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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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Author Details

Vicki Leigh Keedy

Vanderbilt University Medical Center, Nashville, TN

Abstract Details

Meeting

2018 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics and Translational Research

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Abstract Disclosure