Dual inhibition of glucose and glutamine metabolism results in synergistic anti-cancer effects in solid tumor models. Telaglenastat, an investigational, small molecule, glutaminase inhibitor, exhibits modest single agent activity in RCC patients. This phase 1b trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).
mRCC patients received escalating doses of telaglenastat (400-800mg per os [PO] twice daily) in a 3+3 design, plus either everolimus (10mg daily PO; TelaE) or cabozantinib (60mg daily PO; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and anti-tumor activity.
27 patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grade 1-2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No MTD was reached for either combination, leading to a recommended phase 2 dose of 800mg telaglenastat BID with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% (20/21, including 1 partial response [PR]) among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies (5/10 PRs as best response [3 confirmed] in clear cell).
TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pre-treated mRCC patients.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Feb 09 [Epub ahead of print]
Funda Meric-Bernstam, Nizar M Tannir, Othon Lliopoulos, Richard J Lee, Melinda L Telli, Alice C Fan, Angela DeMichele, Naomi B Haas, Manish R Patel, James J Harding, Martin H Voss, Taofeek K Owonikoko, Bradley Carthon, Ramaprasad Srinivasan, Johanna C Bendell, Yonchu Jenkins, Sam H Whiting, Keith Orford, Mark K Bennett, Todd M Bauer
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center ., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center., Hematology/Oncology, Center for Cancer Research at Massachusetts General Hospital Cancer Center., Massachusetts General Hospital Cancer Center, Harvard Medical School., Medicine, Medical Oncology, Stanford University., Medicine-Oncology, Stanford University., Hematology-Oncology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania School of Medicine., Medical Oncology, Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania., Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute., Gastrointestinal Oncology Service, Dept. of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College., GU oncology, Memorial Sloan Kettering Cancer Center., Hematology/Oncology, University of Pittsburgh Medical Center., Winship Cancer Institute, Emory University., Urologic Oncology Branch, National Cancer Institute., pRED Oncology, Sarah Cannon Research Institute., Clinical, Calithera Biosciences, Inc., Clinical Development, Tempest Therapeutics., Calithera Biosciences, Inc., Drug Development Unit, Sarah Cannon Research Institute / Tennessee Oncology, PLLC.