Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours

Background This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. Methods Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules. Results The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8). Conclusions Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity.

Automated summary

The Phase 1 study evaluated the safety and efficacy of Porcupine inhibitor WNT974 in patients with advanced solid tumours. The recommended dose for expansion was 10 mg once-daily, with dysgeusia being the most common adverse event. The study suggested that WNT974 may influence immune cell recruitment to tumours and enhance checkpoint inhibitor activity.