Efficacy of tazemetostat in combination with R-CHOP in elderly patients newly diagnosed with diffuse large B cell lymphoma: results of the EpiRCHOP phase II study of the LYSA.

Background: In the phase I Epi-RCHOP study (NCT02889523), we reported that R-CHOP-tazemetostat was well tolerated with the recommended phase II dose, consistent with monotherapy. Methods: Phase II included newly diagnosed diffuse large B cell lymphoma patients aged 60-80 years who received six cycles of rituximab-CHOP (R-CHOP) with continuous tazemetostat (800 mg BID), plus two cycles of tazemetostat and rituximab (cycles 7 and 8), from July 31, 2020 to July 18, 2022. Primary endpoint was positron emission tomography complete metabolic response (CMR). Sample size was calculated with H0 of 70% and H1 assumption of 80%. Findings: The trial enrolled 122 patients: median age 70 (60-80), 90.2% with stage III-IV, and 73.8% with International Prognostic Index 3-5. Overall, 100 patients (82%) received eight cycles, while 22 had premature treatment discontinuation (PTD), including 12 during the first two cycles. Reasons for PTD were consent withdrawal (N = 10), adverse events (N = 6), death (N = 2), protocol deviation (N = 2), progressive disease (N = 1), and physician decision (N = 1). The median percentage of relative dose intensity of tazemetostat and R-CHOP exceeded 90%, but required a protocol amendment and reduction in vincristine dosage at 1 mg full dose. At the end of treatment or PTD, 92/122 patients (75.4%) achieved CMR, eight (6.6%) partial metabolic response, five (4.1%) progressive disease, two (1.6%) died (septic shock), and 15 (12.3%) were not evaluated. Sensitivity analysis, excluding ten non-evaluated patients who withdrew consent, showed CMR in 82.1%. After a median follow-up of 18.5 months (IQR: 15.4-21), estimated progression-free and overall survival at 18 months were 77.7% (95% CI: 67.5-85.1%) and 88.8% (95% CI: 79.9-93.9%), respectively. Interpretation: R-CHOP plus tazemetostat is feasible with a promising CMR in elderly DLBCL patients. Complementary biomarker studies are needed for a more personalized approach. Funding: This study was sponsored under a grant from Ipsen.