Background <p>This phase II clinical trial evaluated the R2-GemOx-PD1i regimen, a combination of penpulimab (a modified PD1 inhibitor) with lenalidomide and rituximab, gemcitabine, and oxaliplatin, in treating refractory or relapsed (R/R) diffuse large B-cell lymphoma (DLBCL).</p> Methods <p>Patients received an induction treatment of up to six cycles of R2-GemOx-PD-1i at standard doses every 2&#xa0;weeks, followed by pembrolizumab and lenalidomide as maintenance or autologous stem cell transplantation (ASCT) as consolidation. The primary objective was to evaluate the complete response rate (CRR) after the induction phase.</p> Results <p>Fifty-four patients were included, including subgroups treated without intent for consolidation with ASCT (<i>N</i> = 38) and those utilizing R2-GemOx-PD1i as a bridge to ASCT (<i>N</i> = 16). The overall response rate (ORR) for all patients was 66.7%, with a CRR of 57.4%. The median progression-free survival (PFS) was 30.4&#xa0;months, and the median overall survival (OS) was not reached for all patients. Patients receiving R2-GemOx-PD1i without intent for ASCT had ORR and CRR of 63.2% and 52.6%, respectively, with median PFS and OS of 21.2&#xa0;months and not reached, respectively. Patients receiving R2-GemOx-PD1i as a bridge to ASCT had ORR and CRR of 75.0% and 68.8%, respectively, with median PFS and OS of both not reached, respectively. The most frequent treatment-related adverse events were neutropenia (36, 66.6%) and anemia (32, 59.2%). Hypothyroidism was the most common immune-related adverse event (20 [37.0%]).</p> Conclusion <p>The R2-GemOx-PD1i regimen demonstrated encouraging antitumor activity with manageable toxicity in R/R DLBCL, providing some reassurance about its safety and tolerability.</p> Trial registration <p>ClinicalTrials.gov, NCT05186558 (Dec 23, 2021).</p>