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Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours
Jordi Rodon1,2, Guillem Argilés3, Roisin M Connolly4,5
1Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain. JRodon@mdanderson.org.
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.
Clinical Trial Registration:
NCT01351103.
Insights
WNT974, a Porcupine inhibitor, was evaluated in advanced solid tumors. While generally well-tolerated, it showed limited efficacy but modulated Wnt pathway biomarkers and may impact tumor immunity.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Phase 1 clinical trial investigating WNT974, a novel Porcupine inhibitor.
- Focus on safety and efficacy in patients with advanced solid tumors.
Purpose of the Study:
- To assess the safety and tolerability of WNT974.
- To evaluate the preliminary efficacy of WNT974 in advanced solid tumors.
- To explore WNT974's effect on Wnt pathway biomarkers and tumor immune microenvironment.
Main Methods:
- 94 patients received oral WNT974 at doses ranging from 5-30 mg once-daily.
- Dose escalation and expansion cohorts were utilized.
- Biomarker analysis included AXIN2 expression in skin and tumor biopsies.
Main Results:
- Recommended dose for expansion was 10 mg once-daily; maximum tolerated dose was not established.
- Dysgeusia was the most common adverse event (50%).
- No objective responses by RECIST v1.1 were observed, but 16% had stable disease. Wnt pathway inhibition was confirmed by reduced AXIN2 expression in 94% of skin and 74% of tumor biopsies.
Conclusions:
- Single-agent WNT974 demonstrated acceptable safety and tolerability.
- Biomarker data suggest WNT974 may influence immune cell recruitment and enhance checkpoint inhibitor activity.
- Further investigation is warranted to explore WNT974's potential in combination therapies.
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