FDA Approval Summary: Lisocabtagene Maraleucel for Relapsed or Refractory Follicular Lymphoma

Abstract

In May 2024, the FDA granted accelerated approval to lisocabtagene maraleucel for the treatment of adults with relapsed or refractory (R/R) follicular lymphoma (FL) who have received two or more prior lines of systemic therapy. The single-arm, open-label, multicenter, phase 2 TRANSCEND-FL trial evaluating a single dose of lisocabtagene maraleucel in adults with R/R indolent non-Hodgkin lymphoma supported the FL indication. The trial enrolled 139 patients with R/R FL, including 107 with two or more prior lines of therapy. Of the 107 patients, 94 patients comprised the primary efficacy population and the independent review committee-assessed overall response rate was 95.7% (95% confidence interval [CI]: 89.5, 98.8), with 73.4% (95% CI: 63.3, 82.0) achieving complete response. The median duration of response was not reached (95% CI: 18.0 months, NR) and the 1-year remission rate was 81% (95% CI: 71, 88). Serious adverse reactions occurred in 26% of patients, most often due to cytokine release syndrome (CRS), neurologic toxicity, and febrile neutropenia. CRS occurred in 59% (Grade 3: 1%) of patients and neurologic toxicities occurred in 15% (Grade 3: 2%). As a condition of accelerated approval, post marketing studies were required to verify the clinical benefit of lisocabtagene maraleucel in R/R FL. This article summarizes key aspects of the regulatory review.

Introduction

Follicular lymphoma (FL) is an indolent type of non-Hodgkin Lymphoma (NHL) which accounts for 20% of all NHL in the United States (1). Frontline treatment includes CD20-based chemoimmunotherapy, rituximab alone, or rituximab in combination with lenalidomide (2). Although 40% to 80% of patients achieve a complete response (CR) to frontline chemoimmunotherapy, relapse over time is nearly universal and prognosis progressively worsens with each recurrence. Current second-line FL treatment includes chemoimmunotherapy or the combination of rituximab and lenalidomide. There is no consensus on standard-of-care therapies for patients with FL who have received two or more prior lines of therapies. Considerations include T-cell engagers, such as the CD20×CD3 bispecific antibodies or chimeric antigen receptor (CAR) T-cell therapies; the enhancer of zeste homolog 2 (EZH2) inhibitor, tazemetostat; or the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in combination with obinutuzumab (2). Many of these therapies require prolonged treatment durations as compared to a single administration of CAR T-cell therapy. Despite the advances and available therapies following each successive line of therapy, survival outcomes for patients worsens over time (3). Thus, there remains continued need for development of improved and novel therapies for patients with relapsed or refractory (R/R) FL.

On May 15, 2024, FDA approved lisocabtagene maraleucel for the treatment of R/R FL after two or more prior lines of systemic therapy. Lisocabtagene maraleucel is a CD19-directed, genetically modified, autologous T-cell therapy, previously approved for the treatment of adults with R/R large B-cell lymphoma (LBCL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and mantle cell lymphoma. Herein, we summarize the FDA review and key regulatory considerations of this marketing application.

Clinical Trial Design

The approval of lisocabtagene maraleucel was based on the TRANSCEND-FL study (NCT04245839), a single-arm, open-label, multicenter phase 2 trial that evaluated a single infusion of lisocabtagene maraleucel in adults with R/R indolent NHL. Eligible patients had received anti-CD20-directed and alkylating agents and were refractory or had relapsed following such therapy, had measurable PET-positive disease and sufficient bone marrow function to receive lymphodepleting chemotherapy (LDC), and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The study excluded patients with transformed FL, composite diffuse LBCL and FL, or prior CAR T-cell or other genetically modified cell therapy (4). The trial enrolled patients with R/R FL across 3 cohorts: Cohort 1 (fourth-line setting or later), Cohort 2 (third-line setting), and Cohort 3 (second-line setting). Following leukapheresis and optional bridging therapy for disease stabilization, patients initiated LDC with fludarabine and cyclophosphamide followed by a single intravenous infusion of lisocabtagene maraleucel at a dose of 100 × 10⁶ CAR-positive viable T cells.

The primary efficacy outcome measure was overall response rate (ORR) as determined by an independent review committee (IRC) per Lugano criteria (5). Select secondary endpoints included CR rate, duration of response (DOR), and characterization of the pharmacokinetic profile of lisocabtagene maraleucel.

Results

A total of 139 patients with R/R FL underwent leukapheresis in TRANSCEND-FL, including 114 patients who had received 2 or more prior lines of therapies (3L+ FL). Of those 114, 107 patients received lisocabtagene maraleucel with a median administered dose of 100.02 × 10⁶ CAR-positive viable T cells (range, 93.4 to 109.2 × 10⁶ CAR-positive viable T cells) and comprise the safety population. The median time from leukapheresis to product infusion was 50 days (range, 31 to 313 days). The manufacturing failure rate was 4%.

The primary efficacy population included 94 patients who had PET-positive disease at study baseline or confirmation of PET-positive disease after optional bridging therapy and prior to LDC and received a conforming product at the intended dose range, and had a minimum of 9 months of DOR follow-up per IRC. Given the single-arm nature of the trial, presence of PET-positive disease at baseline allowed for assessment of response following treatment with lisocabtagene maraleucel. Further, adequate follow up for DOR, particularly in the context of an indolent disease, provided adequate evidence to assess durability of response.

Efficacy

Baseline characteristics of the primary efficacy population are summarized in Table 1. The median age was 63 years; 63% were male; ECOG performance status was 0 in 64% and 1 in 36%; 55% were White, 9% were Asian, and 3% were Black; and 5% were Hispanic. A total of 89% had Stage III-IV disease, 29% with bulky disease, and 50% had progression of disease within 24 months of initial diagnosis. Patients received a median of 3 prior therapies, with 45% receiving 2 prior lines. Between leukapheresis and administration of lisocabtagene maraleucel, 39% of the efficacy population received bridging therapy.

Table 1.

Basic demographic and disease characteristics in TRANSCEND-FL

Demographic Parameter	N=94 n (%)
Median age (range)	63 years (23–80)
≥65 years - <75 years	30 (32)
≥75 years	9 (10)
Sex	-
Female	36 (38)
Male	58 (62)
Race	-
Asian	8 (9)
Black or African American	3 (3)
White	52 (55)
Ethnicity	-
Hispanic or Latino	5 (5)
Not Hispanic or Latino	65 (69)
Unknown	24 (26)
ECOG performance status
0	59 (63)
1	35 (37)
Relapsed or refractory to last therapy, n (%)	-
Refractory	60 (64)
Relapsed	34 (36)
Number of prior systemic treatments, n (%)	-
2 prior regimens	43 (46)
3 prior regimens	21 (22)
4 prior regimens	16 (17)
≥5 prior regimens	14 (15)
Bulky disease	27 (29)
POD24	47 (50)
Received Bridging therapy	37 (39)

Source: Created by FDA based on Applicant’s submission (13)

Abbreviation: POD24, progressive disease within 24 months of initial diagnosis.

Key efficacy results are shown in Table 2. In the primary efficacy population, the ORR was 95.7% (95% confidence internal [CI]: 89.5, 98.8). The CR rate was 73.4% (95% CI: 63.3, 82.0). The median time to first response was 1.0 month (range, 0.6 to 3.3 months), and median time to first CR was 3.0 months (range, 0.6 to 18.0 months). After a median follow up of 16.8 months, the median DOR was not reached (95% CI: 18.0, NR), with an estimated 1-year remission rate of 81%.

Table 2.

IRC-assessed efficacy results in relapsed or refractory follicular lymphoma

Response Rate	Primary Efficacy Population (N=94)	All Leukapheresed Patients (N=114)
Overall response rate, n (%)	90 (95.7)	105 (92.1)
95% CI	89.5, 98.8	85.5, 96.3
CR, n (%)	69 (73.4)	78 (68.4)
95% CI	63.3, 82.0	59.1, 76.8
PR, n (%)	21 (22.3)	27 (23.7)
95% CI	14.4, 32.1	16.2, 32.6
DOR if best response is CR or PR	N = 90
Median, months (95% CI)	NR (18.04, NR)	—
Rate at 12 months, % (95%CI)	80.9 (71.0, 87.7)	—
Rate at 18 months, % (95% CI)	77.1 (65.9, 85.0)	—
DOR if best response is CR	N=69
Median, months (95% CI)	NR (NR, NR)	—
Rate at 12 months, % (95% CI)	88.2 (77.7. 93.9)	—
Rate at 18 months, % (95% CI)	83.1 (70.0, 90.9)	—

Source: Created by FDA based on Applicant’s submission (13)

Abbreviations: CI, confidence interval; CR, complete response; DOR, duration of response; NR, not reached; PR, partial response.

Safety

Table 3 summarizes common adverse reactions in the TRANSCEND-FL safety population (N = 107). The most common nonlaboratory adverse reactions in ≥20% were cytokine release syndrome (CRS), headache, musculoskeletal pain, fatigue, constipation, and fever. Serious adverse reactions occurred in 26%, most often due to CRS, neurologic toxicity, and febrile neutropenia. Grade 4 laboratory abnormalities in ≥10% were lymphopenia (78%), neutropenia (61%), leukopenia (41%), and thrombocytopenia (11%).

Table 3.

Selected adverse reactions and laboratory abnormalities in TRANSCEND-FL Safety Population (N=107)

AR/Laboratory Abnormality	All Grade n	All Grade %	Grade ≥3 n	Grade ≥3 %
Adverse Reactionsa
Cytokine release syndrome	63	59%	1	1%
Headache	30	28%	0	0%
Musculoskeletal pain	30	28%	0	0%
Fatigue	25	23%	0	0%
Constipation	22	21%	0	0%
Fever	21	20%	0	0%
Infection with pathogen unspecified	17	16%	5	5%
Diarrhea	16	15%	0	0%
Tremor	16	15%	0	0%
Laboratory Abnormalitiesb
Lymphocyte decreased	104	97%	101	94%
White blood cell decreased	104	97%	79	74%
Neutrophil decreased	98	92%	84	79%
Hemoglobin decreased	70	65%	10	9%
Platelet decreased	60	56%	18	17%

Source: Created by FDA based on Applicant’s submission (13)

Abbreviation: AR, adverse reaction.

^aMedDRA preferred terms were grouped as per FDA Grouped term for adverse event analysis.

^bBased on the number of patients with a baseline value and at least one post treatment value for the particular lab.

CRS and neurologic toxicity remain the leading safety concerns with lisocabtagene maraleucel, and CAR T-cell therapies in general. CRS was the most common adverse reaction, occurring in 59% of patients, with Grade 3 events occurring in 0.9%. Median time to onset was 6 days (range, 1 to 17 days). The median time to resolution of first CRS was 3 days (range, 1 to 10 days), with resolution occurring for all those affected. The most common symptoms related to CRS were pyrexia (98.4%) and hypotension (20.6%). Neurologic toxicity occurred in 15% of patients, with Grade 3 events occurring in 2%. Median time to onset was 8.5 days (range, 4 to 16 days), with median time to resolution of 4.5 days (range, 1 to 17 days). The prescribing information for lisocabtagene maraleucel includes a boxed warning for fatal or life-threatening CRS and neurologic toxicity.

In a patient with FL after one prior therapy, an event of fatal immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) occurred. This developed around Day 7 and resulted in death on Day 29 post lisocabtagene maraleucel infusion. A Warning and Precaution for IEC-HS is included in the prescribing information for lisocabtagene maraleucel.

Prolonged cytopenia was defined as cytopenia which persisted beyond the Day 29 visit (±2-day window as allowed by the study). Grade 3 or higher prolonged cytopenias occurred in 22% of patients, including thrombocytopenia in 14%, neutropenia in 16%, and anemia in 34% of patients.

All-grade infections occurred in 22% of 3L+ FL patients treated with lisocabtagene maraleucel, with grade 3 or higher infections in 5.5%. One patient developed progressive multifocal leukoencephalopathy (PML) approximately 3 months after LDC and lisocabtagene maraleucel administration, which led to death on Day 190. The underlying cause for this case was unclear, as immunosuppression, possibly related to LDC, likely contributed. The risk of PML is listed in the Serious Infections, Warning and Precaution portion of the label.

For second primary malignancies (SPMs), 7 events occurred in 5 patients per FDA assessment, which included two cases of acute myeloid leukemia (AML), one case of squamous cell carcinoma, two cases of squamous cell carcinoma in situ, one case of prostate cancer, and one case of rectal cancer. Among patients who developed hematologic malignancies, the first patient developed AML on Day 76 after treatment with lisocabtagene maraleucel. Testing for CAR transgene was negative, as was replication-competent lentivirus testing. The second patient developed AML on Day 359 post lisocabtagene maraleucel; although there was no tissue or bone marrow available for CAR transgene testing, replication-competent lentivirus testing was negative. Both patients had previously received greater than 4 prior lines of therapy and AML was thought to develop, at least partially, due to these prior therapies.

Clinical Pharmacology

B-cell aplasia, defined as <3% of CD19+ B cells in peripheral blood lymphocytes, is an on--target, -off--tumor pharmacodynamic effect of lisocabtagene maraleucel. In the 3L+ FL population, B-cell aplasia was observed in 99% of evaluated patients on Day 8, and was maintained in 92% patients on Day 90 following lisocabtagene maraleucel treatment. Following infusion, lisocabtagene maraleucel exhibited an initial expansion followed by a bi-exponential decline. In the 3L+ FL population, the median time of maximal expansion in peripheral blood occurred 10 days after infusion. Median Cmax and AUC0–28d are 30,530 copies/μg and 253,400 day*copies/μg, respectively. Lisocabtagene maraleucel was present in peripheral blood for an estimated median of 12.0 months (range, 0.3+ to 24.0+ months).

Discussion and Regulatory Insights

Based on ORR and DOR in the primary efficacy population along with an acceptable safety profile, lisocabtagene maraleucel was granted accelerated approval for the treatment of adult patients with R/R FL who have received two or more prior lines of systemic therapy. The FDA’s benefit-risk determination is summarized in Table 4. Key regulatory considerations are summarized herein.

Table 4.

FDA benefit-risk analysis of lisocabtagene maraleucel in follicular lymphoma

Parameter	Summary
Benefit	In a single-arm trial, lisocabtagene maraleucel demonstrated a high ORR of 95.7% (95% CI: 89.5, 98.8). After a median duration of follow-up of 16.8 months, the ORR was durable and the median DOR was not reached (95% CI: 18.0, NR). High and durable ORR based on the length of follow-up in the indicated 3L+ FL population is an intermediate clinical endpoint reasonably likely to predict clinical benefit.
Risk	Overall, the safety events reported in the 3L+ FL population were consistent with those observed in overall NHL trials.
Uncertainties	Given the indolent nature of FL and risk of relapse, concerns remain with limited follow-up for DOR and ultimate clinical benefit.
Conclusion	In the 3L+ FL population, lisocabtagene maraleucel demonstrated a favorable benefit-risk profile, therefore supporting an accelerated approval. Longer duration of follow-up for DOR (at least 24 months) is required to confirm clinical benefit.

Source: Created by FDA based on Applicant’s submission (13)

Abbreviations: CI, confidence interval; DOR, duration of response; FL, follicular lymphoma; NHL, non-Hodgkin lymphoma; NR, not reached; ORR, overall response rate; 3L+, 2 or more prior lines of therapy.

A major regulatory consideration for this application was the approach to a confirmatory trial to verify and describe the clinical benefit of lisocabtagene maraleucel in R/R FL, a requirement following an accelerated approval (6). Two options were considered: 1) a randomized controlled trial (RCT) in R/R FL evaluating lisocabtagene maraleucel versus a standard of care control arm with a time-to-event endpoint such as progression-free survival or overall survival, or 2) additional follow-up of the current patients in the TRANSCEND-FL study. In oncology, there are several examples of postmarketing requirements consisting of enrollment of additional patients or further follow-up of enrolled patients from a single-arm trial to verify clinical benefit (7–10). In such cases, there are several important considerations and for lisocabtagene maraleucel in R/R FL, these included: 1) lisocabtagene maraleucel demonstrated a high magnitude of response with prolonged durability in 3L+ FL in the TRANSCEND-FL study, which is clinically meaningful in patients with R/R FL, 2) the single-arm data from the TRANSCEND-FL study call into question whether an RCT in the same indication can be conducted after an accelerated approval and whether clinical equipoise remains, 3) the safety profile of lisocabtagene maraleucel is well established in patients with NHL, including data from an RCT in LBCL (11), 4) in patients with R/R FL, the outcome with each successive line of therapy is worse, leading to higher mortality after each treatment, and 5) the availability of lisocabtagene maraleucel and 2 other CAR T-cell products under accelerated approval for 3L+ FL may impact the feasibility of accruing and completing a randomized trial. Based on these considerations, a postmarketing requirement for additional follow-up of responding (either CR or PR) patients for at least 24 months for duration of response in TRANSCEND-FL was issued to verify the clinical benefit of lisocabtagene maraleucel in the indicated population. FDA generally intends to require that a confirmatory trial be underway at the time of accelerated approval (12)—the postmarketing requirement for continued follow-up of patients in the ongoing TRANSCEND-FL trial meets this requirement.

Another key review issue was the assessment of the fatal events of IEC-HS and PML during the review of this application. These are serious and life-threatening adverse reactions known to occur during the period of immunosuppression following treatment with CAR T-cell therapies and are included in the Warnings and Precaution of the prescribing information.

Given the replication competent retrovirus used in its manufacturing and the potential for insertional mutagenesis, a boxed warning for T-cell malignancies is already included for all B-cell maturation antigen- and CD19-directed genetically modified autologous T-cell immunotherapies, including lisocabtagene maraleucel. Additionally, since R/R FL is an indolent disease and distinct from other FDA-approved indications of lisocabtagene maraleucel, such as R/R LBCL or CLL/SLL, a separate long-term follow-up study for safety with active surveillance in the indicated patient population was issued as a postmarketing requirement.

Conclusion

Lisocabtagene maraleucel represents an alternative treatment option for patients with R/R FL in the 3L+ setting and beyond. The efficacy and safety findings from the TRANSCEND-FL study demonstrate a favorable benefit-risk profile and support an approval. Accelerated approval was granted based on an ORR endpoint, supported by durability, to allow for an earlier approval due to evidence supporting a meaningful benefit in the context of available therapies in the indicated populations. Additional data and follow-up from the TRANSCEND-FL study are needed to inform the clinical benefit of lisocabtagene maraleucel.