Phase I study of mTORC1/2 inhibitor sapanisertib (TAK-228) in combination with metformin in patients (pts) with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies.
Authors: Coleman Niamh , Naing Aung , Zhang Shizhen , Piha-Paul Sarina Anne Anne , Tsimberidou Apostolia Maria , Janku Filip , Rodon Jordi , Pant Shubham , Dumbrava Ecaterina Elena , Fu Siqing , Hong David S. , Meric-Bernstam Funda , Subbiah Vivek 
Published: June 2021

3017 Background: Sapanisertib (TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance anti-tumor activity of TAK-228. We report preliminary safety, tolerability and efficacy from the dose escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors. Methods: Pts with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3Kpathway alterations, received sapanisertib 3mg or 4mg daily together with metformin once to three times daily(500mg - 1500mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks. Data cut-off date was December 31 2020. 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), all were ECOG PS 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastro-esophageal junction (1), prostate (1), stomach (1), urachus (1) and cervical cancer (1). Median number of prior lines of therapy was 4. 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); 14pts achieved stable disease (SD) as best response. Disease control rate (CR+PR+SD) was 60%. Of the responders in PR, 3/4pts had documented PTENmutations (3/5 pts enrolled with PTENmutation had PR); 2/4 of pts in PR had co-mutations (pt with leiomyosarcoma had both PTENand TSC;pt with breast cancer had both PTENand STK11); 1/4 pts in PR had AKTand mTORmutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1) and endometrial cancer (n = 1).Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. 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%). No dose-limiting toxicities (DLTs) were reported in the 3mg/500mg cohort. 1/6 pt had DLT in the 3mg/ 1000mg cohort (G3 diarrhea) and 2/11pts had DLTs in the 4 mg/1500mg cohort (G3 fatigue, G3 rash). 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 mutations and AKT/mTOR pathway alterations. Clinical trial information: NCT03017833.