Adding the investigational glutaminase inhibitor telaglenastat to everolimus extends progression-free survival (PFS) compared with everolimus alone in patients with heavily pretreated advanced renal cell carcinoma (RCC), according to findings from the phase II ENTRATA study presented at the 2019 ESMO Congress.
In the randomized, double-blind ENTRATA study, the median PFS was 3.8 months in the telaglenastat plus everolimus arm compared with 1.9 months in the placebo plus everolimus arm (HR, 0.64; 95% CI, 0.34-1.20; one-sided P = .079). The improvement in median PFS with the addition of telaglenastat met the prespecified threshold for achieving the primary endpoint (investigator-assessed PFS), which was set at a one-sided P value of 0.2.
“The ENTRATA study supports proof of concept for telaglenastat and supports glutaminase inhibition as a new therapeutic strategy for metastatic RCC for further study,” said study investigator Chung-Han Lee, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center.
Increased glutamine and glucose metabolism supports tumor cell growth and proliferation. In tumors, cells undergo a metabolic shift in which growth factors drive abnormal glucose metabolism, known as the Warburg effect, which deprives the TCA cycle of key metabolites. “To compensate for this metabolic shift, glutamine metabolism is increased to sustain the TCA cycle for growth and proliferation,” said Lee.
Telaglenastat is an oral inhibitor of glutaminase, the key enzyme for conversion of glutamine to glutamate. In preclinical studies, telaglenastat in combination with the mTOR inhibitor everolimus inhibited both glucose and glutamine metabolic pathways and demonstrated synergistic antiproliferative activity. In mouse xenograft models, the combination enhanced the antitumor activity of everolimus.
A phase Ib study of 24 patients with metastatic RCC who had a median of 2 prior lines of therapy showed that the combination of telaglenastat and everolimus was associated with a disease control rate of 92% and a median PFS of 5.8 months, “which compared favorably to historical controls,” Lee said.
Patients with advanced clear cell RCC who had been treated with ≥2 prior lines of systemic therapy, including at least 1 VEGF receptor—targeted TKI, were eligible for ENTRATA. They were randomized in a 2:1 ratio to telaglenastat at 800 mg twice daily plus everolimus at 10 mg/day, or placebo plus everolimus. Patients with treated or stable brain metastases were allowed into the study. Prior mTOR inhibitor therapy was not permitted.
The 69 patients enrolled were heavily pretreated with a median of 3 prior lines of therapy, including 70% who received ≥2 prior TKIs. Median patient age was about 65 years, and 80% (telaglenastat arm) and 87% (placebo arm) were male. Some 68% of patients had an intermediate/poor MSKCC prognostic score. Some 91% in the telaglenastat arm and 83% in the placebo arm received prior PD-1/PD-L1 inhibitor therapy. “Patients had multiple sites of disease, with one-third of patients having bone metastases,” Lee said.
Subgroup analysis by age, sex, race, performance status, number of prior TKIs, MSKCC risk stratification, and prior PD-1/PD-L1-directed therapy did not identify any subgroups with disproportionate benefit, Lee said. “However, the trial was not powered to detect any differences within these subgroups.”
Best tumor response in the telaglenastat/everolimus arm was a partial response in 2.2% and stable disease in 56.5%. in the placebo/everolimus arm, there were no objective responses and best response was stable disease in 47.8%. The secondary endpoint of overall survival is not yet mature.
The rate of treatment-emergent adverse events leading to treatment discontinuation was similar between the arms: 28.3% in the telaglenastat/everolimus and 30.4% in the placebo/everolimus arm. Dose interruption or reduction of any drug due to adverse events occurred in 76.1% of patients randomized to telaglenastat/everolimus compared with 60.9% of those randomized to placebo/everolimus. Grade ≥3 adverse events occurred in 80% of patients in the telaglenastat plus everolimus arm versus 61% in the everolimus plus placebo arm. The most frequently reported grade ≥3 adverse events in the treatment versus control arms, respectively, were anemia (17% vs 17%) and fatigue (4% vs 9%).
Currently ongoing is the CANTATA  study (NCT03428217), which is a global, randomized, double-blind phase II study comparing telaglenastat in combination with cabozantinib versus placebo with cabozantinib in patients with advanced or metastatic renal cell carcinoma.
Motzer RJ, Lee C-H, Emamekhoo H, et al. ENTRATA: Randomized, double-blind, phase 2 study of telaglenastat (tela; CB-839) + everolimus (E) vs. placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA54.