Research in context
Evidence before this study
We searched PubMed on May 28, 2019, using the search terms “PD-1” OR “PD-L1” OR (“MK-3475” OR “pembrolizumab” OR “Keytruda”) OR (“BMS-936558” OR “nivolumab” OR “Opdivo”) OR (“MPDL3280A” OR “atezolizumab” OR “Tecentriq”) OR (“MEDI4736” OR “durvalumab” OR “Imfinzi”) OR (“MSB0010718C” OR “avelumab” OR “Bavencio”) OR (“cetuximab” OR “Erbitux” AND “chemotherapy”) AND “recurrent” OR “metastatic” AND “locally incurable” AND “first line” OR “previously untreated” AND “head and neck squamous cell carcinoma” OR “HNSCC” OR “SCCHN”. There were no limits applied to the search. We also searched the abstracts of the 2017, 2018, and 2019 American Association for Cancer Research Annual Meeting, American Society of Clinical Oncology Annual Meeting, and European Society for Medical Oncology Congress using the same search terms to identify results of any clinical trials that were not yet published in the peer-reviewed literature. We identified a subgroup analysis of the phase 3 CheckMate 141 study of nivolumab versus investigator's choice of therapy for platinum-refractory recurrent or metastatic HNSCC which showed that nivolumab was associated with an overall survival benefit in participants whose disease progressed within 6 months of platinum-based therapy given for locally advanced disease. We did not focus on this report because our study excluded patients whose disease progressed within 6 months of curatively intended systemic therapy given as a component of locoregionally advanced disease management. We also identified several studies of cetuximab given in combination with various chemotherapy regimens and a phase 3 study of bevacizumab plus platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone. We focused on the phase 3 EXTREME study that showed an overall survival benefit for cetuximab in combination with a platinum and 5-fluorouracil because this regimen is the standard for first-line treatment of recurrent or metastatic HNSCC. This regimen was used as the control group in several other studies, including the phase 2 ADVANTAGE study of cilengitide plus cetuximab, a platinum, and 5-fluorouracil, the phase 2 Active8 study of motolimod plus cetuximab, cisplatin, and 5-fluorouracil, and the phase 2 TPExtreme study of cetuximab plus cisplatin and docetaxel.
Added value of this study
The randomised, open-label, phase 3 KEYNOTE-048 study of pembrolizumab given alone or in combination with a chemotherapy regimen of platinum and 5-fluorouracil establishes anti-programmed cell death 1 (PD-1)-based therapy as a first-line treatment option for patients with locally incurable recurrent or metastatic HNSCC. Pembrolizumab monotherapy was associated with a significant overall survival benefit in participants with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 20 or more or 1 or more and had non-inferior overall survival in the total study population compared with standard-of-care therapy with cetuximab, a platinum, and 5-flurouracil. Pembrolizumab given with a platinum and 5-fluorouracil significantly improved overall survival in the PD-L1 CPS of 20 or more population, PD-L1 CPS of 1 or more population, and total population compared with cetuximab, a platinum, and 5-fluorouracil. Compared with standard therapy, the incidence of adverse events of any grade and of grade 3 or worse was lower with pembrolizumab monotherapy and similar with pembrolizumab plus chemotherapy.
Implications of all the available evidence
Our findings of a significant survival benefit for pembrolizumab monotherapy in participants with PD-L1 CPS of 20 or more and of 1 or more and a favourable safety profile relative to standard-of-care therapy suggest that pembrolizumab monotherapy is a new treatment option for patients with PD-L1-positive recurrent or metastatic HNSCC. Our findings of a significant survival benefit for pembrolizumab combined with a platinum and 5-fluorouracil in the total and PD-L1-positive populations along with a manageable safety profile compared with standard therapy suggest that pembrolizumab plus chemotherapy is a new standard-of-care treatment for patients with recurrent or metastatic HNSCC.