FDA Grants Priority Review to Liso-cel for Second-Line Relapsed/Refractory LBCL

FDA

The FDA has accepted and granted priority review to a supplemental biologics license application (sBLA) seeking the approval of the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) in whom frontline therapy has failed.¹

The application is based on data from the phase 3 TRANSFORM trial (NCT03575351), which found that liso-cel significantly improved event-free survival (EFS), complete responses (CRs), and progression-free survival (PFS) vs standard salvage chemotherapy followed by high-dose chemotherapy plus autologous hematopoietic stem cell transplant in this patient population.

At a median follow-up of 6.2 months in both treatment arms, the median EFS in those who received liso-cel (n = 92) was 10.1 months (95% CI, 6.1–not reached [NR]) vs 2.3 months (95% CI, 2.2-4.3) in those who received standard-of-care (SOC) treatment (n = 92; HR, 0.349; 95% CI, 0.229-0.530; P < .0001).² The 6-month EFS rates in the investigative and control arms were 63.3% (95% CI, 52.0%-74.7%) and 33.4% (95% CI, 23.0%-43.8%), respectively; at 12 months, these rates were 44.5% (95% CI, 29.4%-59.6%) and 23.7% (95% CI, 13.4%-34.1%), respectively.

The median PFS in the liso-cel arm was 14.8 months (95% CI, 6.6-NR) vs 5.7 months (95% CI, 3.9-9.4) in the SOC arm (HR, 0.406; 95% CI, 0.250-0.659; P = .0001). The 6-month PFS rate with the CAR T-cell therapy was 69.4% (95% CI, 58.1%-80.6%) vs 47.8% (95% CI, 35.0%-60.6%) with SOC; the 12-month PFS rates were 52.3% (95% CI, 36.7%-67.9%) and 33.9% (95% CI, 20.1%-47.7%), respectively.

Moreover, liso-cel elicited a CR rate of 66% (95% CI, 55.7%-75.8%) vs 39% (95% CI, 29.1%-49.9%) with SOC (P < .0001). The objective response rates (ORRs) achieved in the investigative and control arms were 86% (95% CI, 77.0%-92.3%) and 48% (95% CI, 27.3%-58.5%), respectively.

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the sBLA by June 24, 2022.

“[Liso-cel] as a differentiated CD19-directed CAR T cell therapy has already proven to be an important treatment option for patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy and now has the potential to be a new SOC for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, senior vice president of Cell Therapy Development at Bristol Myers Squibb, stated in a press release. “This acceptance from the FDA brings us one step closer to delivering a practice-changing treatment for primary refractory or relapsed LBCL, making [liso-cel] available to more patients in need, and underscores the advancements we’re making in cell therapy research to transform the lives of patients with difficult-to-treat blood cancers, including lymphoma.”

The trial enrolled patients between the ages of 18 years and 75 years who have aggressive non-Hodgkin lymphoma, including diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal large B-cell lymphoma, or T-cell/histiocyte-rich LBCL.

Patients needed to be refractory or relapsed for a maximum of 1 year following a frontline treatment containing an anthracycline and a CD20-targeted agent. The maximum ECOG performance status permitted was 1. Patients needed to be candidates for hematopoietic stem cell transplantation (SCT).

Following screening plus leukapheresis and randomization, those in the investigative arm were administered 100 x 10⁶ CAR T cells and those in the control arm were given 3 cycles of salvage chemotherapy followed by high-dose chemotherapy plus autologous SCT (ASCT).

Patients on the placebo arm were allowed to crossover to receive liso-cel if they did not respond by 9 weeks after randomization, experienced progressive disease at any time, or began a new antineoplastic therapy following ASCT. Responses were evaluated at weeks 9 and 18, and months 6, 9, 12, 18, 24, and 36.

The primary end point of the trial was EFS, and key secondary end points included CR rate, PFS, and overall survival (OS). Other end points of interest included duration of response, ORRs, and safety. Exploratory end points included cellular kinetics and B-cell aplasia.

Two hundred and thirty-two patients underwent screening and 184 of those patients underwent leukapheresis and randomization. At the time of the 2021 ASH Annual Meeting presentation on the data, 78 patients were still receiving the CAR T-cell therapy and 32 patients were still receiving SOC. A total of 50 patients were allowed to crossover from the control arm to the investigative arm; 46 of these patients received liso-cel as their third-line therapy.

The median age of study participants was 60 years (range, 53.5-67.5) in the liso-cel arm vs 58 years (range, 42-65) in the SOC arm, and the most common LBCL subtype in both arms was DLBCL NOS (58% vs 53%), followed by HGBCL with DLBCL histology (24% vs 23%). Fifty-two percent of those who received the CAR T-cell therapy had an ECOG performance status of 0 vs 62% of those who were given SOC; 73% and 74% of patients, respectively, had refractory disease.

OS data were immature at the time of data cutoff, but a numerical trend favoring the CAR T-cell therapy was observed. The median OS in the liso-cel arm had not yet been reached (95% CI, 15.8-NR) vs 16.4 months (95% CI, 11.0-NR) in the SOC arm (HR, 0.509; 95% CI, 0.258-1.004; P = .0257). The estimated OS rate at 6 months in the investigative and control arms were 91.8% (95% CI, 85.4%-98.2%) and 89.4% (95% CI, 82.9%-96.0%), respectively; these estimated rates were 79.1% (95% CI, 67.1%-91.1%) and 64.2% (95% CI, 50.5%-77.9%), respectively, at 12 months.

All patients who received liso-cel reported treatment-emergent adverse effects (TEAEs) vs 99% of those given SOC. The TEAEs that were most frequently experienced with the CAR T-cell therapy included neutropenia (82%), anemia (63%), and thrombocytopenia (58%).

Ninety-two percent of patients who received liso-cel experienced grade 3 or higher TEAEs vs 87% of those who were given SOC. Common grade 3 or higher TEAEs reported in those who received the CAR T-cell therapy comprised neutropenia (80%), anemia (49%), thrombocytopenia (49%), and lymphopenia (25%). Any-grade serious TEAEs occurred in 48% of those in both treatment arms.

Investigators identified cytokine release syndrome (CRS) and neurological events (NEs) as TEAEs of special interest with liso-cel, and 49% of patients reported any-grade CRS. The median time to onset was 5 days (range, 1-63), and the median time to resolution was 4 days (range, 1-16). Moreover, 12% of patients experienced any-grade NEs. The median time to onset of this effect was 11 days (range, 7-25), and the median time to resolution was 6 days (range, 1-30).

References

1. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb’s supplemental biologics license application for Breyanzi (lisocabtagene maraleucel) as a second-line therapy for relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb; February 17, 2022. Accessed February 17, 2022. https://bit.ly/3Bujynp
2. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (Pts) with relapsed or refractory (R/R) large B lymphoma (LBCL): results from the randomized phase 3 transform study. Blood. 2021;138(suppl 1):91. doi:10.1182/blood-2021-147913