Background: Stromal signature regulated by TGF-β pathway is one of the major mechanisms of tumor immune surveillance, leading to resistance to immune checkpoint inhibitors (ICI). Moreover, TGF-β responsive signatures (TBRS) of stromal cells have been associated with poor prognosis. Vactosertib (TEW-7197) is a potent, highly selective, oral inhibitor of TGFBR1. The safety, anti-tumor effect of vactosertib and its association with TBRS levels were evaluated in patients with advanced solid tumors. Based on in-house TCGA analysis, high fibroblast TBRS (F-TBRS) levels were seen in pancreatic, lung, colorectal (CMS4 subtype), and stomach (GS subtype) cancers in association with poor prognosis (adjusted hazard ratio 1.27; P = 1.06 x 10-8). Methods: 29 patients were enrolled in a phase I modified 3+3 dose-escalating study (NCT02160106) and received vactosertib once daily at the dose range of 30~340 mg for 5 days with 2 days off. RNA sequencing of pre-treatment tumor samples in 16 patients were analyzed to evaluate F-TBRS levels defined as geometric mean values of 171 corresponding gene expressions. Results: Vactosertib was safe and well tolerated, and the maximum tolerated dose was not determined. The most common treatment-related AE (TRAE) was fatigue, while G3/4 abdominal pain, AST elevation, and pulmonary edema were each reported in one patient, respectively. One DLT of stroke was seen at 100mg QD. In per-protocol analysis, 6 out of 17 patients who received ≥140 mg achieved stable disease (35.3%) and showed higher F-TBRS levels than those with progressive disease. Conclusions: Vactosertib, a potent and highly selective oral TGFBR1 inhibitor, showed excellent safety with the current dosing schedule. Furthermore, since high F-TBRS levels are well recognized as one of the main mechanisms related to resistance to ICI, vactosertib would be an ideal therapeutic strategy in combination with ICIs or conventional anti-tumor therapies for solid tumors with high F-TBRS levels. Clinical trial information: NCT02160106
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