As reported in The Lancet by Manali Kamdar, MD, of the University of Colorado Cancer Center, Aurora, and colleagues, an interim analysis of the phase III TRANSFORM trial has shown significantly improved event-free survival with second-line lisocabtagene maraleucel vs standard-of-care salvage immunochemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with relapsed or refractory large B-cell lymphoma (LBCL).1
Manali Kamdar, MD
The trial supported the June 2022 approval of the chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel in the second-line setting. The therapy was approved for third- or later-line treatment of relapsed or refractory LBCL in February 2021.
In the open-label trial, 184 patients with primary refractory or early (≤ 12 months) relapsed LBCL from sites in the United States, Europe, and Japan were randomly assigned between October 2018 and December 2020 to receive lisocabtagene maraleucel in two sequential infusions of CD8-positive and CD4-positive CAR-positive T cells at a total target dose of 100 × 106 CAR-positive T cells (n = 92) or standard-of-care treatment (n = 92). Standard of care consisted of investigator’s choice of three cycles of salvage immunochemotherapy with:
Randomization was stratified by response to first-line therapy (relapsed vs refractory) and secondary age-adjusted International Prognostic Index (IPI; 0–1 vs 2–3). Patients in the standard-of-care group were allowed to cross over to receive lisocabtagene maraleucel as third-line treatment if a complete or partial response was not achieved after three cycles of immunochemotherapy, for progressive disease at any time, or if there was a need to start a new antineoplastic therapy due to absence of a complete response after 18 weeks postrandomization. The primary endpoint was event-free survival on independent review committee assessment in the intention-to-treat population.
Among the patients given lisocabtagene maraleucel, 89 received lisocabtagene maraleucel and 1 received a nonconforming product. In the standard-of-care group, 91 patients started standard-of-care treatment, 43 received high-dose chemotherapy, and 42 underwent autologous HSCT. The overall response rate was 86% vs 48%, with a complete response in 66% vs 39% (P < .0001).
At data cutoff for the interim analysis (March 2021), median follow-up was 6.2 months (interquartile range = 4.4–11.5 months). Median event-free survival was 10.1 months (95% confidence interval [CI] = 6.1 months to not reached) in the lisocabtagene maraleucel group vs 2.3 months (95% CI = 2.2–4.3 months) in the standard-of-care group (stratified hazard ratio [HR] = 0.35, 95% CI = 0.23–0.53, P < .0001). Rates at 6 and 12 months were 63.3% vs 33.4% and 44.5% vs 23.7%. Hazard ratios in stratification subgroups were 0.35 (95% CI = 0.22–0.55) among 67 vs 68 patients refractory to first-line treatment and 0.34 (95% CI = 0.12–1.00) among 25 vs 24 patients with relapse, and 0.30 (95% CI = 0.16–0.55) among 56 vs 55 patients with a secondary age-adjusted IPI of 0 to 1 and 0.40 (95% CI = 0.23–0.72) among 36 vs 37 patients with a secondary age-adjusted IPI of 2 to 3.
Median progression-free survival was 14.8 months (95% CI = 6.6 months to not reached) in the lisocabtagene maraleucel group vs 5.7 months (95% CI = 3.9–9.4 months) in the standard-of-care group (stratified HR = 0.41, 95% CI = 0.25–0.66, P = .0001), with 6- and 12-month rates of 69.4% vs 47.8% and 52.3% vs 33.9%. A total of 46 patients in the standard-of-care group crossed over to receive lisocabtagene maraleucel, primarily during immunochemotherapy; the most common reason for crossover was disease progression, followed by suboptimal response and relapse. Median overall survival was not reached (15.8 months to not reached) in the lisocabtagene maraleucel group vs 16.4 months (95% CI = 11.0 months to not reached) in the standard-of-care group (stratified HR = 0.51, 95% CI = 0.26–1.00, P = .026), with 6- and 12-month rates of 91.8% vs 89.4% and 79.1% vs 64.2%. In an analysis adjusting for crossover, the stratified hazard ratio for overall survival was 0.32 (95% CI = 0.16–0.64) using a two-stage estimator model.
Grade ≥ 3 adverse events occurred in 92% of the lisocabtagene maraleucel group vs 87% of the standard-of-care group, the most common in the lisocabtagene maraleucel group being neutropenia (80% vs 51%), anemia (49% vs 49%), thrombocytopenia (49% vs 64%), and prolonged cytopenia (43% vs 3%). In the lisocabtagene maraleucel group, grade 3 cytokine-release syndrome occurred in one patient (1%), and grade 3 neurologic toxicity occurred in four patients (4%), with no grade 4 or 5 events reported. Serious adverse events occurred in 48% of patients in each group; the most common in the lisocabtagene maraleucel group were cytokine-release syndrome (13%), febrile neutropenia (8%), and pyrexia (7%). Adverse events led to death in one patient in the lisocabtagene maraleucel group and five patients in the standard-of-care group; one death in the standard-of-care group, due to sepsis, was considered related to treatment.
The investigators concluded: “These results support [lisocabtagene maraleucel] as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL.”
DISCLOSURE: The study was funded by Celgene. Dr. Kamdar has served as a consultant to ADC Therapeutics, Celgene, Adaptive Biotechnologies, AbbVie, AstraZeneca, and BeiGene; and has received speakers bureau fees from Seagen and research funding from TG Therapeutics, Genentech, and Novartis.
1. Kamdar M, Solomon SR, Arnason J, et al: Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet 399:2294-2308, 2022.