Second-Line Pembrolizumab vs. Chemotherapy for Advanced Esophageal Cancer

Based on a trial of patients with refractory esophagogastric adenocarcinoma, pembrolizumab was approved in the U.S. for late-line treatment of PD-L1–positive or MSI-high cancers. However, a recent trial of pembrolizumab versus paclitaxel in the second-line treatment of PD-L1–positive gastric and GE junction adenocarcinoma was negative (NEJM JW Oncol Hematol Sep 2018 and Lancet 2018; 392:123).

Researchers now report results of KEYNOTE-181, an industry-sponsored, international, open-label, randomized, phase III trial of second-line treatment with pembrolizumab versus investigators' choice of chemotherapy (paclitaxel, docetaxel, or irinotecan) for 628 patients with esophageal and GE junction adenocarcinoma or squamous cell cancer. Most patients had squamous cancers (61%), most were treated in non-Asian countries (61%), and about a third had a PD-L1 combined positive score (CPS) of ≥10% (34%–37%).

At a median follow-up of 7 months, overall survival (OS; the primary endpoint) in patients with CPS ≥10% was longer with pembrolizumab than with chemotherapy (9.3 vs. 6.7 months; hazard ratio, 0.69; P=0.0074); 12-month survival was also superior with pembrolizumab (43% vs. 20%). OS in all squamous cancers trended higher with pembrolizumab (8.2 vs. 7.1 months), but did not reach the prespecified criterion for superiority. In all patients, superiority for pembrolizumab also was not met. The greatest benefit was seen patients with CPS ≥10% and squamous cancers. Progression-free survival was superior for pembrolizumab only in patients with CPS ≥10% (3.0 vs. 2.6 months; HR, 0.73). In patients with CPS ≥10%, the response rate was superior with pembrolizumab (21.5% vs. 6.1%), as was response duration (9.3 vs. 7.7 months). Grade 3/4 treatment-related adverse events were less common with pembrolizumab than with chemotherapy (18% vs. 41%)