Bettering Survival With Telaglenastat Combinations in RCC

In the field of renal cell carcinoma (RCC), researchers are pursuing clinical trials of novel combination regimens that can approve upon the efficacy of existing drugs. Such a drug is telaglenastat (CB-839), which is currently being evaluated in combination with everolimus (Afinitor) as treatment of patients with advanced or metastatic RCC in the phase 2 ENTRATA study (NCT03163667).

Based on results reported in 2019, the study of 69 patients showed a significant improvement in progression-free survival (PFS) with telaglenastat/everolimus versus telaglenastat and placebo. The median PFS was 3.8 months compared with 1.9 months (HR, 0.64; 95% CI, 0.34-1.20; 1-sided P =.079).

The safety profile with the combination was tolerable with the most common grade ≥3 adverse events being anemia (17% vs. 17%), pneumonia (7% vs. 4%), abdominal pain (7% vs. 0%), thrombocytopenia (7% vs. 0%), fatigue (4% vs. 9%), in the telaglenastat comparator arm versus the control arm respectively. The treatment discontinuation rate observed with telaglenastat plus everolimus was 28% and telaglenastat plus placebo was 30%.

In an interview with Targeted Oncology, Chung-Han Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, provided background on the phase 2 ENTRATA study and discussed the next steps with telaglenastat in the RCC treatment landscape.

TARGETED ONCOLOGY: What was the rationale for the ENTRATA study?

Lee: Telaglenastat is a glutaminase inhibitor. It is well known that kidney cancer is a disease of altered metabolism. The hypothesis was that GLS inhibition of both glucose and glutamine metabolism would improve responses within metastatic kidney cancer.

TARGETED ONCOLOGY: Can you explain the study design?

Lee: The trial that we designed was a randomized, double-blind phase 2 clinical trial of the combination of telaglenastat plus everolimus versus everolimus plus placebo. The design of the trial was for patients who progressed on at least 2 prior lines of systemic therapy and allowed for things like brain metastases. The primary end point was investigator-assessed for progression-free survival with a key secondary end point of overall survival. In terms of prior progression, most patients had progressed on tyrosine kinase inhibitors.

TARGETED ONCOLOGY: What was exciting about the study results?

Lee: The results were that the trial did meet its pre-specified PFS end point and demonstrated an improved PFS with the combination of telaglenastat plus everolimus versus Placebo plus everolimus.

TARGETED ONCOLOGY: Were there any toxicities associated with the combination of telaglenastat and everolimus?

Lee: The toxicities that were seen were fairly similar across both cohorts. There were equal numbers of patients who required either a dose reduction or discontinuation of either drug.

Overall, it's very important to remember that in the study we had very heavily pretreated patients. We were able to treat with full doses of everolimus without adding significant toxicity. That speaks to the safety of the drug.

TARGETED ONCOLOGY: What are the next steps with this research?

Lee: This study serves as a proof of concept of the mechanism of action, and glutaminase inhibition represents a new mechanism of action that has not yet been applied to metastatic kidney cancer. The study that will further define the role of telaglenastat is the CANTATA study, which is a randomized trial of 400 plus patients with the combination of telaglenastat and cabozantinib versus placebo plus cabozantinib (Cabometyx).

_Reference:

_{Motzer RJ, LeeCH, Emamekhoo H, et al. LBA54 - ENTRATA: Randomized, double-blind, phase II study of telaglenastat (tela; CB-839) + everolimus (E) vs placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). Ann Oncol. 2019;30(5): 889-890. doi: 10.1093/annonc/mdz394.048.}