Vactosertib (TGFBR1/ALK5 inhibitor) + pembrolizumab drives 12.6% ORR in MSS/non–MSI-high mCRC—0% in gastric cancer

Vactosertib is an oral TGF-β receptor type 1 (TGFBR1/ALK5) kinase inhibitor designed to blunt TGF-β–mediated immune exclusion, and was combined with pembrolizumab (PD-1) in a multicenter, open-label, single-arm Phase Ib/IIa trial (NCT03724851) in non–MSI-high metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC). Safety population was 120 (mCRC n=108; mGC n=12) with 115 efficacy-evaluable (mCRC n=103; mGC n=12); treatment-related AEs occurred in 70.8% (most commonly pruritus and rash), described as manageable. In non–MSI-high mCRC, ORR was 12.6% overall, enriched in patients without liver metastases (22.5% vs 6.3% with liver metastases), with median OS 13.2 months; no objective responses were seen in mGC—benchmarks for later-line MSS mCRC with approved options like regorafenib or trifluridine/tipiracil are typically very low ORR (often ~1–2%), so a ~13% ORR would be above “usual” shrinkage rates if the population is comparably refractory (the abstract doesn’t clearly state line-of-therapy).