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Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial
Journal article   Peer reviewed

Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial

Chung-Han Lee, Robert Motzer, Hamid Emamekhoo, Marc Matrana, Ivor Percent, James J Hsieh, Arif Hussain, Ulka Vaishampayan, Sandy Liu, Steven McCune, …
Clinical cancer research, Vol.28(15), pp.3248-3255
08/02/2022
DOI: 10.1158/1078-0432.CCR-22-0061
PMCID: PMC10202043
PMID: 35576438
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC10202043/pdf/nihms-1899632.pdfView
Open Access

Abstract

Glutaminase is a key enzyme, which 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 I 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 two prior lines of therapy [including ≥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; one-sided α <0.2). Sixty-nine patients were randomized (46 TelaE, 23 PboE). Patients had a median three 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 versus 1.9 months for PboE [HR, 0.64; 95% confidence interval (CI), 0.34-1.20; one-sided P = 0.079]. One TelaE patient had a partial response 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 to 4 events occurred in 74% TelaE patients versus 61% PboE. TelaE was well tolerated and improved PFS versus PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.
 Angiogenesis Inhibitors - therapeutic use Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - pathology Everolimus Glutaminase - therapeutic use Glutamine Humans Kidney Neoplasms - pathology Protein Kinase Inhibitors - adverse effects Sirolimus - adverse effects

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