Durability Benchmarking of Contemporary Second-Line and Later Therapies for Relapsed or Refractory Follicular...

Background Patients with relapsed or refractory (R/R) follicular lymphoma (FL) after two or more prior lines of therapy can now be treated with mechanistically distinct modalities, including CD19-directed chimeric antigen receptor (CAR) T-cell therapy, CD20×CD3 bispecific antibodies, and a Bruton tyrosine kinase inhibitor plus anti-CD20 combination. Head-to-head data are lacking, and sequencing decisions are made with limited comparative evidence. We benchmarked durability outcomes across pivotal trials using reconstructed individual patient data (rIPD) derived from published Kaplan-Meier (KM) curves. Methods KM curves and numbers-at-risk tables from pivotal prospective studies in ≥2-line R/R FL were digitized and rIPD-reconstructed using a validated algorithm: axicabtagene ciloleucel (ZUMA-5), tisagenlecleucel (ELARA), lisocabtagene maraleucel (TRANSCEND FL), mosunetuzumab, epcoritamab (EPCORE NHL-1), and zanubrutinib plus obinutuzumab versus obinutuzumab (ROSEWOOD). Prespecified durability endpoints were landmark progression-free survival (PFS) at 12 and 24 months and restricted mean survival time to 24 months (RMST24). Overall survival (OS) landmarks were summarized where follow-up permitted. ROSEWOOD served as an internal validity check using a Cox model fit to reconstructed data. Results At 24 months, landmark PFS was 65.4% (95% confidence interval (CI) 52.0-82.4) for liso-cel, 62.0% (50.2-76.6) for axi-cel, 53.8% (45.2-63.9) for zanubrutinib plus obinutuzumab, 49.3% (39.3-61.7) for mosunetuzumab, 43.7% (31.3-61.1) for epcoritamab, and 24.7% (14.9-40.9) for obinutuzumab monotherapy. Twelve-month PFS ranged from 81.8% (74.5-89.8) with liso-cel and 77.9% (69.4-87.5) with axi-cel to 61.6% (53.6-70.8), 60.4% (50.8-72.0), and 59.1% (50.5-69.1) for zanubrutinib plus obinutuzumab, mosunetuzumab, and epcoritamab, respectively; tisagenlecleucel showed 12-month PFS of 68.3% (57.2-81.6) with shorter follow-up (maximum 18.2 months). PFS RMST24 estimates were 19.5 months for liso-cel, 18.6 for axi-cel, 16.5 for zanubrutinib plus obinutuzumab, 16.2 for mosunetuzumab, 14.8 for epcoritamab, and 11.9 for obinutuzumab. OS at 24 months was high across regimens (mosunetuzumab 87.3%, liso-cel 84.6%, axi-cel 82.8%, zanubrutinib plus obinutuzumab 77.3%, and epcoritamab 67.6%). In ROSEWOOD, reconstructed data reproduced the published PFS benefit for zanubrutinib plus obinutuzumab (hazard ratio (HR) 0.48, 95% CI 0.32-0.71; p < 0.001) with a weaker OS signal (HR 0.61, 0.35-1.07; p = 0.08). Conclusions In this rIPD-based durability benchmark for ≥2-line R/R FL, the estimated landmark PFS and RMST24 values varied across regimens, with numerically higher point estimates for the CAR T-cell therapies and the zanubrutinib plus obinutuzumab combination and numerically lower estimates for the bispecific antibodies and the obinutuzumab control; CIs overlapped substantially, and 24-month OS estimates were broadly similar across regimens. Because the source trials enrolled materially different populations, these side-by-side estimates are descriptive benchmarks and should not be read as head-to-head comparisons of efficacy. Faithful internal reproduction of the randomized ROSEWOOD effect supports reconstruction fidelity. The analysis provides a transparent, durability-focused reference framework to support sequencing discussions and hypothesis generation, not comparative effectiveness conclusions.