“The achievement of positive topline results in our first randomized trial is a significant milestone 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.“
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.
International Kidney Cancer Symposium
Scheduled for November 15-16
MIAMI—The 18th International Kidney Cancer Symposium, featuring the most comprehen-sive agenda and program focused on renal cell carcinoma, will be held November 15-16 at the Trump National Doral Miami Hotel. Researchers and medical staff from leading centers worldwide will gather for an exchange of ideas and information that will frame future research and treatment of RCC.
Registration and full details on the agenda is available online through the Association’s website, kidneycancer.org.
Updated Overall Survival Hazard Ratio of 0.99 Reported in Phase 3
TIVO-3 Trial of Tivozanib in Renal Cell Carcinoma
CAMBRIDGE, MA—AVEO Oncology has announced results from the second prespecified analysis of overall survival (OS) in the TIVO-3 trial. TIVO-3 is the Company’s Phase 3 randomized, controlled, multi-center, open-label study to compare tivozanib (FOTIVDA®) to sorafenib in 350 subjects with highly refractory metastatic renal cell carcinoma (RCC). These results include an OS hazard ratio (HR) below 1.00, favoring tivozanib (HR=0.99; 95% CI: 0.76-1.29; P=0.95). TIVO-3 is the first and only positive Phase 3 study in third and fourth line RCC, and the first Phase 3 study in RCC to investigate a predefined subpopulation of patients who received prior immunotherapy, an emerging standard of care for earlier lines of therapy.
The Company plans to discuss the updated OS results with the FDA to identify the appropriate path forward for tivozanib in RCC in the fourth quarter, and to provide an update regarding the potential submission of a New Drug Application for tivozanib in RCC following these discussions.
“These are the first data to demonstrate durable improvements in this highly refractory advanced kidney cancer population, including the post-immunotherapy setting, a predefined subset of the TIVO-3 trial,” said Brian Rini, MD, Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Director, Cleveland Clinic Genitourinary Cancer Program, and principal investigator of the TIVO-3 trial. “The TIVO-3 study suggests the potential for tivozanib to serve as an important new treatment option for patients with advanced RCC. I look forward to seeing tivozanib studied further in theimmunotherapy combination setting, and to continuing to explore its full potential in the evolving RCC treatment landscape.”
EAU Calls Upfront Immune Checkpoint
Inhibition New Metastatic RCC Standard of Care
Updated guidelines from the European Association of Urology (EAU) consider immune checkpoint inhibition with pembrolizumab plus axitinib or ipilimumab plus nivolumab to be a new standard of care for the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC).
According to the guidelines, the EAU recommends that physicians offer pembrolizumab plus axitinib to treatment-naïve patients with any IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) risk disease and ipilimumab plus nivolumab to treatment-naïve patients with IMDC intermediate- and poor-risk disease. The recommendations are based on clinical trials showing that these combinations are associated with a survival benefit in these patients. In the KEYNOTE-426 trial, the combination of pembrolizumab and axitinib was associated with a significant 47% decreased risk of death compared with sunitinib monotherapy. It also was associated with a significant 31% decreased risk of disease progression. In the Checkmate 214 trial, the combination of ipilimumab and nivolumab was associated with a significant 37% decreased risk of death compared with sunitinib monotherapy. KCJ