EMA Validates Application for Liso-Cel in Relapsed/Refractory Follicular Lymphoma

The European Medicines Agency has validated its Type II variation application to expand the indication for lisocabtagene maraleucel (Breyanzi; liso-cel) to use in adult patients with relapsed or refractory follicular lymphoma who have previously received 2 or more lines of systemic treatment.¹

The application was based on findings from the phase 2 TRANSCEND FL study (NCT04245839) in which the CAR T-cell therapy induced an overall response rate (ORR) of 97% (95% CI, 91.6%-99.4%; P <.0001) in patients with third-line or later disease (3L+; n = 101), with a complete response (CR) rate of 94% (95% CI, 87.5%-97.8%; P < .0001).² The median time to first response was 1 month (range, 0.6-3.3) and, at a median follow-up of 16.6 months, the median duration of response (DOR) had not been reached (NR; 95% CI, 18.0-NR). The 12-month DOR rate in this group was 82% (95% CI, 72.5%-88.4%). At a median follow-up of 17.6 months, the median progression-free survival (PFS) was also NR (95% CI, 19.0-NR), and the 12-month PFS rate was 81% (95% CI, 71.4%-87.2%). The median overall survival (OS) was NR, and the 12-month OS rate was 92% (95% CI, 84.8%-96.0%).

“Follicular lymphoma impacts a significant number of people, and those with relapsed or refractory disease tend to experience shorter responses with each new line of therapy,” Anne Kerber, senior vice president and head of Late Clinical Development, Hematology, Oncology and Cell Therapy at Bristol Myers Squibb, stated in a news release.¹ “Breyanzi represents a differentiated CAR T cell therapy, and we look forward to working with the European Medicines Agency to bring this important treatment option to patients with relapsed or refractory follicular lymphoma with the goal of improving outcomes and providing lasting remission.”

The open-label, multicenter, single-arm, phase 2 study included adult patients with relapsed or refractory follicular lymphoma who previously received at least 2 lines of systemic therapy, including an alkylating agent and a CD20 antibody. To participate, patients must have had an ECOG performance status of 0 or 1; they could not have a creatinine clearance of up to 30 mL/min, alanine transaminase greater than 5 times the upper limit of normal or left ventricular ejection fraction under 40%.

Study participants received lymphodepleting chemotherapy comprised of 30 mg/m2 of fludarabine daily plus 300 mg/m2 of cyclophosphamide given daily concurrently for 3 days. Two to 7 days after chemotherapy was completed, they received a single administration of liso-cel. The median dose given was 100.02 x 106 CAR-positive viable T cells (range, 93.4-109.2).

The primary efficacy outcome measure was ORR, and secondary outcome measures included CR rate, DOR, progression-free survival, overall survival, toxicity, pharmacokinetics, and quality-of-life assessment.³

A total of 139 patients were enrolled in the study and underwent leukaphereses (second line or later [2L+], n = 139; 3L+, n = 114; second line [2L], n = 25). A total of 130 patients with 2L+ received liso-cel, and these patients comprised the liso-cel–treated set; 124 were evaluable for efficacy (2L, n = 23; 3L+, n = 101). The median time from leukapheresis to CAR T-cell therapy availability was 29 days (interquartile range [IQR], 25-31), and the time from leukapheresis to infusion was 49 days (IQR, 41-55).

In the liso-cel–treated set, the median patient age was 60 years (range, 23-80); those in the 3L+ group had a median age of 62 years and those in the 2L group had a median of 53 years. Most patients had Ann Arbor stage III or IV disease (86%; 3L+, 89%; 2L, 74%) and about half had high-risk disease (53%; 57%; 35%). In the total set, 45% had POD24 from diagnosis following exposure to a CD20 antibody and an alkylating agent within the first 6 months of diagnosis (3L+, 43%; 2L, 52%). More than half of patients were double refractory (62%; 64%; 48%). Bridging therapy was given to 38% of patients (3L+, 41%; 2L, 22%).

Additional data showed that in the 2L patients, the ORR with liso-cel was 96% (95% CI, 78.1%-99.9%; P < .0001). The median time to first response was 1 months (range, 0.7-2.8) and, at a median follow-up of 16.8 months, the median DOR was NR (95% CI, 19.3-NR). The DOR rate at 12 months was 90% (95% CI, 64.8%-97.4%). Moreover, at a median follow-up of 17.8 months, the median PFS was NR (95% CI, 20.2-NR) and the 12-month PFS rate was 91% (95% CI, 69.5%-97.8%). The median OS was NR, and the 12-month OS rate was 96% (95% CI, 72.9%-99.4%).

In the liso-cel­–treated patients, 75% of patients experienced grade 3 or higher treatment-emergent adverse effects (TEAEs); this included 78% of those in the 3L+ group and 61% of those in the 2L group. Twenty-five percent of patients experienced serious TEAEs; this included 26% of those in the 3L+ group and 17% of those in the 2L group. The most common grade 3 or higher TEAEs were neutropenia (58%; 60%; 52%) and anemia and thrombocytopenia (10%; 11%; 4%). Six percent of patients had febrile neutropenia (3L+, 6%; 2L, 9%).

Cytokine release syndrome occurred in 58% of patients (59%; 52%) and had a median onset of 6 days (range, 1-17; median 6 days; median 6 days). The median duration of this event was 3 days (range, 1-10; median 4 days; median 3 days). Most events were grade 1 with only 1 grade 3 event reported.

In May 2024, the FDA granted accelerated approval to liso-cel for use in adult patients with relapsed or refractory follicular lymphoma who have previously received 2 or more prior lines of systemic therapy.4 The therapy has also been approved by Japan’s Ministry of Health, Labour, and Welfare for relapsed or refractory follicular lymphoma after 1 prior line of systemic treatment in those with high-risk disease and after 2 or more lines of systemic treatment.¹

References

1. European Medicines Agency validates Bristol Myers Squibb’s application for CAR T cell therapy Breyanzi for relapsed or refractory follicular lymphoma. News release. Bristol Myers Squibb. August 19, 2024. Accessed August 19, 2024. https://news.bms.com/news/details/2024/European-Medicines-Agency-Validates-Bristol-Myers-Squibbs-Application-for-CAR-T-Cell-Therapy-Breyanzi-for-Relapsed-or-Refractory-Follicular-Lymphoma/default.aspx
2. Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024;30(8):2199-2207. doi:10.1038/s41591-024-02986-9
3. A study to evaluate the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL) (TRANSCEND FL). ClinicalTrials.gov. Updated July 22, 2024. Accessed August 19, 2024. https://clinicaltrials.gov/study/NCT04245839
4. FDA grants accelerated approval to lisocabtagene maraleucel for follicular lymphoma. FDA. May 15, 2024. Accessed August 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma