343TiP Pembrolizumab (MK-3475) versus standard treatment in patients with recurrent or metastatic head and neck cancer: Methodology of phase 3 randomized trial

Abstract

Background: Prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, with limited treatment options and survival rates following standard-of-care therapies. Pembrolizumab is a humanized IgG4 monoclonal antibody against PD-1 designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It has demonstrated clinical efficacy by investigator-assessed responses (including confirmed and unconfirmed responses) in a phase 1 study of R/M HNSCC. Additionally, preliminary PD-L1 biomarker data suggest that response rates may be greater in PD-L1–positive patients. Trial design: KEYNOTE-040 (NCT02252042) is a global, open-label, phase 3 trial of 600 subjects with R/M HNSCC for whom prior platinum therapy has failed. Patients will be randomly assigned (1:1) to pembrolizumab (200 mg Q3W) or investigator's choice standard of care (single-agent methotrexate, docetaxel, or cetuximab). Randomization will be stratified by ECOG PS (0 vs 1), human papillomavirus (HPV) status in oropharyngeal cancer by p16 immunohistochemistry testing (positive vs negative), and centralized PD-L1 status (≥50% positive vs not positive PD-L1). Pembrolizumab will be given for ≤24 months or until disease progression, unacceptable toxicity, or investigator decision. Imaging will occur per RECIST v1.1 at 9 weeks and then every 6 weeks thereafter, and AEs will be assessed by NCI CTCAE, v4.0. Modified RECIST criteria, which allows for continued treatment after initial radiographic progression until confirmation imaging ≥4 weeks, will be used to account for unique responses seen with immunotherapy. Radiographic responses will be confirmed by independent central review by RECIST v1.1 and modified RECIST and will be analyzed in real time for verification of progressive disease by RECIST v1.1. Survival follow-up will occur every 12 weeks. Primary end points are PFS and OS in all subjects and in subjects with PD-L1 strong positive expression; secondary end points include PFS and OS in subjects with any positive PD-L1 expression, safety and tolerability, TTP, ORR, and DOR. Clinical trial identification: NCT02252042 Disclosure: J.-P. Machiels: research: Novartis, Sanofi, Bayer; consulting/advisory: Merck Sharp & Dohme. E. Cohen: consulting/advisory: Bayer, Novartis, VentiRx, Merck, BMS, AstraZeneca, Eisai; speaker: Biodesix, Bayer. B. Burtness: research: Boehringer-Ingelheim, Genentech; consulting/advisory: VentiRx, Novartis, Genentech, Onyx, Immunogen. Expert testimony: Johnson & Johnson. C. Gause, R. Swaby: employee and stock, Merck & Co., Inc. A. Swift: employee, Merck & Co., Inc. All other authors have declared no conflicts of interest.