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

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