Phase II study of lenvatinib plus pembrolizumab for patients with immunotherapy-naive advanced gastric cancer following first-line therapy

Background Treatment options for refractory gastric cancer are limited. Preclinical data suggest interplay between angiogenesis and immune regulation, with vascular endothelial growth factor impairing antitumor immunity through decreasing antigen presentation, effector function, and immune cell trafficking. This phase II study evaluated lenvatinib plus pembrolizumab in the refractory setting. Patients and methods Eligible patients had advanced gastric or gastroesophageal junction adenocarcinoma with measurable disease, Eastern Cooperative Oncology Group ≤ 1, and progression after ≥1 prior therapy, without prior immune checkpoint inhibitor exposure. Patients received pembrolizumab 200 mg i.v. every 21 days and lenvatinib 20 mg orally daily, with a 7-day lead-in. Primary endpoint was objective response rate. Using Simon optimal two-stage design, 29 patients were planned; the study would be considered positive if ≥6 responses were observed. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). Results Enrollment was prematurely suspended at 24 patients due to evolving practice patterns. Median age was 63 years; 75% were male; 63% were White. Seven patients (29%) received ≥2 lines of therapy. Among 20 assessable patients, 5 (25%) achieved partial responses, including 2 with combined positive score (CPS) <1 tumors. Median duration of response was 31.6 weeks. Median PFS and OS were 12.9 and 21.4 weeks, respectively. Treatment was well tolerated with no new safety signals. Conclusions Lenvatinib plus pembrolizumab did not meet the predefined efficacy threshold in the overall cohort. However, treatment was well tolerated and encouraging responses were seen in patients with CPS <1 tumors. Although the sample size was limited, these findings suggest that further investigation of this treatment strategy in patients with CPS < 1 disease may be warranted.