Pembrolizumab in PD-L1+ Advanced Esophageal Carcinoma

PD-L1 and PD-L2 expression have been associated with poor prognosis in esophageal cancer. Pembrolizumab is a humanized anti-PD-1 monoclonal antibody that blocks interaction with PD-L1 and PD-L2. The multicohort, phase 1b KEYNOTE-028 (NCT02054806) trial was designed to evaluate the safety and efficacy of pembrolizumab in patients with PD-L1+ advanced solid tumors, and Doi and colleagues reported the updated results from the esophageal carcinoma cohort of this study (N=23).¹ Patients with advanced squamous-cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction, with positive PD-L1 expression in the tumor or stroma (as determined centrally by immunohistochemistry), and who had failed standard therapy, received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression, intolerable toxicity, or investigator decision. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR) per RECIST v1.1 criteria by investigator review. 

Of the 23 patients enrolled, 73.9% had squamous histology, and 87% had received ≥2 prior lines of therapy for metastatic disease. As of the August 4, 2015, data cutoff date, the median follow-up duration was 31 weeks (range, 5.7-71). Nine (39%) patients had any-grade drug-related adverse events (DRAEs), most commonly decreased appetite (n = 3; 13.0%). Four (17%) patients had grade 3 DRAEs, with only decreased lymphocytes reported in 2 patients (8.7%). No patients died or discontinued pembrolizumab due to a DRAE. Immune-mediated adverse events, regardless of attribution by investigator, were grade 2 hypothyroidism (n = 2; 9%) and adrenal insufficiency (n = 1; 4%).

ORR was 30.4% (95% confidence interval [CI], 13.2-52.9), all with partial response. The stable disease rate was 9% (n = 2; 95% CI, 1-28); 6-month and 12-month progression-free survival rates were 30% and 22%, respectively. Five of 7 responses were ongoing at data cutoff, with a median duration of response of 40.0 weeks (range, 24.1+ to 46.1+). ORR occurred in 5/17 patients (29%) with squamous histology and in 2/4 patients (40%) with adenocarcinoma. A gene expression signature consisting of 6-gene complex signaling pathway related to pre-existing interferon- Υ adaptive immune response within the tumor microenvironment (IDO1, CXCL10, CXCL9, HLA-DRA, STAT1, and IFN-Υ) in that a higher gene expression signature score was associated with longer delays in disease rogression and increasead progression-free survival. The authors concluded that pembrolizumab shows manageable toxicity and durable antitumor activity in patients with heavily pretreated, chemotherapy-refractory PD-L1+ advanced esophageal carcinoma. Phase 2 and 3 trials of second- and third-line pembrolizumab in patients with advanced esophageal cancer are ongoing.

1. Doi T, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 7.