Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer.
We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts.
We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-naïve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1.
Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.
ESMO open. 2025 May 12 [Epub ahead of print]
M A Gouda, M H Voss, H Tawbi, M Gordon, S S Tykodi, E T Lam, U Vaishampayan, N M Tannir, J Chaves, P Nikolinakos, A Fan, R Lee, D McDermott, G I Shapiro, L Gandhi, S Bhatia, V Katragadda, F Meric-Bernstam
The University of Texas MD Anderson Cancer Center, Houston, USA., Memorial Sloan Kettering Cancer Center, New York., Pinnacle Oncology Hematology, Scottsdale, USA., University of Washington and Fred Hutchinson Cancer Center, Seattle, USA., University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, USA; University of Michigan, Ann Arbor, USA., Karmanos Cancer Institute, Detroit, USA., Northwest Medical Specialties, Tacoma, USA., University Cancer & Blood Center, Athens, USA., Stanford University Medical Center, Stanford, USA., Massachusetts General Hospital, Boston, USA., Beth Israel Deaconess Medical Center, Boston, USA., Dana-Farber Cancer Institute, Boston, USA., NYU Medical Oncology Associates, New York, USA., Cornerstone Pharmaceuticals Inc., East Windsor Township, USA., The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: .