A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.

backgroundTelaglenastat (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. PATIENTS AND

methodsWe 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.

resultsWe 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.

conclusionsTelaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.