Vactosertib plus pembrolizumab in patients with non-microsatellite instability-high metastatic colorectal or gastric cancer: a multicenter, phase Ib/IIa study.

This multicenter, open-label, single-arm, phase Ib/IIa study (NCT03724851) evaluated vactosertib plus pembrolizumab in patients with non-microsatellite instability-high (non-MSI-high) metastatic colorectal cancer (mCRC) or gastric cancer (mGC). The study included dose-escalation and expansion phases. Vactosertib was administered five days per week at predefined dose levels in combination with pembrolizumab (200 mg intravenously every three weeks). The primary outcome was safety and tolerability; the combination demonstrated a manageable safety profile; prespecified secondary outcomes included pharmacokinetics and anti-tumor activity, including objective response rate, duration of response, time to response, progression-free survival, and overall survival; pharmacodynamic biomarkers were evaluated as exploratory outcomes. A total of 120 patients were included in the safety analysis (mCRC: 108, mGC: 12) and 115 in the efficacy analysis (mCRC: 103, mGC: 12). Treatment-related adverse events occurred in 70.8% of patients, with pruritus and rash being the most common. In mCRC, the objective response rate was 12.6%, with higher responses in patients without liver metastases (22.5%) than in patients with liver metastases (6.3%) by RECIST v1.1. The median overall survival was 13.2 months. No objective responses were observed in mGC. Vactosertib plus pembrolizumab showed clinical activity in non-MSI-high mCRC, particularly in patients without liver metastases.