Regulatory Considerations for Approval of Chimeric Antigen Receptor T Cell Therapies for Treatment of Hematological Malignancies
Authors: Elmacken Mona , Mahat Upendra , Verdun Nicole , Fashoyin-Aje Lola 
Published: December 2024

Background:
Chimeric Antigen Receptor T cell therapies (CAR T) have become an integral component in the treatment of hematologic malignancies (HM) since the first CAR T approval in 2017. Herein, we highlight key regulatory considerations for approved CAR Ts, including trial design, treatment setting, clinical endpoints, approval pathway, and confirmatory studies.
Methods:
Food and Drug Administration (FDA) clinical review documents for biologics license applications (BLA) of CAR T cell therapies approved 2017 to June 2024 were identified. Product name, approval type, clinical trial endpoints, study population and confirmatory trial information were abstracted, pooled, and analyzed descriptively.
Results:
A total of 18 BLAs (original, n.6; supplemental, n.12) for 6 CAR Ts (anti-CD19, n=4; anti BCMA, n=2) were approved. All 6 products had ≥1 supplemental approvals. Approvals were for the following indications: large B cell lymphoma (LBCL; 6), multiple myeloma (MM; 4), follicular lymphoma (FL; 3), B cell acute lymphoblastic leukemia (B ALL; 2), mantle cell lymphoma (MCL; 2), and chronic lymphocytic leukemia/ small cell lymphoma (CLL/SLL; 1). Most approvals (78%) were in the late line setting (≥3L). Number of approvals per product were: Breyanzi (6), Kymriah (3), Yescarta (3), Abecma (2), Carvykti (2), and Tecartus (2).
All 6 original BLAs were based on single arm trials conducted in the relapsed refractory setting, and all but one BLA were granted traditional approval. Most supplemental applications (8/12) were granted traditional approval and among the 12 supplemental applications, 42% were for approvals in the 2nd line setting. All 4 randomized controlled trials (RCTs) were the basis of approvals to expand the indication, and 3 of the 4 RCTs were conducted in the 2nd line setting.
A single pivotal trial supported the approval for each BLA, and the 18 trials enrolled a total of 2,165 patients comprising 6 HMs across 11 disease indications. The mean number of patients enrolled in the 12 single arm trials (n=1427) was 118 (range: 62, 356). The distribution of patients by race/ethnicity (Asian, Black, White, Hispanic/Latino), sex (female), age group (&gt;=65, &gt;=75 years) in each disease type was: LBCL (4%, 4%, 84%, 10%, 33%, 33% and 7%), FL (7%, 2%, 74%, 4%, 38%, 32% and 5%), MM (2%, 9%, 73%, 8%, 40%, 36% and 7%); B ALL ( 8%, 1%, 71%, 9%, 46%, 9% and 1%), MCL (3%, 2%, 80%, 9%, 21%, 61% and 11%), and CLL/SLL (1%, 2%, 78%, 2%, 30%, 54% and 10%). Response rate was the endpoint supporting approval in all single arm trials. Confirmatory trials were required in all 5 accelerated approvals; one of the confirmatory trials was ongoing at the time of approval and all are currently ongoing.
Conclusions:
The approval of CAR Ts has expanded the treatment landscape for HMs. These products have demonstrated high magnitude of benefit (ORR: median 83%; range 45 to 98%) and durable response rates, which FDA considers to be evidence of clinical benefit. With such outcomes, it can be infeasible to conduct RCTs after the drug is approved or, unethical unless patients are randomized to a comparably efficacious drug. For this reason, FDA has recommended that sponsors consider conducting RCTs that can be analyzed early to assess effects on an intermediate clinical endpoint like response rate to support accelerated approval and continue the study to completion to evaluate progression free survival or overall survival.1 Such an approach provides a unique opportunity to evaluate effects on endpoints that denote clinical benefit. It is critical to evaluate novel therapies in the context of trials that enroll representative study populations. Assessment of the representativeness of the trial population compared to the population for whom the therapy is developed could be based on demographic characteristics such as age group, sex, race, and ethnicity.2 We note that in diseases that disproportionally impact racial and ethnic minorities and older adults, the trial populations are predominantly White males less than 75 years old. This may reflect access barriers to CAR T trials.
1 FDA draft guidance Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.
2 FDA draft guidance Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies.