P-279 Pembrolizumab for patients with previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: phase 2 KEYNOTE-180 study

Abstract

Background: Programmed death ligand 1 (PD‐L1) is frequently overexpressed in esophageal cancer, and its expression has been associated with poor prognosis. Thus, immunotherapy via PD‐1/PD‐L1 blockade may provide benefit for patients with esophageal cancer. Pembrolizumab is a humanized monoclonal antibody that targets the PD‐1 receptor and blocks its interaction with both of its ligands, PD‐L1 and PD‐L2, thereby permitting activation of an antitumor cytotoxic immune response. In the multicohort, phase 1b KEYNOTE‐028 study, pembrolizumab showed manageable toxicity, had an objective response rate (ORR) of 30.4%, and median duration of response (DOR) was not reached in 23 patients with PD‐L1‐positive advanced esophageal cancer. The single‐arm, multicenter, phase 2 KEYNOTE‐180 study (ClinicalTrials.gov, NCT02559687) was designed to further evaluate pembrolizumab as monotherapy in patients with previously treated advanced/metastatic esophageal cancer. Trial Design: Key eligibility criteria include age ≥18 years; advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction (EGJ); measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 (v1.1), as determined by central imaging vendor review; documented progression during or after 2 prior standard lines of therapy for metastatic disease; Eastern Cooperative Oncology Group performance status 0‐1; no prior anticancer therapy within 2 weeks of study treatment; no active autoimmune disease or brain metastases; and provision of a tumor sample for retrospective biomarker analysis. Patients with metastatic Siewert type I EGJ adenocarcinoma must have known HER2 status and, if HER2+, must have documented progression on treatment containing trastuzumab. Eligible patients are to receive pembrolizumab 200 mg every 3 weeks for 35 cycles ( 2 years) or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. Response is to be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review and RECIST adapted for immunotherapy response patterns. Treatment may be discontinued in patients who have a complete response, and eligible patients may continue treatment beyond initial RECIST‐defined progression. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (up to 90 days for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Patients are to be followed for survival every 9 weeks. The primary efficacy end point is ORR per RECIST v1.1 by central imaging vendor review. Secondary end points include progression‐free survival, overall survival, and DOR. Exploratory analyses include evaluation of immune‐related gene expression profiles and PD‐L1 expression status as predictors of pembrolizumab efficacy. Enrollment in KEYNOTE‐180 is ongoing in 9 countries and will continue until approximately 100 patients are enrolled.