Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models.
To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo).
CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021.
Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity.
The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review.
A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo.
In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents.
ClinicalTrials.gov Identifier: NCT03428217.
JAMA oncology. 2022 Sep 01 [Epub ahead of print]
Nizar M Tannir, Neeraj Agarwal, Camillo Porta, Nicola J Lawrence, Robert Motzer, Bradley McGregor, Richard J Lee, Rohit K Jain, Nancy Davis, Leonard J Appleman, Oscar Goodman, Walter M Stadler, Sunil Gandhi, Daniel M Geynisman, Roberto Iacovelli, Begoña Mellado, Juan Manuel Sepúlveda Sánchez, Robert Figlin, Thomas Powles, Lalith Akella, Keith Orford, Bernard Escudier
The University of Texas MD Anderson Cancer Center, Houston., Huntsman Cancer Institute, University of Utah, Salt Lake City., University of Pavia, Pavia, Italy., Auckland District Health Board and The University of Auckland, Auckland, New Zealand., Memorial Sloan Kettering Cancer Center, New York, New York., Dana-Farber Cancer Institute, Boston, Massachusetts., Massachusetts General Hospital, Boston, Massachusetts., H. Lee Moffitt Cancer & Research Institute, Tampa, Florida., Vanderbilt University Medical Center, Nashville, Tennessee., University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Comprehensive Cancer Centers of Nevada, Las Vegas., University of Chicago, Chicago, Illinois., Florida Cancer Specialists, Lecanto, Florida., Fox Chase Cancer Center, Philadelphia, Pennsylvania., Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy., Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain., 12 de Octubre Hospital, Madrid, Spain., Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California., St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK., Calithera Biosciences, Inc, South San Francisco, California., Gustave Roussy, Villejuif, France.