KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC)

Date 22 October 2018
Event ESMO 2018 Congress
Session Presidential Symposium 3
Topics Immunotherapy
Head and Neck Cancers
Presenter Barbara Burtness
Authors B. Burtness1, K.J. Harrington2, R. Greil3, D. Soulières4, M. Tahara5, G. De Castro Jr.6, A. Psyrri7, N. Baste Rotllan8, P.C. Neupane9, Å. Bratland10, T. Fuereder11, B.G.M. Hughes12, R. Mesia13, N. Ngamphaiboon14, T. Rordorf15, W.Z. Wan Ishak16, A. Roy17, J. Cheng18, F. Jin19, D. Rischin20
  • 1Internal Medicine, Yale University School of Medicine, 06517 - New Haven/US
  • 2Targeted Therapy, The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre, London/GB
  • 3Iiird Medical Department, Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Paracelsus Medical University Salzburg, 5020 - Salzburg/AT
  • 4Department Of Medicine - Department Of Hemato-oncology, Centre Hospitalier de l’Université de Montréal, Montréal/CA
  • 5Head And Neck Medical Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 6Clinical Oncology, ICESP - Instituto do Câncer do Estado de São Paulo, 01426-030 - Sao Paulo/BR
  • 7Internal Medicine/medical Oncology, Attikon University Hospital, 12462 - Athens/GR
  • 8Department Of Head And Neck Surgical & Medical Oncology, Gustave Roussy Institute, 94800 - Villejuif/FR
  • 9Medicine/oncology, University of Kansas Medical Center, Kansas City/US
  • 10Oncology, Oslo University Hospital, 0379 - Oslo/NO
  • 11Dep. Of Medicine I, Clinical Div. Of Oncology & Comprehensive Cancer Center, Medizinische Universitaet Wien (Medical University of Vienna), 1090 - Vienna/AT
  • 12Cancer Care Services, Royal Brisbane and Women's Hospital and University of Queensland, 4006 - Brisbane/AU
  • 13Servicio De Oncologia Medica, Catalan Institut of Oncology, Hospitalet de Llobregat, Barcelona/ES
  • 14Medicine, Ramathibodi Hospital, Mahidol University, 10400 - Bangkok/TH
  • 15Oncology, University Hospital Zürich, 8091 - Zurich/CH
  • 16Clinical Oncology Unit, University Malaya, Kuala Lumpur/MY
  • 17Bards, Merck & Co., Inc., Kenilworth/US
  • 18Mrl, Merck & Co., Inc., 07033 - Kenilworth/US
  • 19Mrl, Merck & Co., Inc., Kenilworth/US
  • 20Medical Oncology, Peter MacCallum Cancer Center, 3002 - Melbourne/AU



KEYNOTE-048 was an open-label, randomized phase 3 study of P or P + chemotherapy (C) vs EXTREME (E) as first-line systemic therapy for R/M HNSCC (NCT02358031).


Patients (pts) with R/M HNSCC not curable by local therapy and with no prior systemic therapy (R/M setting) who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W, P + C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + C) given until PD, unacceptable toxicity, 6 cycles (C), or 24 mo (P). Primary end points for P vs E and P + C vs E were PFS and OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 and total populations (pop). Cutoff date for this final PFS/interim OS analysis was Jun 13, 2018 (minimum follow-up, ~17 mo).


882 pts were randomized: 301 to P, 281 to P + C, 300 to E. P was superior to E for OS in CPS ≥20 (N = 255; median 14.9 vs 10.7 mo; HR 0.61 [95% CI 0.45-0.83]; P = 0.0007) and ≥1 (N = 512; median 12.3 vs 10.3 mo; HR 0.78 [95% CI 0.64-0.96]; P = 0.0086); OS for P was non-inferior to E in the total pop (N = 601). P did not prolong PFS in CPS ≥20 (P = 0.5); per the analysis plan, no further PFS testing was done for P vs E. Confirmed ORR (P vs E) was 23% vs 36% for CPS ≥20, 19% vs 35% for CPS ≥1, and 17% vs 36% for the total pop; median DOR was 20.9 vs 4.2 mo, 20.9 vs 4.5 mo, and 20.9 vs 4.5 mo. Gr 3-5 drug-related AE rates were 17% (P) vs 69% (E). P + C was non-inferior and superior to E for OS in the total pop (N = 559; median 13.0 vs 10.7 mo; HR 0.77 [95% CI 0.63-0.93]; P = 0.0034); OS for P + C was not significantly superior to E in CPS ≥20 and ≥1 at this interim analysis. PFS was not prolonged with P + C (P = 0.2). For P + C vs E, confirmed ORR was 36% vs 36%, median DOR was 6.7 vs 4.3 mo, and gr 3-5 drug-related AE rates were 71% vs 69%.


For first-line R/M HNSCC, P significantly improved OS over E in the PD-L1 CPS ≥20 and ≥1 populations and was noninferior in the total population with favorable safety. P + C significantly improved OS in the total population with safety comparable to E. P and P + C responses were durable. These data support pembrolizumab and pembrolizumab + platinum + 5-FU as new first-line standards of care for R/M HNSCC. The study continues to the final OS analysis.

Clinical trial identification

NCT02358031: Trial initiation, February 6, 2015

Editorial Acknowledgement

Medical writing and editorial assistance was provided by Melanie Leiby, an employee of Merck & Co., Inc., Kenilworth, NJ, USA.