San Francisco, CA (UroToday.com) — Calithera Biosciences, Inc., a clinical stage biotechnology company focused on discovering and developing novel small molecule drugs for the treatment of cancer and other life-threatening diseases, announced positive results from its randomized placebo-controlled 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.
“The achievement of positive topline results in our first randomized trial is a significant milestone for Calithera because it provides clinical proof of concept for telaglenastat,” said Susan Molineaux, PhD, president, and chief executive officer of Calithera. “This study demonstrates a clinically meaningful improvement in progression free survival in patients with advanced renal cell carcinoma who have been treated with many prior lines of therapy, including immunotherapy and multiple tyrosine kinase inhibitors. We look forward to the outcome of the ongoing CANTATA trial of telaglenastat in combination with cabozantinib for patients with advanced clear cell RCC.”
Patients enrolled were heavily pre-treated with a median of three prior lines of therapy for advanced metastatic disease including 70% with two or more prior tyrosine kinase inhibitors (TKI), and 68% with intermediate/poor MSKCC prognostic score. Eighty-eight percent of patients received prior PD-1/PD-L1 therapy. 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 primary endpoint of the trial was PFS per investigator assessment with a predetermined threshold of p≤0.2 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. Grade 3 or higher adverse events occurred in 80.4% of patients in the telaglenastat plus everolimus arm versus 60.9% in the everolimus plus placebo arm. The most frequently reported Grade ≥3 adverse events in the treatment versus control arms, respectively, were anemia (17.4% vs. 17.4%), pneumonia (6.5% vs. 4.3%), abdominal pain (6.5% vs. 0%), thrombocytopenia (6.5% vs. 0%), and fatigue (4.3% vs. 8.7%). Adverse events leading to discontinuation of any study drug were comparable (28.3% vs. 30.4%).
The ENTRATA trial (NCT03163667) is 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. Calithera intends to present data at an upcoming medical meeting.
Telaglenastat is an investigational, novel 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 also 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. CANTATA will enroll approximately 400 patients and is designed with registrational intent. The primary endpoint is PFS by blinded independent review. Calithera expects data from this trial in the second half of 2020.