Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study

Eur J Cancer. 2025 May 15:221:115395. doi: 10.1016/j.ejca.2025.115395. Epub 2025 Apr 4.

Abstract

Background: 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.

Keywords: Chemotherapy; Pembrolizumab; Programmed cell death ligand 1; Recurrent/metastatic head and neck squamous cell carcinoma.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Agents, Immunological* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Cetuximab / administration & dosage
  • Female
  • Follow-Up Studies
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / mortality
  • Head and Neck Neoplasms* / pathology
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local* / drug therapy
  • Neoplasm Recurrence, Local* / pathology
  • Progression-Free Survival
  • Squamous Cell Carcinoma of Head and Neck* / drug therapy
  • Squamous Cell Carcinoma of Head and Neck* / mortality
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Squamous Cell Carcinoma of Head and Neck* / secondary

Substances

  • pembrolizumab
  • Antibodies, Monoclonal, Humanized
  • Cetuximab
  • Antineoplastic Agents, Immunological

Associated data

  • ClinicalTrials.gov/NCT02358031