FDA Grants Priority Review to Expand Liso-Cel Indications in R/R Follicular Lymphoma and MCL

Anne Kerber, MD

The FDA has granted priority review to 2 supplemental biologics license applications (sBLAs) for lisocabtagene maraleucel (Breyanzi) to expand into new indications to include adult patients with relapsed or refractory follicular lymphoma and relapsed or refractory mantle cell lymphoma (MCL) following exposure to a BTK inhibitor.¹

Japan’s Ministry of Health, Labour, and Welfare also accepted for review a supplemental new drug application seeking the approval of liso-cel in patients with relapsed or refractory follicular lymphoma.

The applications are supported by findings from the phase 2 TRANSCEND FL study (NCT04245839) and the MCL cohort of the phase 1 TRANSCEND NHL 001 study (NCT02631044).

Data from the primary analysis of TRANSCEND FL were shared during the 17th International Conference on Malignant Lymphoma and showed that liso-cel induced an objective response rate (ORR) or 97% (95% Ci, 91.6%-99.4%) by independent review committee (IRC) assessment in evaluable patients (n = 101); this included a 94% (95% CI, 87.5%-97.8%) complete response (CR) rate.² Findings from the primary analysis of the MCL cohort of TRANSCEND NHL 001 were also shared during the meeting. In the primary analysis set (n = 74), liso-cel elicited an ORR of 86.5% (95% CI, 76.5%-93.3%) per IRC assessment, which included a CR rate of 74.3% (95% CI, 62.8%-83.8%) and a partial response rate of 12.2%; 6.8% of patients had stable disease and 6.8% were not evaluable.³ In the efficacy analysis set (n = 83), the ORR was 83.1% (95% CI, 73.3%-90.5%) by IRC assessment, which included a 72.3% (95% CI, 61.4%-81.6%) CR rate.

Under the Prescription Drug User Fee Act, the FDA will decide on the applications in follicular lymphoma and MCL by May 23, 2024, and May 31, 2024, respectively.¹

“Patients living with follicular lymphoma and mantle cell lymphoma often experience cycles of remission and relapse with multiple lines of treatment, and we are committed to delivering innovative treatment solutions to this population,” Anne Kerber, MD, senior vice president and head of Late Clinical Development, Hematology, Oncology, Cell Therapy (HOCT) at Bristol Myers Squibb, stated in a press release. “Breyanzi offers the potential for durable response, and these filing acceptances in the United States and Japan support our commitment to delivering our best-in-class CAR T cell therapy treatments to as many eligible patients as possible.”

About TRANSCEND FL

The open-label, single-arm, multicohort, multicenter study enrolled patients with relapsed or refractory follicular lymphoma who had prior exposure to an anti-CD20 antibody and alkylator combination. Patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and have acceptable bone marrow, kidney, liver, and cardiac function. Patients were placed in 1 of 3 cohorts: those in the second line, those in the third line, and those in the fourth or later line).

Participants underwent screening and then received leukapheresis upon enrollment. They were permitted to receive bridging therapy while liso-cel was being manufactured. Those who had PET-positive disease went on to receive lymphodepletion chemotherapy comprised of 30 mg/m² of fludarabine and 300 mg/m² of cyclophosphamide for 2 days. Liso-cel was administered 2 to 7 days later, at a target dose of 100 x 106 CAR-positive T cells.

The primary end point of TRANSCEND FL was ORR with a best overall response of CR or a PR per IRC and Lugano 2014 criteria. Key secondary end points comprised CR rate, duration of response (DOR), DOR if best overall response is CR, and investigator-assessed progression-free survival (PFS), overall survival (OS), cellular kinetics, safety, and quality-of-life measures. An important exploratory end point was B-cell aplasia.

Additional data from the primary analysis of the study showed that the median DOR with liso-cel was not yet reached (NR; 95% CI, 18.0-NR), with a 12-month DOR rate of 81.9% (standard error [SE], 3.99). The median PFS was NR (95% CI, 19.0-NR) at a median follow-up of 17.5 months and the PFS rate at 12 months was 80.7% (SE, 3.99).

Updated data from the study were shared during the 2023 ASH Annual Meeting.⁴ In the second-line follicular lymphoma efficacy set (n = 23), liso-cel elicited an ORR of 96% (95% CI, 78.1%-99.9%; P < .0001) with a CR rate of 96% (95% CI, 78.1%-99.9%; P < .0001). The median DOR was NR (95% CI, 19.3-NR) at a median follow-up of 16.8 months; the 12-month DOR rate was 89.8% (95% CI, 64.8%-97.4%). 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 69.5%-97.8%). The median OS was NR, and the 12-month OS rate was 95.7% (95% CI, 72.9%-99.4%).

In patients with third- or later-line disease (n = 101), the ORR with the product was 97% with a CR rate of 94%. At a median follow-up of 16.6 months, the median DOR was also NR (95% CI, 18.0-NR) and the 12-month DOR rate was 81.9% (95% CI, 72.5%-88.4%). At a median follow-up of 17.5 months, the median PFS was NR (95% CI, 19.0-NR) and the 12-month PFS rate was 80.7% (95% CI, 71.4%-87.2%). The median OS was NR, and the 12-month OS rate was 92.1% (95% CI, 84.8%-96.0%).

Liso-cel showcased a manageable safety profile in those with second-line follicular lymphoma, with no grade 3 or higher CRS or infections and low rates of neurologic events and cytopenia.

Moreover, data from an exploratory analysis indicated that most patients with second- or third-line disease experienced clinically significant improvements in quality of life (QOL), disease symptoms, and functioning following liso-cel administration.⁵ Those who were given the CAR T-cell therapy in the second-line setting were found to have greater improvements in most primary domains vs those who received the product in the third-line setting, including role and cognitive functioning, fatigue, pain, and Functional Assessment of Cancer Therapy Lymphoma scores.

About TRANSCEND NHL 001

The MCL cohort of TRANSCEND NHL 001 included those with PET-positive MCL who had a confirmed tissue diagnosis, were at least 18 years of age, and who received 2 or more lines of treatment, including a BTK inhibitor, an alkylator, and a CD20-targeted agent.³ Patients were required to have an ECOG performance status ranging from 0 to 1 and have acceptable bone marrow, organ, and cardiac function. Those with secondary central nervous system lymphoma or who had prior autologous or allogeneic hematopoietic stem cell transplant were allowed to enroll.

Patients first underwent leukapheresis and then were able to receive bridging therapy comprised of standard regimens. After re-confirmation of PET-positive disease, they went on to receive 3 days of lymphodepletion comprised of fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m2 daily. Two to 7 days later, they were infused with liso-cel, which was given at a target dose of 50 x 106 CAR-positive T cells (dose level 1) or 100 x 106 CAR-positive T cells (dose level 2).

The co-primary end points of the trial were safety and ORR, and secondary end points included CR rate, DOR, PFS, OS, cellular kinetics, and health-related QOL.

At a median follow-up of 22.8 months (95% CI, 16.7-23.0), the median DOR for all patients in the efficacy analysis set was 15.7 months (95% CI, 6.2-24.0). The 12- and 18-month continued response rates were 52.9% (95% CI, 40.1%-64.2%) and 42.7% (95% CI, 29.9%-54.9%), respectively. Those who achieved a CR experienced a median DOR of 16.8 months (95% CI, 7.5-24.0). In complete responders, the 12- and 18-month continued response rates were 57.8% (95% CI, 44.2%-69.2%) and 46.7% (95% CI, 32.8%-59.4%), respectively. The median DOR for partial responders was 2.2 months (95% CI, 1.5-2.4).

At a median follow-up of 23.5 months (95% CI, 17.7-23.8), the median PFS for the overall efficacy analysis set was 15.3 months (95% CI, 6.6-24.9). In complete responders, partial responders, and nonresponders, the median PFS was 17.8 months (95% CI, 8.3-24.9), 3.2 months (95% CI, 2.5-NR), and 1.6 months (95% CI, 0.4-24.0), respectively.

The respective PFS rates at 12 and 18 months in the overall efficacy analysis set were 52.8% (95% CI, 40.6%-63.6%) and 43.9% (95% CI, 31.8%-55.4%); those rates were 59.8% (95% CI, 46.3%-71.0%) and 49.4% (95% CI, 35.7%-61.8%) among complete responders. The median OS in the overall efficacy analysis set was 18.2 months (95% CI, 12.9-36.3). In complete responders, partial responders, and nonresponders, the median OS was 36.3 months (95% CI, 15.7-NR), 17.1 months (95% CI, 2.6-NR), and 3.1 months (95% CI, 0.9-10.6), respectively. The respective OS rates at 12 and 18 months were 61.8% (95% CI, 50.2%-71.4%) and 50.8% (95% CI, 39.2%-61.2%); in complete responders, those rates were 72.9% (95% CI, 59.6%-82.5%) and 59.8% (95% CI, 45.9%-71.3%), respectively.

The most common treatment-emergent AEs were CRS (any-grade, 61%; grade ≥3, 1%), neutropenia (59%; 56%), anemia (44%; 37.5%), fatigue (35%; 2%), thrombocytopenia (30%; 25%), hypokalemia (24%; 8%), headache (23%; 0%), decreased appetite (20%; 5%), nausea (18%; 2%), diarrhea (17%; 0%), hypophosphatemia (17%; 9%), peripheral edema (17%; 1%), pyrexia (17%; 0%), and confused state (16%; 2%).

References

1. Regulatory applications accepted in the US and Japan for Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) in relapsed or refractory follicular lymphoma (FL) and relapsed or refractory mantle cell lymphoma (MCL). News release. Bristol Myers Squibb. January 30, 2024. Accessed January 30, 2024. https://news.bms.com/news/corporate-financial/2024/Regulatory-Applications-Accepted-in-the-U.S.-and-Japan-for-Bristol-Myers-Squibbs-Breyanzi-lisocabtagene-maraleucel-in-Relapsed-or-Refractory-Follicular-Lymphoma-FL-and-Relapsed-or-Refractory-Mantle-Cell-Lymphoma-MCL/default.aspx
2. Morschhauser F, Dahita S, Palomba ML, et al. TRANSCEND FL: Phase 2 study results of lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). Hematol Oncol. 2023;41(suppl 2):877-880. doi:10.1002/hon.3196_LBA4
3. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in R/R MCL: primary analysis results from the MCL cohort of the single-arm, multicenter, seamless design TRANSCEND NHL 001 study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract LBA3.
4. Morschhauser F, Dahiya S, Palomba ML, et al. TRANSCEND FL: phase 2 study primary analysis of lisocabtagene maraleucel as second-line therapy in patients with high-risk relapsed or refractory follicular lymphoma. Blood. 2023;142(suppl 1):602. doi:10.1182/blood-2023-179474
5. Cartron G, Garcia-Sancho AM, Reguera JL, et al. Patient-reported outcomes (PROs) from the phase 2 TRANSCEND FL study of lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed or refractory follicular lymphoma (FL). Blood. 2023;142(suppl 1):668. doi:10.1182/blood-2023-180175