Glutaminase Inhibitor That Starves Tumor Cells May Improve Survival in Metastatic RCC

A novel glutaminase inhibitor, CB-839, may provide a survival benefit in combination with cabozantinib (Cabometyx) by cutting off the energy supply to tumor cells in patients with metastatic renal cell carcinoma (RCC). The combination with CB-839 is being investigated in the randomized phase II CANTATA study (NCT03428217). Investigators hope to improve on the outcomes from cabozantinib alone for patients who have received a tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor. Cabozantinib is FDA approved as a second-line treatment following prior TKI therapy.

RATIONALE

CB-839 is an oral inhibitor of glutaminase, which is essential to the conversion of glutamine, an amino acid, into glutamate, which aids cell signaling. By inhibiting this process, CB-839 deprives tumor cells of energy, the availability of glutamate to the cells decreases, and cell proliferation is blocked.¹

The inhibition of glutaminase production preferentially reduces tumor cell growth over normal cells due to abnormal tumor metabolism, according to Nizar M. Tannir, MD, professor and deputy chairman in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center and the lead principal investigator and chair of the steering committee for the CANTATA trial. In addition, the glutamine that builds up in tumor cells as a result of the inhibition of glutaminase helps to fuel T-cell growth, which may increase the tumor-fighting potential of CB-839.

Cabozantinib has synergy with CB-839 because the 2 agents have different mechanisms of action, Tannir said.² Whereas CB-839 targets tumor cell energy supply and supports T-cell development, cabozantinib inhibits several kinases, including VEGF, MET, and RET, and impairs tumor growth and angiogenesis.

TRIAL DESIGN

The trial’s primary endpoint is progression-free survival (PFS), which will be assessed by an independent radiology committee. Secondary endpoints include overall survival and PFS as assessed by investigators.

WHO IS ELIGIBLE?

The study is enrolling participants with measurable clear cell RCC who have received 1 or 2 prior lines of therapy, including at least 1 antiangiogenic therapy or nivolumab (Opdivo) combined with ipilimumab (Yervoy).

REFERENCES

1. Glutaminase inhibitor CB-839. NCI Drug Dictionary. National Cancer Institute website. cancer.gov/publications/ dictionaries/cancer-drug/def/glutaminase-inhibitor-cb-839. Accessed June 12, 2018.

2. Tannir NM, Fan AC, Lee RJ, et al. Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either evero¬limus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC). J Clin Oncol. 2018;36(suppl 6S; abstr 603). meetinglibrary.asco.org/record/156891/abstract.