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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 May 16 [Epub ahead of print]
Chung-Han Lee, Robert Motzer, Hamid Emamekhoo, Marc Matrana, Ivor Percent, James J Hsieh, Arif Hussain, Ulka Vaishampayan, Sandy Liu, Steven McCune, Vijay Patel, Montaser Shaheen, Johanna Bendell, Alice C Fan, Benjamin A Gartrell, Oscar B Goodman, Petros G Nikolinakos, Arash Rezazadeh Kalebasty, Yousef Zakharia, Zhentao Zhang, Hema Parmar, Lalith Akella, Keith Orford, Nizar M Tannir
Memorial Sloan Kettering Cancer Center, New York, NY, United States., University of Wisconsin-Madison, Madison, WI, United States., Ochsner Health System, United States., Florida Cancer Specialists and Research Institute/Sarah Cannon Research Institute, punta gorda, United States., Washington University in St. Louis, St. Louis, MO, United States., University of Maryland Medical Center, Baltimore, MD, United States., University of Michigan Medical School, Ann Arbor, Michigan, United States., University of California, Los Angeles, Los Angeles, United States., WellStar Health System, Marietta, GA, United States., Florida Cancer Specialists & Research Institute, St. Petersburg, FL, United States., University of Arizona Cancer Center, United States., Sarah Cannon Research Institute, Basel, Switzerland., Stanford University, Stanford, CA, United States., Montefiore Medical Center, Bronx, NY, United States., Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, United States., University Cancer & Blood Center, LLC, Athens, GA, United States., Norton Cancer Institute, Louisville, KY, United States., University of Iowa Hospitals and Clinics, Iowa City, IA, United States., Parkview Cancer Institute, Fort Wayne, IN, United States., Calithera Biosciences Inc, South San Francisco, CA, United States., Calithera Biosciences, Inc., South San Francisco, CA, United States., The University of Texas MD Anderson Cancer Center, Houston, TX, United States.