Telaglenastat Added to Everolimus Doubles PFS in Heavily Pretreated RCC

Susan Molineaux, PhD

Combining telaglenastat (CB-839) with everolimus (Afinitor) doubled the median progression-free survival (PFS) versus everolimus alone in heavily pretreated patients with advanced renal cell carcinoma (RCC), according to Calithera Biosciences, the company developing the glutaminase inhibitor.

The median PFS was 3.8 months with the addition of telaglenastat compared with 1.9 months with everolimus alone, which translated to a 36% reduction in the risk of disease progression or death (HR, 0.64; one-sided P = .079).

“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,” Susan Molineaux, PhD, president and chief executive officer of Calithera, said in a press release. “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.”

Genetic changes in RCC tumors have been shown to increase metabolism of glutamine, and telaglenastat is designed to inhibit tumor cell consumption of glutamine, Calithera explained in the press release. Further, the investigational treatment has demonstrated synergistic antitumor activity when combined with standard RCC therapies in preclinical studies.

The double-blind, multicenter, randomized phase II ENTRATA trial (NCT03163667) accrued 69 patients with advanced clear cell RCC who had received ≥2 prior lines of systemic therapy. The MSKCC prognostic score was intermediate/poor risk for 68% of patients. Patients had received a median of 3 prior lines of therapy for metastatic disease. Seventy percent of patients had received ≥2 prior TKIs and 88% had received a PD-1 or PD-L1 inhibitor. Prior treatment with mTOR inhibitors was not allowed.

Patients on the trial were randomized to standard daily everolimus plus telaglenastat tablets or placebo twice daily in 28-day cycles. The primary endpoint of ENTRATA was investigator-assessed PFS (threshold for success: one-sided P ≤.2). Date were not yet mature for the secondary endpoint of overall survival. Calithera plans to present full data from the trial at an upcoming medical meeting.

Adverse events (AEs) rates across all grades occurred at similar rates between the telaglenastat and control arms; however, grade ≥3 AEs were higher with telaglenastat at 80.4% versus 60.9% with everolimus alone. The most common grade ≥3 AEs in the telaglenastat 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%). Discontinuations related to AEs occurred in 28.3% versus 30.4% of the telaglenastat combination and everolimus-alone arms, respectively.

Telaglenastat is also being explored in combination with cabozantinib (Cabometyx) in the phase II CANTATA trial. The double-blind trial is randomizing patients with advanced clear cell RCC to cabozantinib plus either placebo or telaglenastat. Patients must have received 1 or 2 prior lines of systemic therapy. The target enrollment is 400 patients and PFS is the primary endpoint. Data from the trial are anticipated from Calithera by the end of 2020.

Calithera Achieves Positive Topline Results in Randomized Phase 2 ENTRATA Study of Telaglenastat with Everolimus in Renal Cell Carcinoma. Calithera Biosciences, Inc. Published online June 17, 2019. Accessed June 18, 2019. https://bit.ly/2WQhbKH.