European Medicines Agency Validates Type II Variation Application for Liso-cel in Second-line LBCL

The European Medicines Agency (EMA) has verified its type II variation application to extend the indication for lisocabtagene maraleucel (liso-cel; Breyanzi) to include the treatment of adult patients with diffuse large B-cell lymphoma, high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (LBCL), and grade 3B follicular lymphoma, who are refractory or have relapsed within 12 months of initial therapy and are candidates for hematopoietic stem cell transplant (HSCT).¹

The application, which will now undergo the EMA’s centralized review process, is based on findings from the pivotal phase 3 TRANSFORM trial (NCT03575351), in which liso-cel led to a significant improvement in event-free survival (EFS), complete response (CR) rates, and progression-free survival (PFS) compared with standard platinum-based salvage chemotherapy followed by high-dose chemotherapy and HSCT in this population. 

At a median follow-up of 6.2 months (range, 0.9-20.0) in both treatment arms, the median EFS was 10.1 months (95% CI, 6.1–not reached [NR]) with liso-cel (n = 92) vs 2.3 months (95% CI, 2.2-4.3) with standard-of-care (SOC) therapy (n = 92; HR, 0.349; 95% CI, 0.229-0.530; P < .0001).² The 6-month EFS rates were 63.3% (95% CI, 52.0%-74.7%) and 33.4% (95% CI, 23.0%-43.8%), respectively. The 12-month EFS rates were 44.5% (95% CI, 29.4%-59.6%) and 23.7% (95% CI, 13.4%-34.1%), respectively.

“Rates of relapsed or refractory LBCL after first-line therapy are very high and few patients are able to benefit from stem cell transplant, which has been the second-line standard of care for nearly 30 years,” Anne Kerber, senior vice president of Cell Therapy Development at Bristol Myers Squibb, stated in a news release. “We look forward to working with the EMA with the goal of establishing [liso-cel] as a new second-line standard of care for people living with relapsed or refractory LBCL and, ultimately, bringing the curative potential of cell therapy to more patients.”

On February 17, 2022, the FDA accepted and granted 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 therapy has failed.³

The global, randomized, multicenter TRANSFORM trial enrolled patients with LBCL that was primary refractory or relapsed within 12 months following frontline therapy containing a CD20-antibody and anthracycline.

Patients were randomized to receive liso-cel or standard-of-care salvage therapy, including rituximab (Rituxan) plus dexamethasone, high-dose cytarabine, and cisplatin, rituximab plus ifosfamide, carboplatin and etoposide, or rituximab plus gemcitabine, dexamethasone, and cisplatin per investigators’ choice before proceeding to high-dose chemotherapy and HSCT.

The primary end point of the study was EFS, which was defined as time from randomization to death from any cause, progressive disease, failure to achieve CR or partial response, or start of new antineoplastic therapy due to efficacy concerns. CR rate served as a key secondary end point. Other efficacy end points included PFS, overall survival (OS), overall response rate (ORR) and duration of response.

Additional results demonstrated a median PFS of 14.8 months (95% CI, 6.6-NR) with liso-cel vs 5.7 months (95% CI, 3.9-9.4) with SOC (HR, 0.406; 95% CI, 0.250-0.659; P = .0001). The 6-month PFS rates were 69.4% (95% CI, 58.1%-80.6%) and 47.8% (95% CI, 35.0%-60.6%), respectively. 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, the CR rate was 66% (95% CI, 55.7%-75.8%) with liso-cel vs 39% (95% CI, 29.1%-49.9%) with SOC (P < .0001). The ORRs were 86% (95% CI, 77.0%-92.3%) and 48% (95% CI, 27.3%-58.5%), respectively.

OS data were immature at the time of data cutoff. The median OS was not reached with liso-cel (95% CI, 15.8-NR) vs 16.4 months (95% CI, 11.0-NR) with SOC (HR, 0.509; 95% CI, 0.258-1.004; P = .0257). The estimated 6-month OS rates were 91.8% (95% CI, 85.4%-98.2%) and 89.4% (95% CI, 82.9%-96.0%), respectively. The estimated 12-month rates were 79.1% (95% CI, 67.1%-91.1%) and 64.2% (95% CI, 50.5%-77.9%), respectively.

Liso-cel also demonstrated comparable safety in the second-line setting consistent with its use in third- and later-line settings, with low rates of severe cytokine release syndrome (CRS) and neurologic events.

The most common treatment-emergent adverse effects (TEAEs) that occurred with liso-cel were neutropenia (82%), anemia (63%), and thrombocytopenia (58%). The rate of grade 3 or higher TEAEs was 92% with liso-cel vs 87% with SOC. The most common grade 3 or higher TEAEs experienced with liso-cel were neutropenia (80%), anemia (49%), thrombocytopenia (49%), and lymphopenia (25%). Any-grade serious TEAEs occurred in 48% of patients in both arms.

Forty-nine percent of patients treated with liso-cel experienced 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 neurologic events. The median time to onset was 11 days (range, 7-25), and the median time to resolution was 6 days (range, 1-30).

References

1. European Medicines Agency validates Bristol Myers Squibb’s application for CAR T Cell therapy Breyanzi in relapsed or refractory large B-cell lymphoma after first-line therapy. News release. Bristol Myers Squibb. June 20, 2022. Accessed June 20, 2022. https://bit.ly/3OmqSqu
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 June 20, 2022. https://bit.ly/3Bujynp