Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial

• Type of Material: Article
• Authors: Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center; Nizar M Tannir, The University of Texas MD Anderson Cancer Center; Othon Iliopoulos, Massachusetts General Hospital; Richard J Lee, Massachusetts General Hospital; Melinda L Telli, Stanford University; Alice C Fan, Stanford University; Angela DeMichele, Penn Medicine Abramson Cancer Center; Naomi B Haas, Penn Medicine Abramson Cancer Center; Manish R Patel, Florida Canc Specialists Sarah Cannon Res Inst; James J Harding, Memorial Sloan Kettering Cancer Center; Martin H Voss, Memorial Sloan Kettering Cancer Center; Taofeek Owonikoko, Emory University; Bradley Carthon, Emory University; Ramaprasad Srinivasan, National Cancer Institute, NIH, Bethesda; Johanna C Bendell, Sarah Cannon Research Institute/ Tennessee Oncology; Yonchu Jenkins, Calithera Biosciences, Inc; Sam H Whiting, Calithera Biosciences, Inc; Keith Orford, Calithera Biosciences, Inc; Mark K Bennett, Calithera Biosciences, Inc; Todd M Bauer, Sarah Cannon Res Inst Tennessee Oncol
• Language: English
• Date: 2022-04-15
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-21-2972
• Title of Journal or Parent Work: CLINICAL CANCER RESEARCH
• Volume: 28
• Issue: 8
• Start Page: 1540
• End Page: 1548
• Keywords: Science & Technology; Life Sciences & Biomedicine; DIAGNOSIS; Oncology; GLUTAMINASE

Abstract

Purpose: Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC). Patients and Methods: mRCC patients received escalating doses of telaglenastat [400-800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity. Results: Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 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 maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily 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]. Conclusions: TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.