Phase I study of mTORC1/2 inhibitor sapanisertib in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies.

Abstract

Abstract Background: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. We report preliminary safety, and efficacy of sapanisertib in combination with metformin. Methods: Patients with advanced metastatic solid tumors refractory to standard treatment, with/without mTOR/AKT/PI3Kpathway alterations, received sapanisertib 3mg or 4mg daily together with metformin once to three times daily (500mg - 1500mg). Results: 30 pts were enrolled across 4 cohorts (3mg/500mg; 3mg/1000mg, 4mg/1000mg; 4mg/1500mg). 19 were female (63%), median age was 57 (range: 30–77). Tumor types included sarcoma (6), breast (4), ovarian (4) among others. Most common genomic alterations included PIK3CA (27%), PTEN(17%), AKT1/2 (10%), mTOR (10%). Of 30 pts evaluable for response, 4 pts achieved partial response (PR); 15 pts achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3/4pts had documented PTEN mutations (3/5 pts enrolled with PTEN mutations had PR); 2/4 of pts in PR had co-mutations (pt with leiomyosarcoma had both PTEN and TSC; pt with breast cancer had both PTEN and STK11); 1/4 pts in PR had AKT and mTOR mutation. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%) fatigue (2/30; 7%) hypertriglyceridemia (1/30; 3%) rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). 4mg/1000mg was defined as the maximum tolerated dose. Conclusions: The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with anti-tumor activity observed in patients with advanced malignancies harboring PTEN/ AKT/mTOR pathway alterations.