811 - 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)

Background

Altered glucose and glutamine (gln) metabolism is a hallmark of RCC. Glutaminase (GLS) is a key enzyme in gln metabolism and drives proliferation of RCC cells when overexpressed. Tela, a novel, first-in-clinic, selective GLS inhibitor, blocks critical gln-dependent pathways and synergizes preclinically with signal transduction inhibitors (eg, E). In a phase I study in mRCC, telaE was well tolerated and had encouraging clinical activity. We present here results of a randomized phase II study of telaE vs pboE in 3L+ mRCC (NCT03163667).

Methods

Eligible pts had ≥2 prior lines of systemic therapy for mRCC, including ≥1 VEGFR-targeted tyrosine kinase inhibitor (TKI), KPS ≥70%, and measurable disease (RECIST 1.1). Pts were stratified by prior lines of TKI and MSKCC risk and randomized 2:1 to receive tela (800 mg PO BID) or pbo, plus E (10 mg PO QD), until disease progression/unacceptable toxicity. Primary endpoint is investigator-assessed progression-free survival (PFS) (RECIST 1.1; 1-sided alpha <0.2).

Results

69 pts were randomized (Table). Median PFS was 3.8 mo for telaE vs 1.9 mo for pboE (HR = 0.64 [95% CI, 0.34-1.20], 1-sided P = 0.079).Gr ≥3 adverse events (AEs) occurred in 80% telaE pts vs 60% pboE; most common were anemia (17% vs 17%), pneumonia (7% vs 4%), abdominal pain (7% vs 0%), thrombocytopenia (7% vs 0%), fatigue (4% vs 9%). Discontinuation rates due to AEs were similar (28% telaE, 30% pboE). There were no treatment-related deaths. Subgroup analyses were consistent w/ primary analysis. Survival data will be presented.Table:

LBA54

Conclusions

The addition of tela improved PFS over pboE, w/ tolerable safety profile in heavily treated mRCC pts, including refractory to multiple TKIs and immune checkpoint inhibitors. ENTRATA met its primary endpoint, supporting proof of concept for GLS inhibition w/ tela as a new therapeutic approach in RCC.

Clinical trial identification

NCT03163667; May 23, 2017.

Editorial acknowledgement

Medical writing support was provided by Ingrid Koo, PhD, and funded by Calithera Biosciences, Inc.

Legal entity responsible for the study

Calithera Biosciences, Inc.

Funding

Calithera Biosciences, Inc.

Disclosure

R.J. Motzer: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Incyte; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Bristol-Myers Squibb. C. Lee: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelexis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Pfizer; Leadership role: Kidney Cancer Association. H. Emamekhoo: Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bayer. M. Matrana: Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Genentech; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Strata Oncology. J.J. Hsieh: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution), Research funding for Kidney Cancer Therapeutics; Institutional funding for clinical trials: Eisai; Advisory / Consultancy, Research grant / Funding (self), Research funding for Kidney Cancer Genomics: Novartis; Research grant / Funding (self), Research funding for Kidney Cancer Genomics: BostonGene; Research grant / Funding (self), Research funding for Kidney Cancer Genomics: Cancer Genetics Inc; Research grant / Funding (institution), Institutional funding for clinical trials: Calithera; Research grant / Funding (institution), Institutional funding for clinical trials: BMS; Research grant / Funding (institution), Institutional funding for clinical trials: Exelixis; Leadership role, Medical Steering Committee: Kidney Cancer Association. A. Hussain: Advisory / Consultancy, Consultant; Site PI for sponsored clinical trial: Bayer; Advisory / Consultancy, Advisory Board: AstraZeneca; Advisory / Consultancy, Consultant: Bristol-Myers Squibb; Advisory / Consultancy, Advisory Board: Exelexis; Research grant / Funding (institution), Site PI for sponsored clinical trial: Sotio; Research grant / Funding (institution), Site PI for sponsored clinical trial: Calithera; Research grant / Funding (institution), Site PI for sponsored clinical trial: Merck; Research grant / Funding (institution), Site PI for sponsored clinical trial: Roche; Research grant / Funding (institution), Site PI for sponsored clinical trial: Constellation; Research grant / Funding (institution), Site PI for sponsored clinical trial: Clovis. U.N. Vaishampayan: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research support: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research support: Exelixis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (self), Research support: Novartis; Leadership role, Board Member: Michigan Society of Hematology Oncology. S. Liu: Honoraria (self): Merck; Honoraria (self): Exelixis. S. McCune: Research grant / Funding (institution), PI on this trial for our institution: Calithera. H. Parmar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences. Y. Shen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences. S.H. Whiting: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences; Spouse / Financial dependant: Seattle Genetics. N.M. Tannir: Research grant / Funding (self), Research grant / Funding (institution), Principal Investigator on clinical trials; institutional - direct costs on clinical trials: Calithera. All other authors have declared no conflicts of interest.