Telaglenastat Plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 ENTRATA Trial. Clinical cancer research : an official journal of the American Association for Cancer Research Lee, C. H., Motzer, R., Emamekhoo, H., Matrana, M., Percent, I., Hsieh, J. J., Hussain, A., Vaishampayan, U., Liu, S., McCune, S., Patel, V., Shaheen, M., Bendell, J., Fan, A. C., Gartrell, B. A., Goodman, O. B., Nikolinakos, P. G., Kalebasty, A. R., Zakharia, Y., Zhang, Z., Parmar, H., Akella, L., Orford, K., Tannir, N. M. 2022

Abstract

Glutaminase is a key enzyme that supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects which translated to encouraging safety and efficacy findings in a phase 1 trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).Eligible patients with mRCC, previously treated with at least 2 prior lines of therapy (including {greater than or equal to}1 VEGFR-targeted tyrosine kinase inhibitor [TKI]) were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; 1-sided alpha <0.2).69 patients were randomized (46 TelaE, 23 PboE). Patients had a median 3 prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE vs 1.9 months for PboE (hazard ratio [HR]=0.64; 95% confidence interval [CI]: 0.34, 1.20; 1-sided P=0.079). One TelaE patient had a partial response (PR) and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; Grade 3-4 events occurred in 74% TelaE patients vs. 61% PboE.TelaE was well tolerated and improved PFS vs PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.

View details for DOI 10.1158/1078-0432.CCR-22-0061

View details for PubMedID 35576438