ASCO 2021: CANTATA: Primary Analysis of a Global, Randomized, Placebo-Controlled, Double-Blind Trial of Telaglenastat + Cabozantinib Versus Placebo + Cabozantinib in mRCC Patients Who Progressed on Immune Checkpoint Inhibitor or Anti-Angiogenic Therapies

( Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC), driven by overexpression of glutaminase, a key enzyme of glutamine metabolism. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and is critical downstream pathways. Pre-clinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, against RCC tumors utilizing dual inhibition of glucose and glutamine metabolic pathways. In a phase 1 study, telaglenastat + cabozantinib showed encouraging safety/efficacy as >=second-line therapy for mRCC with an objective response rate of 50% and 100% disease control rate. At the 2021 America Society of Clinical Oncology (ASCO) annual program, Dr. Nizar Tannir presented results of the CANTATA trial, comparing telaglenastat + cabozantinib versus placebo + cabozantinib in previously treated patients with clear-cell mRCC.

For CANTATA, eligible patients had 1-2 prior lines of systemic therapy for mRCC, including ≥1 anti-angiogenic therapy or nivolumab + ipilimumab, KPS ≥70%, measurable disease (RECIST 1.1), no prior cabozantinib or other MET inhibitor. Patients were randomized 1:1 to receive cabozantinib (60 mg PO QD) with either telaglenastat (800 mg PO BID) or placebo, until disease progression/unacceptable toxicity, and were stratified by prior PD-(L)1 inhibitor therapy (Y/N) and IMDC prognostic risk group. The study design for CANTATA is as follows:


There were 444 patients randomized (221 to telaglenastat + cabozantinib; 223 to placebo + cabozantinib). Baseline characteristics were balanced between arms, including 67% with IMDC intermediate risk disease in the telaglenastat + cabozantinib arm and 68% in the placebo + cabozantinib arm. Prior nivolumab + ipilimumab was received by 29% of patients in each arm.  The median follow-up for the trial was 11.7 months, and 276 patients received prior immune checkpoint inhibitor. Median PFS was 9.2 months for telaglenastat + cabozantinib versus 9.3 months for placebo + cabozantinib (HR 0.94, 95% CI 0.74-1.21):



The subgroup analyses for PFS were consistent with the overall analysis:


The overall response rate (confirmed) was 31.2% with telaglenastat + cabozantinib versus 27.8% placebo + cabozantinib. Overall survival was not mature at the time of data cutoff. In a prespecified subgroup analysis in patients with prior immune checkpoint inhibitor, median PFS was numerically longer with telaglenastat + cabozantinib than placebo + cabozantinib (11.1 versus 9.2 months, respectively; unstratified HR 0.77, 95% CI 0.56, 1.06):


In the placebo + cabozantinib arm, median PFS was 9.2 months for patients with prior immune checkpoint inhibitor exposure and 9.5 months for patients without, and objective response rate was 32% and 20%, respectively; if immune checkpoint inhibitor included nivolumab + ipilimumab, objective response rate was 37%. Rates of adverse events were similar between arms. Grade 3-4 adverse events occurred in 71% of telaglenastat + cabozantinib patients and 79% of placebo + cabozantinib patients and included hypertension (17% vs 18%) and diarrhea (15% vs 13%). Cabozantinib was discontinued due to adverse events in 10% of telaglenastat + cabozantinib patients and 15% of placebo + cabozantinib patients.

Dr. Tannir provided the following concluding statements for his presentation of the CANTATA study:

  • The addition of telaglenastat did not improve the efficacy of cabozantinib in mRCC in this study as there was no significant difference in PFS between the arms
  • Telaglenastat + cabozantinib was well tolerated with adverse events consistent with known risks of both agents
  • Data in the prior immune checkpoint inhibitor subgroups may inform future development of telaglenastat trials
  • The study provides valuable insight on efficacy outcomes of a contemporary population of patients with mRCC who receive cabozantinib in the second/third-line setting

Dr. Tannir also provided the following perspectives on the implications of this negative trial:

  • While the addition of telaglenastat did not improve outcomes with cabozantinib in this unselected population of patients with clear cell RCC, future studies are warranted to determine the impact of glutaminase inhibition in biomarker-selected patient populations with high dependence on glutamine/glutaminase, and in combination with other therapeutic partners
  • The development of telaglenastat continues in patient populations in which glutaminase appears to be particularly important. The ongoing KEAPSAKE trial is evaluating telaglenastat plus standard of care pembrolizumab + chemotherapy in first-line KEAP1/NRF2-mutated non-squamous metastatic NSCLC (NCT04265534)

Clinical trial information: NCT03428217

Presented by: Nizar M. Tannir, M.D., FACP, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Co-Authors: Neeraj Agarwal, Camillo Porta, Nicola Jane Lawrence, Robert J. Motzer, Richard J. Lee, Rohit K. Jain, Nancy B. Davis, Leonard Joseph Appleman, Oscar B. Goodman, Walter Michael Stadler, Sunil G. Gandhi, Daniel M. Geynisman, Roberto Iacovelli, Begona Mellado, Robert A. Figlin, Thomas Powles, Lalith V Akella, Keith W. Orford, Bernard Escudier; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; University of Bari 'A. Moro' and Policlinico Consorziale di Bari, Bari, Italy; Auckland City Hospital, Auckland, New Zealand; Memorial Sloan Kettering Cancer Center, New York, NY; Massachusetts General Hospital, Boston, MA; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Pittsburgh Medical Center, Pittsburgh, PA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; The University of Chicago, Chicago, IL; Florida Cancer Specialists, Lecanto, FL; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Hospital Clínic, Provincial de Barcelona, Barcelona, Spain; Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom; Calithera Biosciences, Inc., South San Francisco, CA; Gustave Roussy, Villejuif, France

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021