342TiP Phase 3 trial of pembrolizumab as a first-line treatment in subjects with recurrent/metastatic head and neck squamous cell carcinoma: KEYNOTE-048

Abstract

Background: Cetuximab plus platinum and 5-fluorouracil (5-FU) is the only combination regimen recommended by current guidelines as the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Given the regimen's toxicities, there is unmet medical need in this area. Colocalization of T cells expressing programmed death-1 (PD-1) receptor and tumor cells expressing its ligands, PD-L1 and PD-L2, facilitates immune evasion in HNSCC. Pembrolizumab is a potent and highly selective humanized monoclonal antibody that directly blocks the interaction of PD-1 and each of its ligands; preliminary data from the KEYNOTE-012 trial suggest that durable response is demonstrated by pembrolizumab for R/M HNSCC patients. Trial design: This is a randomized, active-controlled, open-label, phase 3 trial to determine the efficacy and safety of pembrolizumab as monotherapy or in combination with chemotherapy relative to standard of care in patients with first-line R/M HNSCC (ClinicalTrials.gov, NCT02358031). Key inclusion criteria were confirmed R/M HNSCC considered incurable by local therapies, no prior systemic therapy in the R/M setting, ECOG 0 or 1, and tumor biopsy tissue for PD-L1 biomarker analysis. Approximately 780 patients will be enrolled and randomly assigned 1:1:1 to (i) pembrolizumab, (ii) pembrolizumab + platinum + 5-FU, or (iii) cetuximab + platinum + 5-FU. Pembrolizumab, 5-FU, and cetuximab will be administered at doses of 200 mg every 3 weeks (Q3W), 1000 mg/m2/day over 4 days Q3W, and 400 mg/m2 (initial load) then 250 mg/m2 every week, respectively; platinum therapy will comprise cisplatin 100 mg/m2 Q3W or carboplatin AUC 5 mg/mL/min Q3W. Patients will be stratified according to PD-L1 expression status, ECOG PS, and HPV status. The primary endpoint is progression-free survival per RECIST 1.1 as assessed by central radiologist review. Secondary endpoints were overall survival, proportion progression free at 6 and 12 months, overall response rate, and response duration. Relative pharmacokinetics and safety/tolerability profile of pembrolizumab alone or in combination with chemotherapy will also be evaluated.