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

Author(s): Barbara Burtness, MD1; Danny Rischin, MBBS, FRACP, MD2; Richard Greil, MD3; Denis Soulières, MD, MSc, FRCPC4; Makoto Tahara, MD, PhD5; Gilberto de Castro Jr, MD, PhD6; Amanda Psyrri, MD, PhD7; Irene Brana, MD, PhD8; Neus Basté, MD8; Prakash Neupane, MD9; Åse Bratland, MD, PhD10; Thorsten Fuereder, MD11; Brett G.M. Hughes, BSc, MBBS12; Ricard Mesia, MD13; Nuttapong Ngamphaiboon, MD14; Tamara Rordorf, MD15; Wan Zamaniah Wan Ishak, MD16; Joy Ge, PhD17; Ramona F. Swaby, MD17; Burak Gumuscu, MD, PhD17; and Kevin Harrington, MBBS, PhD, FRCP, FRCR18
Source: DOI: 10.1200/JCO.21.02198 Journal of Clinical Oncology 40, no. 21 (July 20, 2022) 2321-2332.
Lucio Gordan MD

Again, further evidence of continued efficacy and tolerability of IO and IO/chemotherapy in SCCHN as compared to EGFR-blockade/chemotherapy. The PD-L1 negative space remains a more difficult scenario, hence new biomarkers are critically important. The long-term response and CR of a percentage of patients are real and intriguing (patient characteristics leading to such response).


The phase III KEYNOTE-048 ( identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048.


Participants with R/M HNSCC and no prior systemic therapy for R/M 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 overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% 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 overall survival 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]).


Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. 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 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1–expressing HNSCC.

Author Affiliations

1Yale University School of Medicine and Yale Cancer Center, New Haven, CT 2Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Australia 3Paracelsus Medical University, Salzburg Cancer Research Institute, and Cancer Cluster Salzburg, Salzburg, Austria 4Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada 5National Cancer Center Hospital East, Kashiwa, Japan 6Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil 7National Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece 8Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain 9University of Kansas Medical Center, Kansas City, KS 10Oslo University Hospital, Oslo, Norway 11Medical University of Vienna, Vienna, Austria 12Royal Brisbane and Women’s Hospital and University of Queensland, Brisbane, Queensland, Australia 13Catalan Institute of Oncology, Badalona, Barcelona, Spain 14Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 15University Hospital, Zurich, Switzerland 16Clinical Oncology Unit, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 17Merck & Co Inc, Kenilworth, NJ 18The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, National Institute for Health Research Biomedical Research Centre, London, United Kingdom

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