Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) Links in PDF documents are not guaranteed to work. To follow a web link, please use the MCD Website. Decision Summary A. 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. B. 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. C. 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 A. The Centers for Medicare & Medicaid Services (CMS) covers autologous treatment for cancer with T-cells Created on 08/07/2019. Page 1 of 69 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. B. 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. C. 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 Created on 08/07/2019. Page 2 of 69 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 hyperplasiawhen a cell divides faster than normaland dysplasiaa 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 Created on 08/07/2019. Page 3 of 69 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.