Calithera announced the positive results from its Phase 2 ENTRATA study of telaglenastat (CB-839) in combination with everolimus in patients with advanced renal cell carcinoma (RCC). The combination doubled the median progression-free survival (PFS) in heavily pre-treated patients with advanced RCC and had a well-tolerated safety profile. Telaglenastat is the first glutaminase inhibitor to demonstrate clinical activity for the treatment of cancer.
ENTRATA was a randomized, double-blind Phase 2 trial designed to evaluate the efficacy and safety of telaglenastat in combination with everolimus versus placebo with everolimus in patients with advanced clear cell RCC who have been treated with at least two prior lines of systemic therapy, including at least one VEGFR-targeted TKI. Patients were stratified by prior TKI treatment and MSKCC prognostic score. The trial enrolled 69 patients at multiple centers in the United States. The primary endpoint of the trial was PFS per investigator assessment with a predetermined threshold of p≤0.2 one-sided. Telaglenastat, when added to everolimus, doubled the median PFS to 3.8 months as compared to 1.9 months for everolimus alone and reduced the risk of disease progression or death by 36% (HR=0.64, p=0.079 one-sided). The secondary endpoint of overall survival is not yet mature. Frequency of all-grade adverse events in the telaglenastat-containing arm were comparable to that of everolimus alone. The most frequently reported Grade ≥3 adverse events in the treatment versus control arms, respectively, were anemia, pneumonia, abdominal pain, thrombocytopenia and fatigue. Adverse events leading to discontinuation of any study drug were comparable.
About Clear Cell Renal Cell Carcinoma
Clear cell renal cell carcinoma is a cancer of the kidney and represents around 75-80% of cases of renal cell carcinoma. The name “clear cell” refers to the appearance of the cancer cells when viewed with a microscope. Clear cell renal cell carcinoma occurs when cells in the kidney quickly increase in number, creating a mass. Though the exact cause of clear cell renal cell carcinoma is unknown, smoking, the excessive use of certain medications, and several genetic predisposition conditions (such as von Hippel Lindau syndrome) may contribute to the development of this type of cancer. Treatment often begins with surgery to remove as much of the cancer as possible, and may be followed by radiation therapy, chemotherapy, biological therapy, or targeted therapy.
Telaglenastat is a glutaminase inhibitor specifically designed to block glutamine consumption in tumor cells. RCC tumors commonly exhibit specific genetic alterations that cause cancer cells to increase metabolism of glutamine. In preclinical studies, telaglenastat produced synergistic antitumor effects when used in combination with standard-of-care RCC therapies, including everolimus and cabozantinib.
Telaglenastat is currently being investigated in the CANTATA trial, a global, randomized, double-blind Phase 2 trial designed to evaluate the efficacy and safety of telaglenastat in combination with cabozantinib versus placebo with cabozantinib in patients with advanced clear cell RCC who have been treated with one or two prior lines of systemic therapy.