FDA Grants Priority Review to Liso-Cel for R/R Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

FDA

The FDA has granted priority review to the supplemental biologics license application (sBLA) seeking approval to expand the indication of lisocabtagene maraleucel (liso-cel; Breyanzi) to include patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had prior exposure to a BTK inhibitor and a BCL-2 inhibitor.¹

The sBLA is supported by data from the primary analysis of the phase 1/2 TRANSCEND CLL 004 study (NCT03331198) in which the CAR T-cell therapy elicited rapid and deep responses in this population.²

At a median follow-up of 21.0 months (95% CI, 17.5-26.6), the complete response (CR)/CR with incomplete hematologic recovery (Cri) rate by independent review committee (IRC) assessment was 18% (95% CI, 11%-28%) in the full study population who received liso-cel at dose level 2 (DL2), which was 100 x 10⁶ CAR-positive T cells (n = 87). The IRC-assessed objective response rate (ORR) was 47% (95% CI, 36%-58%). Moreover, the rate of undetectable minimal residual disease (uMRD) in the blood was 64% (95% CI, 53%-74%).

In the subset of patients who received liso-cel at DL2 and had progressed on BTK inhibitors and did not respond to venetoclax (Venclexta; n = 49), the IRC-assessed CR/CRi rate with the CAR T-cell therapy was also 18% (95% CI, 9%-32%), with an IRC-assessed ORR of 43% (95% CI, 29%-58%) and an uMRD rate of 63% (95% CI, 48%-77%) in the blood.

Under the Prescription Drug User Fee Act, the agency will decide on the application by March 14, 2024.¹

“Currently, there is no standard of care for people living with relapsed or refractory CLL or SLL after treatment with BTK inhibitor– and BCL-2 inhibitor–based regimens, leaving a critical unmet need for a treatment option that provides deep and lasting responses,” Anne Kerber, senior vice president and head of Late Clinical Development, Hematology, Oncology, Cell Therapy at Bristol Myers Squibb, stated in a press release. “This FDA acceptance brings us one step closer to offering these patients, for the first time, a personalized, T-cell–based treatment option. We’re proud to further our commitment to bring the potential of CAR T-cell therapy to more patients, building on [liso-cel’s] foundation as a differentiated treatment option that has shown clinical benefit in the broadest array of B-cell malignancies.”

The open-label, multicenter, phase 1/2 study enrolled patients with relapsed or refractory CLL or SLL with an indication for treatment who had at least 2 or 3 prior lines of therapy fail them and who were ineligible for or progressed on BTK inhibitor therapy.² Patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1 and have acceptable bone marrow, organ, and cardiac function. If they had Richter transformation or active central nervous system involvement, they were excluded.

Patients were screened and then underwent leukapheresis upon enrollment. As the CAR T-cell therapy was manufactured, bridging therapy was permitted. Once eligibility criteria were reaffirmed, they went on to receive lymphodepletion, which was comprised of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 3 days. Two to 7 days later, liso-cel was administered at dose level 1, which was 50 x 10⁶ CAR-positive T cells or DL2.

The first phase of the research evaluated the CAR T-cell therapy at DL1 and DL2 and the second phase evaluated liso-cel at DL2.

The primary efficacy analysis set (PEAS) was comprised of patients who had progressed on BTK inhibition and did not respond to venetoclax and received liso-cel at DL2. Primary and key secondary end points were evaluated in this subset by the following hierarchy: CR/CRi rate by IRC assessment and International Workshop on Chronic Lymphocytic Leukemia criteria, ORR, and uMRD rate in the blood.

Other secondary end points of interest included duration of response (DOR), duration of CR (DOCR), time to response (TTR), time to CR (TTCR) by IRC assessment, progression-free survival (PFS), overall survival (OS), uMRD CR rate in the blood, and safety.

In the full study population, 117 patients received liso-cel; 21 of the patients were not evaluable for efficacy, leaving 96 patients to comprise the efficacy analysis set. Eighty-seven of these patients received the CAR T-cell therapy at DL2. In the subset of patients who progressed on BTK inhibition and did not respond to venetoclax, 70 received the CAR T-cell therapy and 17 were not efficacy evaluable, leaving 53 patients to comprise the PEAS. A total of 49 patients received liso-cel at DL2.

The median age of those in the full study population was 65.0 years (range, 49-82); 44% had bulky lymph nodes and 83% had high-risk cytogenetics. The median number of prior lines of systemic therapy received was 5 (range, 2-12). All had prior exposure to BTK inhibition and 88%, 2%, and 10% of patients were refractory, relapsed, or intolerant, respectively. Eighty percent of patients had prior venetoclax; 76% were refractory and 3% were intolerant. Sixty percent of all patients had progressed on BTK inhibition and were not responsive to venetoclax.

The median age in the subset of patients who progressed on BTK inhibition and were not responsive to venetoclax was 66.0 years (range, 49-78). Just under half of patients had bulky lymph nodes (46%) and most patients had high-risk cytogenetics (86%). The median number of prior lines of systemic treatment received was 5 (range, 2-12). All of these patients were refractory to BTK inhibition. Ninety-six percent of these patients were refractory to venetoclax and 4% were intolerant only. Seventy-nine percent of these patients received bridging therapy.

Additional findings presented at the 2023 ASCO Annual Meeting showed that in the full study population, the median time to first response was 1.5 months (range, 0.8-17.4) and the median time to first CR/CRi was 4.4 months (range, 1.1-17.9); 59% (95% CI, 48%-69%) of patients achieved uMRD in the bone marrow. The median DOR was not reached (NR) in those who had a CR/CRi. At a median follow-up of 24.0 months (95% CI, 18.3-26.4), the median PFS and OS were NR in those who had a CR/CRi.

In the subset who progressed on BTK inhibition and did not respond to venetoclax, the median time to first response and first CR/CRi were 1.2 months (range, 0.8-17.4) and 3.0 months (range, 1.1-6.1), respectively; the uMRD rate in the bone marrow was 59% (95% CI, 44%-73%). The median DOR in those who had a CR/CRi was NR. At a median follow-up of 20.8 months (95% CI, 17.6-25.2), the median PFS and OS were NR in those who had a CR/CRi.

The safety profile of liso-cel was manageable. The most common treatment-emergent adverse effects (TEAEs) were neutropenia (61%), anemia (52%), and thrombocytopenia (41%). Cytokine release syndrome (CRS) occurred in 85% of patients and was mostly grade 1 (37%) or grade 2 (39%); 9% of patients had grade 3 CRS and no patients had grade 4 or 5 CRS. The median time to onset was 4.0 days (range, 1-18) and the median time to resolution was 6.0 days (range, 2-37).

Neurological events occurred in 45% of patients, with 11%, 15%, 18%, and 1% of events being grade 1, 2, 3, and 4, respectively. No grade 5 events occurred. The median time to onset was 7.0 days (range, 1-21) and the median time to resolution was 7.0 days (range, 1-83).

References

1. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Breyanzi (lisocabtagene maraleucel) for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. November 9, 2023. Accessed November 9, 2023. https://news.bms.com/news/details/2023/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Bristol-Myers-Squibbs-Application-for-Breyanzi-lisocabtagene-maraleucelfor-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx
2. Siddiqi T, Maloney DG, Kenderian S, et al. Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic lymphoma (SLL): primary analysis of TRANSCEND CLL 004. J Clin Oncol. 2023;41(suppl 16):7501. doi:10.1200/JCO.2023.41.16_suppl.7501