A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours.

Abstract

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or <1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8 mg cohort and 14 in the 16 mg cohort (50% M and 50% F, mean age of 51.4 y). All patients have been discontinued: 16 due to disease progression; 1 due to AEs, 2 developed contra-indication to denosumab & pembrolizumab, 1 withdrawal of consent. PK parameters of ETC-159 in the first cycle were consistent with prior single agent data. TEAEs were reported in all subjects in the study with most events being grade 1/2, with dysgeusia (65%), β-CTX increase (30%), fatigue (25%), constipation (20%), and nausea (20%) being the most common. DLTs were G3 colitis and G3 immune-related enteritis (16 mg, 2 patients), and pneumonitis and erythema with fever (8 mg, 1 patient). Other drug related SAEs were G2 thyroiditis, hematuria, and thrombocytopenia. No fractures or other drug related skeletal SAEs. Of the 15 evaluable patients, 6 (40%) demonstrated clinical benefit (1 PR, 5 SDs) in combination with pembrolizumab (2 ovarian, 1 lung, 1 pancreatic, 1 urachal, 1 MSS CRC patient with RSPO fusion), at the first assessment, in a predominantly MSS population (65% MSS, 25% unknown, 10% MSI). Pharmacodynamics, (hair follicle Axin2 reduction), was detected at both dose levels and was ≥80% from baseline on D15. Conclusions: ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844 .