The potential benefit of glutaminase inhibitors in cancer is predicated on data suggesting that tumor cells have an increased dependence on glutamine due to their altered glucose metabolism via the Warburg effect. The conversion of glutamine to glutamate via the enzyme glutaminase thus serves to fuel cancer cell proliferation and survival. Blocking glutaminase with small molecule inhibitors such as telaglenastat has been shown to deprive cancer cells of glutamine as a fuel source, inhibiting their growth. RCCs are highly metabolic tumors that express high levels of glutaminase. Preclinical data demonstrated synergy in RCC models with the addition of telaglenastat to cabozantinib. Clinically, the phase 2 ENTRATA study of telaglenastat in combination with everolimus showed a tolerable safety profile and a longer median progression-free survival of 3.8 months relative to 1.9 months on everolimus alone. A phase 1 dose-expansion study of telaglenastat with cabozantinib in heavily pretreated RCC showed a 50% overall response rate and a 100% disease control rate.
These data together prompted the randomized CANTATA trial, the schema of which is shown below. A total of 444 patients, stratified by prior immune checkpoint blockade and IMDC risk stratification were randomized in a 1:1 fashion to the treatment arms shown below. The primary endpoint was progression-free survival as assessed by an independent review committee.
The study was designed to have 85% power to detect a hazard ratio for the primary outcome of 0.69 for combination therapy versus cabozantinib alone, with a 2-sided alpha of 0.05. The primary analysis data cut-off date was August 31, 2020.
As shown below, patient characteristics were balanced between arms.
Unfortunately, the primary endpoint of this study was not met, with similar median progression-free survival between the two treatment arms of approximately 9.2 months. There were no clear differences between response rates as well.
Subgroup analysis was suggestive of a numerical trend towards an improved outcome in patients with IMDC-poor-risk disease, as well as in patients who received prior immune checkpoint blockade.
A majority of patients in both treatment arms had received prior immune checkpoint blockade (62%). The median PFS of patients who had received prior ICI was 11.1 months in the telaglenastat/cabozantinib arm, and 9.2 months in the cabozantinib alone arm.
Overall survival data is not currently mature.
Treatment-related adverse events are shown below and are notable for similar rates in all presented events including diarrhea and hypertension between the two arms.
Dr. Tannir concluded that telaglenastat did not improve the median progression-free survival of metastatic RCC patients treated with cabozantinib in this study. Telaglenastat was well tolerated. Future work may focus on patients who previously received immune checkpoint blockade or tumor contexts that are especially dependent on glutaminase, though the mechanism whereby immunotherapy-treated patients would uniquely benefit from glutaminase inhibition is unclear.
Presented by: Nizar Tannir, MD, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021