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, presented supporting data for its previously reported 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 telaglenastat-everolimus 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.
Calithera announced top-line results from the ENTRATA trial in June. Data from the study were accepted as a late-breaker abstract and will be shared for the first time this morning during an oral presentation at the European Society for Medical Oncology (ESMO) Congress 2019 in Barcelona, Spain (#LBA54).
“Outcomes for late-line metastatic renal cell carcinoma are often poor using currently available medications with a similar mechanism of action,” said Chung-Han Lee, MD, PhD, Memorial Sloan Kettering Cancer Center, who will present the data. “New treatments with novel mechanisms of action are greatly needed for this patient population. The results from the randomized ENTRATA trial demonstrate activity of telaglenastat in RCC and provide proof of concept for glutaminase inhibition as a new mechanism of action that may improve outcomes for patients with this disease.”
“We continue to be encouraged by these data, which suggest that glutaminase inhibition – and telaglenastat in particular – could offer advanced RCC patients a novel therapeutic option,” said Susan Molineaux, PhD, president and chief executive officer of Calithera. “ENTRATA demonstrates a clinically meaningful improvement in progression-free survival among patients with advanced disease who have been treated with many prior lines of therapy. We are evaluating telaglenastat in the ongoing CANTATA trial in combination with cabozantinib for patients with advanced clear cell RCC, and we look forward to learning how telaglenastat performs in this setting.”
Key demographics in patients enrolled in the phase 2 ENTRATA study were balanced between the two treatment arms (telaglenastat in combination with everolimus versus placebo with everolimus) and were heavily pre-treated, with a median of three prior lines of therapy for advanced metastatic disease including 70% (72% vs. 65%) with two or more prior tyrosine kinase inhibitors (TKI), and 68% (70% vs. 65%) with intermediate/poor MSKCC prognostic score. Eighty-eight percent of patients received prior PD-1/PD-L1 therapy (91% vs. 83%).
When added to everolimus, telaglenastat 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. Overall response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1) was 2.2% vs. 0%, and stable disease was 56.5% vs. 47.8%. 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 randomized in a 2:1 ratio, and stratified by prior TKI treatment and MSKCC prognostic score. The trial enrolled 69 patients at multiple centers in the United States.
Telaglenastat is an investigational first-in-class glutaminase inhibitor specifically designed to block glutamine consumption in tumor cells. RCC tumors commonly exhibit metabolic alterations that increase their dependence on glutamine. In preclinical studies, telaglenastat produced synergistic antitumor effects when used in combination with standard-of-care RCC therapies.
Telaglenastat is also being investigated in the CANTATA trial (NCT03428217), a global, randomized, double-blind trial designed to evaluate the efficacy and safety of telaglenastat in combination with cabozantinib versus placebo with cabozantinib in patients with advanced or metastatic RCC who have been treated with one or two prior lines of systemic therapy including at least one vascular endothelial growth factor tyrosine kinase inhibitor or the combination of nivolumab and ipilimumab. In April 2018, the U.S. Food and Drug Administration granted Fast Track designation to telaglenastat in this indication. The primary endpoint is progression-free survival by blinded independent review, and a key secondary endpoint is overall survival. Calithera plans to report top-line efficacy and safety data from the trial in the second half of 2020.
Calithera Biosciences, Inc. 2019. “Data From Randomized Phase 2 ENTRATA Study Demonstrate Telaglenastat with Everolimus Improves Progression-Free Survival in Renal Cell Carcinoma”. GlobeNewswire News Room. https://www.globenewswire.com/news-release/2019/09/28/1922137/0/en/Data-From-Randomized-Phase-2-ENTRATA-Study-Demonstrate-Telaglenastat-with-Everolimus-Improves-Progression-Free-Survival-in-Renal-Cell-Carcinoma.html.