CAR-T Therapy:

Update and Payer Impact

As currently approved CAR-T therapies expand their indications, and additional therapies move through the pipeline, this exciting opportunity and innovation will continue to create challenges and priorities for payers.

Chimeric antigen receptor T-cell (CAR-T) therapy is an innovative type of immunotherapy that uses a patient’s own immune system to help fight their cancer by collecting T-cells from the patient’s body and genetically modifying them to destroy cancer cells before infusing them back into the patient.1 CAR-T therapy has been an exciting and promising advancement in the oncology space.

Current CAR-T Landscape

Anja Shaughnessey, Pharm.D., PRS, R.Ph. Senior Pharmacy Program Manager Point32Health

There are currently six U.S. Food and Drug Administration (FDA)-approved CAR-T therapies; the first one was approved in 2017. All of the currently approved CAR-T therapies are indicated for hematologic malignancies, in the second-line or later settings, but some experts anticipate a shift in place in treatment for CAR-T therapies in the near future.2 See Table 1 for a breakdown of approvals and indications.

Autologous vs. Allogeneic

Currently available CAR-T therapies are autologous, meaning a patient’s own immune cells are used to produce the therapy. By 2020, there were several manufacturers focusing on the development of allogeneic “off-the-shelf” CAR-T therapies, which use T-cells from healthy donor blood or umbilical cord blood. In October 2021, the FDA placed a hold on clinical trials for AlloCAR T™ (Allogene Therapeutics), which is allogeneic, after a report of chromosomal abnormality was detected after a single dose of AlloCAR T™ administration in one patient. The hold was lifted in January 2022.3 The use of allogeneic CAR-T cells may have promising advantages over autologous therapy, including immediate access to cryopreserved product for on-demand patient treatment, potential standardization of CAR-T cell product, time for multiple cell modifications, redosing or combination of CAR-T cells directed against different targets, and lower costs using an industrialized process.4 However, there are several concerns and challenges associated with allogenic CAR-T therapies: understanding the risk of chromosomal abnormalities, quality control, durability, T-cell exhaustion, qualifying material, and batch-to-batch variability.5

Table 1. CAR-T Therapies: Approvals and Indications

CAR-T Therapy Approval Indication REMS Program?

2017 Patients up to age 25 with B-cell precursor ALL, refractory, or in second or later relapse Yes tisagenlecleucel (KYMRIAH®)

2018 Adult patients with relapsed or refractory LBCL after at least two lines of systemic therapy Yes

2022 Adults with relapsed or refractory follicular lymphoma after at least two lines of systemic therapy Yes

2017 Adults with relapsed or refractory LBCL after at least two lines of systemic therapy Yes axicabtagene ciloleucel (YESCARTA®)

2021 Adults with relapsed or refractory follicular lymphoma after at least two lines of systemic therapy Yes

2022 Adults with LBCL refractory to first-line chemoimmunotherapy or who relapse after up to 12 months of first-line chemoimmunotherapy Yes

2020 Adults with relapsed or refractory MCL* Yes brexucabtagene autoleucel (TECARTUS®)

2021 Adults with relapsed or refractory B-cell precursor ALL Yes

2021 Adults with relapsed or refractory LBCL after at least two lines of systemic therapy Yes lisocabtagene maraleucel (BREYANZI™) idecabtagene vicleucel (ABECMA®) ciltacabtagene autoleucel (CARVYKTI™)

2022 LBCL refractory to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy OR refractory to or relapse after first-line chemoimmunotherapy and are not eligible for HSCT due to comorbidities or age Yes

2021 Adults with relapsed or refractory multiple myeloma after at least four lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody Yes

2022 Adults with relapsed or refractory multiple myeloma after at least four lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody Yes

Abbrevations: ALL = acute lymphoblastic leukemia; HSCT = hematopoietic stem cell transplantation; LBCL = large B-cell lymphoma; MCL = mantle cell lymphoma; REMS = Risk Evaluation and Mitigation Strategy due to cytokine release syndrome and neurologic toxicities

*Approved under accelerated approval; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trial

Recent CAR-T Approvals

Ciltacabtagene autoleucel (CARVYKTI™)

In February 2022, the FDA approved ciltacabtagene autoleucel (cilta-cel) (CARVYKTI™; Janssen Biotech Inc.) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.6 Cilta-cel is a B-cell maturation antigen (BCMA)-directed, genetically modified autologous CAR-T therapy, with each dose customized using collected and modified T-cells from the patient that are then infused back into the patient.6 CARTITUDE-1 was an open-label, multicenter clinical trial evaluating the safety and efficacy of cilta-cel.7 The trial evaluated cilta-cel in 97 patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody and who had disease progression on or after the last chemotherapy regimen.7 Overall response rate and duration of response established efficacy, as evaluated by an Independent Review Committee (IRC) using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.7 Results showed the overall response rate was 97.9%, and among the 95 patients who responded, median duration of response was 21.8 months with a median duration of follow-up of 18 months.7 Cilta-cel comes with a boxed warning for cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome, Immune Effector Cell-Associated Neurotoxicity Syndrome, Parkinsonism and Guillain-Barré syndrome and their associated complications, and prolonged and/or recurrent cytopenia.6 Janssen is required by the FDA to conduct a postmarketing observational study of patients treated with cilta-cel to evaluate and assess long-term safety.6

Axicabtagene ciloleucel (YESCARTA®)

The FDA approved axicabtagene ciloleucel (axi-cel) (YESCARTA®, Kite Pharma Inc.) for adult patients with large B-cell lymphoma, refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy in April 2022.8 Efficacy was established in the ZUMA-7 randomized, openlabel, multicenter trial of adult patients with primary refractory large B-cell lymphoma or relapse within 12 months following completion of first-line chemoimmunotherapy.9 In the trial, 359 patients were randomized to receive a single infusion of axicel after fludarabine and cyclophosphamide lymphodepleting chemotherapy or to second-line standard therapy (two or three cycles of chemoimmunotherapy followed by high-dose therapy and autologous hematopoietic stem cell transplantation [HSCT] in patients attaining complete remission or partial remission).9 The primary efficacy measure, event-free survival, was significantly longer in the axi-cel arm with a hazard ratio of 0.40; estimated 18-month event-free survival was 41.5% in the axi-cel arm compared to 17% for standard therapy.8 Estimated median event-free survival was longer for patients on axi-cel compared to standard therapy (8.3 months vs. 2 months).9 The best objective response rate was statistically significantly higher for patients on axi-cel compared to standard therapy (83% vs. 50%, respectively).9 About 35% of patients receiving standard therapy received on-protocol HSCT, and lack of response to chemotherapy was the most common reason for not receiving the HSCT.9 The axicel label carries a warning for CRS and neurologic toxicities.8

Previously, axi-cel was approved by the FDA in 2017 for the treatment of adult patients with certain types of large B-cell lymphoma who had not responded to or who had relapsed after at least two other kinds of systemic treatment.10 Subsequently, in 2021, the FDA granted accelerated approval to axi-cel for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.11

Tisagenlecleucel (KYMRIAH®)

Tisagenlecleucel (tisa-cel) (KYMRIAH®, Novartis Pharmaceutical Corporation) was granted accelerated approval in May 2022 for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.12 In the primary efficacy analysis, the ELARA trial evaluated tisacel in 90 adult patients who were refractory or relapsed within

(BREYANZI®) lisocabtagene maraleucel (BREYANZI®)

Bristol Myers Squibb

Bristol Myers Squibb autologous CAR-T therapy NHL phase 1-2 autologous CAR-T therapy follicular lymphoma/MZL phase 2

PBCAR269A Precision Biosciences allogeneic T-cell therapy multiple myeloma phase 1-2

CTX110 CRISPR Therapeutics

UCART123 Cellectis allogeneic CRISPR/Cas9 geneedited CAR-T therapy B-cell malignancies phase 1-2 allogeneic CAR-T therapy acute myeloid leukemia phase 1

Abbreviations: ALL = acute lymphocytic leukemia; CMV = cytomegalovirus; IV = intravenous; MZL = marginal zone lymphoma; NHL = non-Hodgkin’s lymphoma; PTLD = post-transplant lymphoproliferative disorder six months after completion of two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent) or relapsed after HSCT.13 Tisa-cel was administered after lymphodepleting chemotherapy as a single intravenous infusion with a target dose of 0.6 to 6.0 x 108 CAR-positive viable T cells.13 The main efficacy endpoints, overall response rate and duration of response, were determined by an IRC.13 Results showed an overall response rate of 86% with a complete response rate of 68%. Median duration of response was not reached with 75% of responders still within response at nine months.13 The most common adverse reactions were CRS, infection, fatigue, musculoskeletal pain, headache, and diarrhea.12 Like axi-cel, tisacel carries a boxed warning for CRS and neurologic toxicities and is available only through a restricted program under a REMS.

In 2017, tisa-cel was the first CAR-T therapy the FDA approved, indicated forthe treatment of patients up to age 25 with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.14 The FDA granted tisa-cel supplemental approval in 2018 to treat adults 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.15

Lisocabtagene maraleucel (BREYANZI®)

In June 2022, the FDA approved lisocabtagene maraleucel (lisocel) (BREYANZI®, Bristol Myers Squibb) to treat adult patients with large B-cell lymphoma who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line immunotherapy; refractory to or relapse after firstline chemoimmunotherapy and are not eligible for HSCT due to comorbidities or age.16 Approval was based on efficacy results from two studies, TRANSFORM and PILOT. TRANSFORM was a trial for adult patients with primary refractory large B-cell lymphoma or relapse within 12 months of achieving complete response to first-line therapy.17 In TRANSFORM, 184 patients were randomized to receive a single infusion of liso-cel following fludarabine and cyclophosphamide lymphodepleting chemotherapy or to receive second-line standard therapy (three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained complete or partial response).17 Event-free survival, the primary efficacy measure was significantly longer in the liso-cel arm, with a hazard ratio of 0.34.17 In the liso-cel arm, estimated one-year event-free survival was 45% compared to 24% in the standard therapy arm.17 Estimated median event-free survival was 10.1 months for lisocel, compared to 2.3 months for standard therapy.17 About 47% of patients receiving standard therapy received HSCT as planned; lack of response to chemotherapy was the most common reason for not receiving HSCT. Progression-free survival was significantly longer in the liso-cell arm, with a hazard ratio of 0.41.17

The PILOT study evaluated efficacy in transplant ineligible patients with relapsed or refractory large B-cell lymphoma after one line of chemoimmunotherapy.18 The study included patients who were ineligible for high-dose therapy and HSCT due to organ function or age but who had adequate organ function for CAR-T therapy.18 Complete response rate and duration of response were the primary efficacy measures. Of the 61 patients who received liso-cel, 54% achieved complete response, and the median duration of response was not reached in patients who achieved complete response.18 Median duration of response was 2.1 months in patients with a best response of partial response.18

Liso-cel carries a boxed warning for CRS and neurologic toxicities and is available only through a REMS because of these risks.16 CRS occurred in 45% of patients in studies of liso-cel as a secondline therapy for large B-cell lymphoma and neurologic toxicities occurred in 27%.16

Previously, the FDA approved liso-cel in 2021 to treat adult patients with certain types of large B-cell lymphoma who had not responded to, or who had relapsed after, at least two other types of systemic treatment.19

ICER Reviews

The Institute for Clinical and Economic Review (ICER) previously published a report on CAR-T therapies for treatment of B-cell malignancies in 2018 highlighting that although the pricing of axi-cel and tisa-cel aligned with patient benefit at the time, changes were needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.20 In May 2021, ICER released its final evidence report evaluating several treatments for multiple myeloma, including CAR-T therapies cilta-cel and idecabtagene vicleucel (ide-cel) (ABECMA®, Bristol Myers Squibb).21 ICER gave cilta-cel an evidence rating of B+, meaning there is moderate certainty of a small or substantial net health benefit, with high certainty of at least a comparable net health benefit.21 Both idecel and cilta-cel were determined to provide a net health benefit when compared to usual care. For ide-cel, the only CAR-T agent having gained FDA approval for multiple myeloma at the time of the report, a majority of panelists from ICER’s independent appraisal committee voted that it represents “low” long-term value for money at current pricing.21