Introduction PD-(L1) inhibitors have limited efficacy in MSS/pMMR recurrent ovarian cancers. Upregulation of the Wnt pathway has been associated with immune exclusion in the tumour microenvironment. ETC-159 is a small molecule porcupine inhibitor that suppresses WNT secretion. Ph1B trial explored the combination of ETC-159 with PD-1 inhibition in PROC.

Methods In a Phase 1B open label study patients ≥ 18 years, with adequate organ function and MSS/pMMR PROC were eligible. ETC-159 was dosed orally QOD in combination with 200 mg pembrolizumab IV every 21 days. Responses were evaluated via RECIST1.1 and iRECIST. PK, PD and tumour profiling were assessed at multiple time points throughout the trial.

Results Six PROC patients were treated with the combination in dose escalation & expansion. The majority (66%) were high- grade serous ovarian carcinomas with a median 4 lines (2–7) of previous treatments. SAEs were pneumonitis and erythema with fever (8 mg, 1 patient). No fractures or other skeletal SAEs were observed. Of 6 evaluable patients, two patients had a PR. 1 harbouring a SUFU-1 mutation (on treatment for 27 weeks) and another with BRCA2 mutant who had progressed on PARPi and immunotherapy. Two others achieved SD as best response for 12 and 18 weeks, respectively, with 1 more currently ongoing. A disease control rate (SD/PR/CR ≥ 12 weeks) of 67% was observed.

Conclusion/Implications Preliminary data suggest Wnt signalling inhibition with ETC-159 in combination with pembrolizumab is tolerable with no unexpected safety signals and may provide clinical benefit for platinum resistant MSS/pMMR ovarian cancer patients.