Tahara M.Greil R.Rischin D.Harrington K.J.Burtness B.de Castro G.Psyrri A.Braña I.Neupane P.Bratland Å.Fuereder T.Hughes B.G.M.Mesía R.Ngamphaiboon N.Rordorf T.Ishak W.Z.W.Lin J.Gumuscu B.Lerman N.Soulières D.Mahidol University2025-04-282025-04-282025-05-15European Journal of Cancer Vol.221 (2025)09598049https://repository.li.mahidol.ac.th/handle/123456789/109806Background: Pembrolizumab monotherapy and pembrolizumab-chemotherapy demonstrated superior overall survival (OS) versus cetuximab-chemotherapy (EXTREME) in the primary analysis of the phase III KEYNOTE-048 study of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the first-line setting. We report updated data with 5 years of follow-up. Methods: Adults with previously untreated R/M HNSCC incurable by local therapy were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab plus chemotherapy, or EXTREME. The primary endpoints were OS and progression-free survival (PFS). Results: Overall, 882 participants were assigned to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Median study follow-up was 69.2 months (pembrolizumab) and 68.6 months (pembrolizumab-chemotherapy). Median OS remained longer for pembrolizumab versus EXTREME in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20 (HR, 0.61; 95 % CI, 0.46–0.81) and CPS ≥ 1 populations (HR, 0.74; 95 % CI, 0.61–0.89), and similar in the total population (HR, 0.82; 95 % CI, 0.69–0.97). Pembrolizumab-chemotherapy prolonged median OS in the PD-L1 CPS ≥ 20 (HR, 0.63; 95 % CI, 0.47–0.84), CPS ≥ 1 (HR, 0.65; 95 % CI, 0.53–0.79), and total (HR, 0.72; 95 % CI, 0.60–0.86) populations. The 5-year OS rate in the total population was 14.4 % for pembrolizumab versus 6.5 % for EXTREME and 16.0 % for pembrolizumab-chemotherapy versus 5.2 % for EXTREME. There was no clinically meaningful difference in PFS among pembrolizumab, pembrolizumab-chemotherapy, or EXTREME groups in any populations. Conclusions: These 5-year follow-up results support the use of pembrolizumab and pembrolizumab-chemotherapy as first-line standards of care for R/M HNSCC. Clinical Trial Information: NCT02358031. Prior Presentation: Presented at the European Society for Medical Oncology Congress, September 9–13, 2022.Biochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1016/j.ejca.2025.1153952-s2.0-10500285689218790852