Abstract CT282: KEYNOTE-975: A randomized, double-blind, placebo-controlled phase 3 trial of pembrolizumab vs placebo in participants with esophageal carcinoma receiving concurrent definitive chemoradiotherapy
Authors: Shah Manish A. , Bennouna Jaafar , Doi Toshihiko , Shen Lin , Kato Ken , Adenis Antoine , Mamon Harvey , Moehler Markus , Fu Xiaolong , Cho Byoung Chul , Bhagia Pooja , Shih Chie-Schin , Desai Anjali , Enzinger Peter 
Published: September 2020

Abstract
Background: For patients with unresectable esophageal cancer (EC), definitive chemoradiotherapy (dCRT) is a standard treatment option. Platinum plus fluoropyrimidine-based regimens are comparable in dCRT and are considered standard options; however, overall survival (OS) is still poor, indicating a need for more effective therapies. The programmed cell death 1 inhibitor pembrolizumab showed promising response as third- and second-line monotherapy in patients with advanced, unresectable EC in the KEYNOTE-180 and KEYNOTE-181 studies, respectively. In the phase 3 KEYNOTE-181 trial, pembrolizumab extended OS vs chemotherapy in patients with a PD-L1 combined positive score (CPS) ≥10. KEYNOTE-975 is a randomized, multicenter, double-blind, phase 3 study investigating pembrolizumab in combination with dCRT. Methods: Key patient eligibility criteria are age ≥18 years; presence of cTX N+M0 or cT2-T4a NXM0, locally advanced esophageal squamous cell carcinoma (SCC) or adenocarcinoma or Siewert type 1 adenocarcinoma of the esophagogastric junction; ineligible for curative surgery; no previous chemotherapy or radiation for EC; and suitable for dCRT. Patients will be randomly assigned 1:1 to pembrolizumab or placebo added to dCRT, administered as pembrolizumab 200 mg or placebo Q3W for 8 cycles followed by pembrolizumab 400 mg or placebo Q6W for 5 cycles (13 cycles total). The dCRT regimen will be the site's choice of continuous infusion 5-FU + cisplatin (FP) with radiotherapy (RT) 50 Gy, FP with RT 60 Gy, or FOLFOX with RT 50 Gy. Randomization will be stratified by PD-L1 positivity (CPS ≥10 vs CPS &lt;10), RT dose (50 Gy vs 60 Gy), and region/histology (SCC East Asia vs SCC rest of world and adenocarcinoma regardless of region). The primary objectives of KEYNOTE-975 are to compare pembrolizumab and placebo added to dCRT in OS and event-free survival within the prespecified analysis cohorts: patients with CPS ≥10, patients with SCC, and all patients (intention-to-treat population). The secondary objective is to assess the safety and tolerability profile of pembrolizumab vs placebo added to dCRT (adverse events, overall and leading to study drug discontinuation). Exploratory objectives include comparing time to deterioration and change from baseline in quality of life measures, characterizing health utility scores, and identifying molecular biomarkers that may be determinants of response.
Citation Format: Manish A. Shah, Jaafar Bennouna, Toshihiko Doi, Lin Shen, Ken Kato, Antoine Adenis, Harvey Mamon, Markus Moehler, Xiaolong Fu, Byoung Chul Cho, Pooja Bhagia, Chie-Schin Shih, Anjali Desai, Peter Enzinger. KEYNOTE-975: A randomized, double-blind, placebo-controlled phase 3 trial of pembrolizumab vs placebo in participants with esophageal carcinoma receiving concurrent definitive chemoradiotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT282.