphoma (Schuster et al., 2017; Neelapu et al., 2017; Kochenderfer et al., 2017; Locke et al., 2017) and two relevant articles for leukemia (Maude et al., 2014; Maude et al., 2018) that met our inclusion criteria. We reviewed articles submitted through public comment, and included any that met this search criteria. We also searched the bibliography of each of the above articles, the citation list of clinical guidelines, professional society position statements and each public comment to find additional sources of clinical evidence for our review. We identified no new evidence from this search that met our criteria. The full-text, peer-reviewed published literature articles that present the results of a clinical trial for tisagenlecleucel or axicabtagene ciloleucel are summarized below by FDA indication. Abstracts were excluded because they do not provide sufficient information about the clinical trial to support further review. Reviews, retrospective studies/case reports and commentaries were not included because they did not present the results of a data analysis (reviews), were of insufficient evidentiary weight compared to prospective clinical trials, or were subjective (commentaries). NCCN clinical guidelines and CMS approved compendia information were researched as part of this analysis. We include publicly accessible information, including the Summary Basis of Approval from the FDA website and professional society position statements as summarized in the Evidence Summary section that follows. Evidence Summary Tisagenlecleucel for Relapsed or Refractory ALL Maude SL, Frey N, Shaw PA et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. N Engl J Med 2014;371:1507-17. The authors reported the two year outcomes of their Phase I/II clinical trial, which was a prospective, single arm, single center, open label, pilot study designed to assess the safety and feasibility of CART19 therapy (CTL019the precursor to tisagenlecleucel; Novartis) in children and adults with chemotherapy-resistant or refractory CD19+ leukemia. Conditioning chemotherapy with etoposide/cyclophosphamide, fludarabine/cyclophosphamide, methotrexate/eytarabine, or cyclophosphamide/vincristine/adriamycin was administered one week prior to CTL019 infusion unless medically contraindicated. The administration of tocilizumab was standard for all occurrences of severe CRS. Severe CRS was defined as hypotension requiring two or more vasopressors or respiratory failure requiring mechanical ventilation. The administration of immunoglobulin was standard for all occurrences of B-cell aplasia. A CR was defined by morphologic assessment of the bone marrow as M1 (less than five percent leukemic blasts) with no evidence of extramedullary disease. A total of 30 patients with relapsed or refractory ALL were treated. Twenty-five were five to 22 years of age (pediatric cohort: median age at infusion was 11 years; 56% male); five were 26 to 60 years of age (adult cohort: median age at infusion was 47 years; 80% male). Median follow-up was seven months (range, 1 - 24). At one month, 27 of 30 (90%) patients achieved a CR. Nineteen of 27 patients remained in remission with 15 patients receiving no further treatment and four patients withdrawing from the study t