Two trials have shown that adding PD-1 blockade to standard chemoradiation improves outcomes for locoregionally advanced nasopharyngeal carcinoma. DIPPER gave adjuvant camrelizumab following CRT while CONTINUUM added sintilimab to neoadjuvant gem/cis and CRT. In this biomarker analysis, RNA sequencing from 407 patients across both trials (187 CONTINUUM as discovery, 220 DIPPER as validation) was used to define three metabolic subtypes of NPC and then build a machine learning classifier of immunotherapy benefit. Of these subtypes, MS1 (63% of patients) had intermediate metabolic activity with an immune-infiltrated but immunosuppressive microenvironment that derived a significant EFS benefit from anti-PD-1 therapy. In this group, 3-year EFS was 90.2% with PD-1 blockade vs 69.6% without in the CONTINUUM cohort and 92.5% vs 74.3% in the DIPPER cohort. MS2 (18%) featured fatty acid metabolism enrichment and mast cell infiltration with excellent prognosis regardless of immunotherapy (3-year EFS ~94% either way). MS3 (19%) was metabolically hyperactivated with an immune-desert phenotype driven by DNA hypermethylation and no benefit from immunotherapy. Notably, no baseline clinical feature (T category, N category, EBV-DNA, or PD-L1) predicted differential benefit. | Huang, J Clin Oncol 2026
