As reported in JAMA Oncology by Nizar M. Tannir, MD, FACP, and colleagues, the phase II CANTATA trial showed no improvement in progression-free survival with the addition of the glutaminase inhibitor telaglenastat to cabozantinib in previously treated patients with metastatic clear cell renal cell carcinoma.

As stated by the investigators, “Dysregulated metabolism is a hallmark of renal cell carcinoma. 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.”

Nizar M. Tannir, MD, FACP

Study Details

In the double-blind trial, 444 patients from sites in the United States, Europe, Australia, and New Zealand were randomly assigned between November 2018 and September 2019 to receive cabozantinib at 60 mg daily plus telaglenastat at 800 mg twice daily (n = 221) or placebo (n = 223), with treatment continued until disease progression or unacceptable toxicity. Patients had disease progression after one or two prior lines of therapy, including one or more antiangiogenic therapies or nivolumab/ipilimumab. A total of 276 patients (62%) had received prior immune checkpoint inhibitors, including nivolumab/ipilimumab in 128; 93 patients in the nivolumab/ipilimumab group had not received prior antiangiogenic therapy.

The primary endpoint was progression-free survival on blinded independent radiology review.

Progression-Free Survival

Median follow-up at the time of progression-free survival analysis was 11.7 months. Median progression-free survival was 9.2 months (95% confidence interval [CI] = 7.6–11.1 months) in the telaglenastat/cabozantinib group vs 9.3 months (95% CI = 7.6–11.0 months) in the control group (hazard ratio = 0.94, 95% CI = 0.74–1.21, P = .65).

An objective response was observed in 69 patients (31%) in the combination group, including complete response in 2 (1%), and in 62 patients (28%) in the control group, including complete response in 2 (1%). Median durations of response were 12.0 vs 11.2 months, respectively.

Overall survival data were not mature at the time of analysis. Preliminary evaluation showed no difference between groups, with median durations of 22.2 months vs 24.8 months. Statistical testing was not performed due to lack of significance in the progression-free survival analysis, and no further analysis is planned.

Adverse Events

Grade 3 or 4 adverse events occurred in 71% of patients in the telaglenastat/cabozantinib group vs 79% of the control group. The most common in the combination group were hypertension (17% vs 18% in control group), diarrhea (15% vs 13%), palmar-plantar erythrodysesthesia syndrome (7% vs 7%), and fatigue (7% vs 9%). Adverse events led to discontinuation of telaglenastat or placebo in 12% vs 13% of patients, and adverse events led to discontinuation of cabozantinib in 10% of the combination group vs 15% of the control group. Adverse events led to death in six patients in the combination group, with one (intracranial hemorrhage) considered related to treatment, and in three patients in the control group, with none considered related to treatment.

The investigators concluded, “In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic renal cell carcinoma. Telaglenastat plus cabozantinib was well tolerated with adverse events consistent with the known risks of both agents.”

Dr. Tannir, of the Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by Calithera Biosciences, Inc. For full disclosures of the study authors, visit jamanetwork.com.