Reference Detail

Ref Type

Abstract

PMID

Authors

Niamh Coleman, Aung Naing, Shizhen Zhang, Sarina Anne Anne Piha-Paul, Apostolia Maria Tsimberidou, Filip Janku, Jordi Rodon, Shubham Pant, Ecaterina Elena Dumbrava, Siqing Fu, David S. Hong, Funda Meric-Bernstam, Vivek Subbiah

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	39	15_suppl	May 20, 2021

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.3017

Abstract Text

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 documentedPTENmutations (3/5 pts enrolled withPTENmutation 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References