Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial

JAMA Oncol. 2022 Oct 1;8(10):1411-1418. doi: 10.1001/jamaoncol.2022.3511.


Importance: 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.

Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo).

Design, setting, and participants: 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.

Interventions: 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.

Main outcomes and measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review.

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03428217.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / mortality
  • Double-Blind Method
  • Female
  • Glutamates / therapeutic use
  • Glutaminase / therapeutic use
  • Glutamine / therapeutic use
  • Humans
  • Immune Checkpoint Inhibitors
  • Ipilimumab / therapeutic use
  • Male
  • Middle Aged
  • Nivolumab / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use


  • cabozantinib
  • Nivolumab
  • Ipilimumab
  • Glutaminase
  • Immune Checkpoint Inhibitors
  • Glutamine
  • Protein Kinase Inhibitors
  • Angiogenesis Inhibitors
  • Glutamates

Supplementary concepts

  • Clear-cell metastatic renal cell carcinoma

Associated data

  • ClinicalTrials.gov/NCT03428217