Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer

Abstract

PURPOSE Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.

Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

“…The randomised phase III KEYNOTE-181 trial investigated the effect of pembrolizumab monotherapy versus chemotherapy of the investigator's choice (paclitaxel, docetaxel, irinotecan) in patients with advanced or metastatic ESCC (64%) or EAC (36%) with progression after one prior chemotherapy independent of PD-L1 expression [16]. The primary endpoint was split and comprised OS in all patients, ESCC patients and PD-L1 CPS ≥ 10 patients.…”

Anti-PD-1 Inhibitor for the Treatment of Esophageal Cancer Refractory or Intolerant to Previous Chemotherapy: A Meta-Analysis of Randomized Controlled Trials

“…After carefully title and abstract screening, 29 studies were left for full text screening. In accordance to the inclusion criteria, only three studies [9][10][11] were included for this analysis. The study selection chart is presented in Fig.…”

“…Three studies mentioned of PFS [9][10][11]. The combination data indicated that the two groups had similar PFS (HR:0.94,95%CI:0.71,1.26,P = 0.69),the analysis was with high heterogeneity (I 2 = 85%, P = 0.001) (Fig.…”

The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

“…Furthermore, the phase II KEYNOTE-180 trial demonstrated a disappointing tumor response of pembrolizumab in the third line setting (ORR 5.2%) in GEJ cancer [ 27 ]. Likewise, the phase III KEYNOTE-181 trial failed to show improved OS of pembrolizumab over chemotherapy in the intention-to-treat population of patients with unresectable or advanced stage esophageal cancer who progressed on first line therapy [ 28 ]. Lastly, the phase III KEYNOTE-061 trial failed to show OS benefit of pembrolizumab over chemotherapy in the second line setting in non-selected GC/GEJC population [ 29 ].…”