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Increased Efficacy of Pembrolizumab or Pembrolizumab-Chemotherapy with Increasing PD-L1 Expression in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Subgroup analysis by PD-L1 combined positive score in KEYNOTE-048 study
11 Apr 2022
Cancer Immunology and Immunotherapy;  Head and neck cancers

In a post hoc analysis of efficacy in KEYNOTE-048 study conducted among patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab and pembrolizumab-chemotherapy demonstrated antitumour activity, with pembrolizumab-chemotherapy leading to numerically longer overall survival (OS) than cetuximab-chemotherapy in subgroup with PD-L1 combined positive score (CPS) 1-19. In the PD-L1 CPS <1 subgroup, neither pembrolizumab nor pembrolizumab-chemotherapy demonstrated improvement in OS compared with cetuximab-chemotherapy. These results support previous findings and demonstrate increased efficacy for pembrolizumab or pembrolizumab-chemotherapy with increasing PD-L1 expression according to Dr Barbara Burtness of the Yale University School of Medicine and Yale Cancer Center in New Haven, CT, US and colleagues who published the findings on 25 March 2022 in the Journal of Clinical Oncology.

The phase III KEYNOTE-048 study investigated pembrolizumab monotherapy or pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy in patients with previously untreated recurrent or metastatic HNSCC. Efficacy was assessed in PD-L1 CPS ≥20, CPS ≥1, and total populations. Pembrolizumab monotherapy significantly improved OS in the PD-L1 CPS ≥20 and CPS ≥1 populations and led to noninferior OS in the total population, with favourable safety versus cetuximab-chemotherapy. Pembrolizumab-chemotherapy significantly improved OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations compared with cetuximab-chemotherapy and demonstrated comparable safety. This study established first-line pembrolizumab monotherapy or pembrolizumab-chemotherapy as the standard of care for most patients with recurrent or metastatic HNSCC.

KEYNOTE-048 included planned efficacy analyses in the total population and in participants with PD-L1 CPS ≥1 and CPS ≥20. To further characterise the predictive value of PD-L1 expression on outcome, the study team conducted efficacy analyses in the PD-L1 CPS <1 and CPS 1-19 subgroups.

Participants with recurrent or metastatic HNSCC and no prior systemic therapy for recurrent or metastatic disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS <1 and CPS 1-19 subgroups were performed.

Of 882 participants enrolled, 128 had PD-L1 CPS <1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median OS was 7.9 versus 11.3 months in the PD-L1 CPS <1 subgroup (hazard ratio [HR] 1.51, 95% confidence interval [CI] 0.96 to 2.37) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR 0.86, 95% CI 0.66 to 1.12). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median OS was 11.3 versus 10.7 months in the PD-L1 CPS <1 subgroup (HR 1.21, 95% CI 0.76 to 1.94) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR 0.71, 95% CI 0.54 to 0.94).

The authors concluded that increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. However, PD-L1 CPS <1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥1 tumours. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for informing treatment decisions in low PD-L1–expressing recurrent or metastatic HNSCC.

Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ.


Burtness B, Rischin D, Greil R, et al. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. JCO; Published online 25 March 2022. DOI:10.1200/JCO.21.02198

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