ABSTRACT Although programmed cell death 1 inhibitors (PD1i) are recommended in guidelines for relapsed/refractory extranodal NK/T‐cell lymphoma (ENKTL), their role in frontline therapy remains unclear. In this retrospective, multi‐center study of 755 newly diagnosed ENKTL patients, 17.9% received first‐line PD1i. Despite harboring more adverse risk features, the PD1i group showed significantly improved progression‐free survival (hazard ratio = 0.62, p = 0.007) and overall survival (hazard ratio = 0.55, p = 0.027) after a median follow‐up of 32.9 months. The benefit was also observed in key subgroups (non‐upper aerodigestive tract, advanced stage, intermediate/high‐risk). Conventional multivariate Cox regression before propensity score matching, robust multivariate Cox analysis after matching, and the time‐varying Cox model employed in landmark analysis consistently demonstrated that PD1i therapy served as an independent favorable prognostic factor for both progression‐free survival and overall survival. The random forest algorithm revealed enhanced efficacy with PD1i‐asparaginase combination therapy, showing about a 50% reduction in event probability, particularly in advanced‐stage and intermediate/high‐risk patients. Multi‐state survival modeling indicated PD1i primarily delays disease progression rather than post‐progression survival. Safety data showed that adding PD1i to asparaginase‐based chemotherapy resulted in an expected increase in hematologic toxicities, but with a reduced risk of severe/fatal infections and rare severe immune‐related adverse events, demonstrating a favorable risk–benefit profile. Overall, in this study, frontline PD1i, particularly in combination with asparaginase, yielded significantly improved outcomes and demonstrated a manageable safety profile in intermediate‐/high‐risk and advanced ENKTL. This evidence supports its incorporation into first‐line treatment and underscores the need for prospective randomized trials.
Liu et al. (Sun,) studied this question.