Network meta-analysis (NMA) of pembrolizumab for first-line (1L) treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

person Karthik Ramakrishnan Merck & Co., Inc., Kenilworth, NJ info_outline Karthik Ramakrishnan, Ali Mojebi, Dieter Ayers, Diana Romana Chirovsky, Rebekah Borse, Sam Keeping

Authors person Karthik Ramakrishnan Merck & Co., Inc., Kenilworth, NJ info_outline Karthik Ramakrishnan, Ali Mojebi, Dieter Ayers, Diana Romana Chirovsky, Rebekah Borse, Sam Keeping Organizations Merck & Co., Inc., Kenilworth, NJ, PRECISIONheor, Vancouver, BC, Canada, PRECISIONheor, Inc, Vancouver, BC, Canada Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Merck & Co., Inc Background: In the KEYNOTE-048 trial, pembrolizumab as monotherapy (P) and in combination with platinum+5FU chemotherapy (P+C) versus cetuximab+platinum+5FU (EXTREME regimen) significantly improved overall survival (OS) in the combined positive score (CPS) ≥1 (hazard ratio: 0.74; 95% confidence interval: 0.61-0.90) and total (0.72; 0.60-0.87) R/M HNSCC populations, respectively, and was approved by the FDA in these patient populations. While the EXTREME regimen is considered standard of care in 1L R/M HNSCC, other systemic treatment options including cetuximab+platinum+docetaxel (TPEx regimen), platinum+paclitaxel/taxane (Pt+T), and platinum+5FU (Pt+F) are also commonly used. Due to lack of head-to-head comparisons with pembrolizumab, an NMA was conducted to estimate the comparative efficacy of P and P+C versus these interventions in 1L R/M HNSCC. Methods: A systematic literature review (SLR) was conducted on November 13, 2019 to identify randomized controlled trials for the relavant interventions. Data were extracted for the OS and progression-free survival (PFS) outcomes. NMA analyses were conducted for the total population and for the CPS ≥1 and CPS ≥20 subgroups in a Bayesian framework using proportional hazards (base case) and time-varying (sensitivity analysis) treatment-effect models. The deviance information criterion was used to compare the goodness-of-fit of the alternative survival models. Results: The SLR identified 28 trials, of which six trials matched the trial eligibility criteria of KEYNOTE-048 and were included in the NMA. Results from the fixed-effects NMA for P and P+C are summarized in table below for the FDA indicated population. Improvement in OS was noted for P and P+C versus EXTREME, Pt+T, and Pt+F, and a trend in improved OS versus TPEx was observed. The sensitivity analysis showed improved OS over time across all comparisons. PFS was improved with P and P+C versus Pt+F and comparable versus other interventions. These results were generally consistent for P and P+C in the CPS (CPS ≥1 or CPS ≥20) patient subgroups. Additionally, NMA results versus EXTREME were consistent with the KEYNOTE-048 trial results. Conclusions: Pembrolizumab (P or P+C), showed improved OS and comparable PFS outcomes versus alternative 1L R/M HNSCC interventions, consistent with the efficacy results versus EXTREME observed in the KEYNOTE-048 trial. Estimated fixed effects hazard ratios (95% credible intervals) for OS and PFS. Intervention P* P* P+C* P+C* Outcome OS PFS OS PFS EXTREME 0.73 (0.60-0.88) 1.11 (0.93-1.32) 0.72 (0.60-0.86) 0.89 (0.74-1.06) TPEx 0.83 (0.63-1.10) 1.26 (0.98-1.62) 0.83 (0.63-1.08) 1.01 (0.78-1.29) Pt+T** 0.58 (0.39-0.87) -- 0.58 (0.39-0.85) -- Pt+F 0.59 (0.45-0.79) 0.61 (0.46-0.81) 0.59 (0.45-0.76) 0.49 (0.37-0.65) *P in CPS ≥ 1 and P+C in total population. **PFS data not available in Pt+T trial.