Lisocabtagene Maraleucel sNDA for Second-Line Relapsed/Refractory LBCL Accepted for Review in Japan

The Ministry of Health, Labour, and Welfare has accepted a supplemental new drug application for lisocabtagene maraleucel (liso-cel; Breyanzi) for the second-line treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL).¹

The application is based on data from the phase 3 TRANSFORM trial (NCT02575351), where the CAR T-cell therapy was found to result in a significant improvement in event-free survival (EFS), complete responses (CRs), and progression-free survival (PFS) compared with standard salvage chemotherapy followed by high-dose chemotherapy plus autologous hematopoietic stem cell transplant (ASCT) in this population.²

"I am pleased we are the first company in Japan to file an application for a cell therapy in second-line relapsed or refractory LBCL," Makoto Sugita, vice president of R&D Japan at Bristol-Myers Squibb K.K., stated in a press release. "This filing brings us one step closer to delivering a potentially practice-changing treatment for primary relapsed or refractory 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.”

TRANSFORM enrolled patients with 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.

To be eligible, patients needed to be between the ages of 18 years and 75 years, refractory or relapsed for a maximum of 1 year after a first-line treatment containing an anthracycline and a CD20-targeted agent. The maximum ECOG performance status that was allowed on the trial was 1, and patients needed to be eligible to undergo hematopoietic stem cell transplantation.

Participants underwent screening (n = 232) and leukapheresis (n = 184) and randomization. Those in the liso-cel arm were given 100 x 10⁶ CAR T cells and those in the SOC arm were administered 3 cycles of salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant.

Notably, those on the control arm were permitted to cross over to receive the CAR T-cell therapy (n = 50) if they did not experience a response by 9 weeks post randomization, experienced disease progression at any time, or started a new antineoplastic therapy after ASCT. Investigators examined responses to treatment at weeks 9 and 18, and months 6, 9, 12, 18, 24, and 36.

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

The median age in the patients who received the CAR T-cell therapy was 60 years (range, 53.5-67.5) vs 58 years (range, 42-65) with SOC. The most common LBCL subset in both arms was DLBCL NOS (58% vs 53%), followed by HGBCL with DLBCL histology (24% vs 23%). The ECOG performance status was 0 in 52% of those who received liso-cel vs 62% with SOC. Moreover, 73% of patients on the investigative arm had refractory disease vs 74% of those on the SOC arm.

At a median follow-up of 6.2 months, the median EFS achieved with 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) with standard-of-care (SOC) treatment (n = 92; HR, 0.349; 95% CI, 0.229-0.530; P < .0001).2 The 6-month EFS rate in the liso-cel arm was 63.3% (95% CI, 52.0%-74.7%) vs 33.4% (95% CI, 23.0%-43.8%) with SOC; the 12-month rates were 44.5% (95% CI, 29.4%-59.6%) and 23.7% (95% CI, 13.4%-34.1%), respectively.

The median PFS with the CAR T-cell therapy was 14.8 months (95% CI, 6.6-NR) compared with 5.7 months (95% CI, 3.9-9.4) with SOC (HR, 0.406; 95% CI, o.250-0.659; P = .0001). The PFS rates at 6 months in the investigative and control arms were 69.4% (95% CI, 58.1%-80.6%) and 47.8% (95% CI, 35.0%-60.6%), respectively; the 12-month rates were 52.3% (95% CI, 36.7%-67.9%) and 33.9% (95% CI, 20.1%-47.7%), respectively.

The CAR T-cell therapy induced a CR rate of 66% (95% CI, 55.7%-75.8%) compared with 39% (95% CI, 29.1%-49.9%) with SOC (P < .0001). Liso-cel produced an objective response rate (ORR) of 86% (95% CI, 77.0%-92.3%) vs 48% (95% CI, 27.3%-58.5%) with SOC.

Although OS data were immature at the time of data cutoff, a numerical trend favoring liso-cel was noted. The median OS in the CAR T-cell therapy had not yet been reached (95% CI, 15.8-NR) compared with 16.4 months (95% CI, 11.0-NR) with SOC (HR, 0.509; 95% CI, 0.258-1.004; P = .0257). At 6 months, the estimated OS rates 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. At 12 months, the estimated OS rate was 79.1% (95% CI, 67.1%-91.1%) with liso-cel vs 64.2% (95% CI, 50.5%-77.9%) with SOC.

Regarding safety, the treatment-emergent adverse effects (TEAEs) that were most experienced with liso-cel included neutropenia (82%), anemia (63%), and thrombocytopenia (58%). Grade 3 or higher TEAEs experienced by those who received CAR T-cell therapy included neutropenia (80%), anemia (49%), thrombocytopenia (49%), and lymphopenia (25%). Any-grade serious TEAEs were experienced in 48% of those in both treatment arms.

Forty-nine percent of patients experienced any-grade cytokine release syndrome. The median time to onset was 5 days (range, 1-63), and the median time to resolution was 4 days (range, 1-16). Twelve percent of patients had any-grade neurological events, with a median time to onset of 11 days (range, 7-25) and a median time to resolution of 6 days (range, 1-30).

In February 2022, the FDA granted a priority review to a supplemental biologics license application seeking the approval of liso-cel for the treatment of adult patients with relapsed or refractory LBCL in whom frontline threapy has failed.³

References

1. Japan’s Ministry of Health, Labour and Welfare accepts Bristol Myers Squibb’s application for Breyanzi (lisocabtagene maraleucel) as a second-line therapy for relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb; March 25, 2022. Accessed March 25, 2022. https://bit.ly/3IARReR
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
3. 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 March 25, 2022. https://bit.ly/3Bujynp