Everolimus, CB-839 Combination Active in Advanced RCC

The combination of CB-839, a first-in-class selective inhibitor of glutaminase, and everolimus seems to have disease activity in patients with advanced renal cell carcinoma (RCC), according to the results of a phase I study (abstract ENA-0419) presented at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany.

“To date, tumors in 93% of patients with clear cell and papillary renal cell cancers have had tumor control from the regimen, with a median time without their cancer growing of 8.5 months,” said Funda Meric-Bernstam, MD, of the University of Texas MD Anderson Cancer Center in Houston, in a press release. “For more than half of these patients their time on this treatment has been longer than the time they remained on their prior treatment, which is considered to be a good sign.”

CB-839 targets glutaminase, an enzyme involved in the conversion of glutamine to glutamate, which is an important nutrient for cancer cells. Early preclinical studies of CB-839 showed that the drug had broad monotherapy activity in RCC, a disease where glutaminase is highly expressed.

This study included patients with previously treated advanced or metastatic RCC, including clear cell and papillary RCC. All patients had four or fewer previous lines of therapy, an ECOG performance status of 0 or 1, and RECIST-measurable disease. Prior treatment with mTOR inhibitors or a checkpoint inhibitor was allowed. The median number of prior therapies was two.

The patients were assigned to escalating doses of CB-839 between 400 and 800 mg twice daily combined with a fixed dose of 10-mg everolimus. Disease assessment was performed every 8 weeks.

According to Meric-Bernstam, out of 15 patients with clear cell and papillary RCC who have received the drug combination, 93% had their tumor controlled by the regimen. One patient experienced a partial response, with a 30% decrease in tumor size; an additional 13 patients have stable disease. One patient had progressive disease.

Overall, the combination treatment was well tolerated. The researchers observed only one dose-limiting toxicity, a grade 3 rash that occurred at the 400-mg dose. No grade 4 or 5 adverse events occurred, and any grade 3 events were consistent with late-stage cancer or everolimus toxicity, according to the study abstract.

“These results suggest that CB-839 is a very tolerable drug with significant potential in combination therapy for kidney cancer patients,” Meric-Bernstam concluded.