Lisocabtagene Maraleucel (liso-cel) Versus Standard of Care (SOC) with Salvage Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL): Primary Analysis of the Randomized, Phase 3 Transform Study

Background: Liso-cel is an autologous, CD19-directed, CAR T cell product administered at equal target doses of CD8⁺ and CD4⁺ CAR⁺ T cells. Results of a prespecified interim analysis of the TRANSFORM study (NCT03575351) demonstrated superior efficacy of liso-cel compared with the SOC of salvage immunochemotherapy (CT) followed by high-dose chemotherapy and ASCT in responders, as 2L treatment for patients (pts) with LBCL primary refractory to or relapsed within 12 months of first-line (1L) therapy (Kamdar et al. Lancet 2022). At the interim analysis, the primary endpoint of EFS and key secondary endpoints of CR rate and PFS met statistical significance in favor of liso-cel and OS data were immature. Here we report results from the primary analysis with a median follow-up of 17.5 months.

Methods: TRANSFORM is a global, randomized, multicenter, phase 3 study comparing efficacy and safety of liso-cel versus SOC (R-DHAP, R-ICE, or R-GDP followed by BEAM + ASCT) in adults (aged ≤ 75 years) with LBCL primary refractory to or relapsed ≤ 12 months after 1L therapy who were eligible for ASCT. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function. Pts in the liso-cel arm underwent lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 10⁶ CAR⁺ T cells. Bridging therapy with R-DHAP, R-ICE or R-GDP was allowed at investigator discretion. Pts in the SOC arm received 3 cycles of CT. Responding pts (CR or PR) proceeded to high-dose chemotherapy + ASCT. Crossover to receive liso-cel was allowed for pts in the SOC arm not achieving CR or PR after 3 cycles of CT, not in CR after ASCT, or demonstrating PD at any time.

The primary endpoint was event-free survival (EFS) based on independent review committee (IRC). Key secondary endpoints included IRC-assessed CR rate, PFS, and OS. The primary endpoint of EFS was met at the interim analysis and is updated here; thus, only the key secondary endpoints were retested at the primary analysis, as prespecified by the statistical analysis plan. The significance threshold to reject the null hypothesis for the key secondary endpoints was ≤ 0.021 (adjusted for the actual number of events available for analysis and the alpha spent at previous interim analyses). Median follow-up for the primary analysis was 17.5 months (range, 0.9‒37.0).

Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were as previously reported, 33% of pts were aged ≥ 65 y, 64% had DLBCL (55% not otherwise specified, 8% transformed from indolent lymphomas), 12.5% had double-hit lymphoma, and 73% were refractory (PD, stable disease, PR, or CR with relapse within 3 months) to 1L therapy. Median (95% CI) EFS was not reached (NR; 9.5–NR) for liso-cel versus 2.4 months (2.2–4.9) for SOC (Figure). CR rate and PFS met statistical significance; CR rate was 74% for liso-cel versus 43% for SOC (P < 0.0001) and median PFS (95% CI) was NR (12.6–NR) for liso-cel versus 6.2 months (4.3–8.6) for SOC (HR, 0.400; P < 0.0001) (Table). Of 26 pts with a PR at the interim analysis, the response deepened to CR for 9 pts at the primary analysis (6/18 in the liso-cel arm; 3/8 in the SOC arm). Of 91 pts treated in the SOC arm, 61 (67%) crossed over to receive liso-cel. At the primary analysis, 66 pts had died (28 in the liso-cel arm and 38 in the SOC arm, including 29 after crossover); the most frequent cause of death was disease progression. Median OS favored liso-cel versus SOC, although it did not meet statistical significance (NR versus 29.9 mo, respectively; HR, 0.724; P = 0.0987). Safety results were consistent with those reported in the interim analysis.

Conclusions: This primary analysis, with a median follow-up of 17.5 months, confirmed the clinical benefit of liso-cel over SOC. In TRANSFORM, liso-cel resulted in statistically significant and clinically meaningful improvements in EFS, CR rate, and PFS. These data reinforce liso-cel as a 2L treatment in pts with primary refractory or early relapsed LBCL.