1. Telaglenastat addition to cabozantinib did not show improvements in clinical benefit.

2. Adverse events of grades 3 or 4 occurred slightly less in the combination arm, with the most common consisting of hypertension and diarrhea.

Evidence Rating Level: 1 (Excellent)

Study Rundown: In preclinical trials, telaglenastat (an oral glutaminase inhibitor) showed synergy with cabozantinib (an inhibitor of multiple tyrosine kinase receptors) in renal cell carcinoma (RCC). This study explored the efficacy and safety of telaglenastat and cabozantinib in patients with advanced RCC who had disease progression on first and second-line therapies, specifically at least one antiangiogenic therapy or nivolumab plus ipilimumab. Patients were randomly assigned to receive cabozantinib and either telaglenastat or placebo. Median progression-free survival (PFS), both investigator-assessed and independent radiology committee-adjudicated (IRC), were not statistically significant between the two arms. Overall response rates (ORR) and median duration of response were marginally higher in the combination arm. Occurrence of treatment-emergent adverse events (TEAEs) were similar between arms. TEAEs of grades 3 or 4 occurred slightly less in the combination arm, with the most common events being hypertension and diarrhea. More patients discontinued treatment due to adverse events from cabozantinib in the placebo group than the combination group. Limitations to this study include a predominantly male population and the absence of biomarkers that could provide knowledge on the effects of each agent on glucose and glutamine metabolism. The strength of this study is that is has limited bias given its design. Also, while telaglenastat did not show benefit with cabozantinib, it did not exacerbate adverse events associated with cabozantinib, potentially making it worthwhile to test telaglenastat with other therapeutic partners. Overall, telaglenastat is not a viable therapeutic partner for cabozantinib.

Click to read the study in JAMA Oncology

Relevant Reading: Combination drug regimens for metastatic clear cell renal cell carcinoma

In-Depth [randomized control trial]: This international phase II trial included 444 patients with metastatic clear-cell RCC following progression on first and second-line therapies, including at least one antiangiogenic therapy or nivolumab plus ipilimumab. Patients were randomly assigned in a 1:1 ratio to receive either telaglenastat plus cabozantinib or placebo plus cabozantinib; 221 were in the former arm and 223 were in the latter arm. Median IRC-assessed PFS was 9.2 months and 9.3 months in the combination group and placebo group, respectively (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.74 to 1.21; P=0.65). Median investigator-assessed PFS was 9.2 months and 8.4 months, respectively (HR, 1.00; 95% CI, 0.79 to 1.25; P=0.97). ORR was 31% and 28%, respectively. Median duration of response was 12.0 months and 11.2 months, respectively. TEAEs of grades 3 and 4 occurred in 71% of patients in the combination group and in 79% in the placebo group, with the most common events being hypertension (17% in combination group vs. 18% in placebo group) and diarrhea (15% vs. 13%, respectively). Adverse events that led to the discontinuing of cabozantinib occurred in 10% of patients in the combination group and 15% of patients in the placebo group. Overall, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC.

Image: PD

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