Nizar M. Tannir, MD
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). Although there are several treatment options available for patients with metastatic RCC, some patients still have progressive disease after prior lines of therapy.
Inhibition of glutaminase is preferentially inhibitory to tumor cells over normal cells due to abnormal tumor metabolism, according to Tannir, 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.
Figure. CB-839 in Patients with Clear Cell RCC
Cabozantinib has synergy with CB-839 because the 2 agents have very different mechanisms of action, Tannir said. 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.
These previous studies have made the investigators optimistic about the outcome of the CANTATA trial. “If the combination is proven to be superior to cabozantinib plus placebo, then the FDA will hopefully approve the combination [in patients with clear cell RCC] after either TKI or immune checkpoint therapy,” Tannir said.
- Glutaminase inhibitor CB-839. NCI Drug Dictionary. National Cancer Institute website. Accessed June 12, 2018. cancer.gov/publications/ dictionaries/cancer-drug/def/glutaminase-inhibitor-cb-839.
- Glutaminase inhibitor CB-839. Calithera website. Accessed June 12, 2018. calithera.com/glutaminase-inhibitor-cb-839/.
- Emberley E, Bennett M, Chen J, et al. CB839, a selective glutamase inhibitor, has anti-tumor activity in renal cell carcinoma and synergizes with cabozantinib and everolimus. Presented at: Keystone Symposia, Tumor Metabolism: Mechanisms and Targets; March 5-9, 2017. Whistler, Canada. calithera.com/wp-content/uploads/2017/12/03.2017-Keystone- poster-Emberley-2017.pdf.
- Meric-Bernstam F, Tannir NM, Mier JW, et al. Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), alone and in combination with everolimus (E) in patients (pts) with renal cell cancer (RCC). J Clin Oncol. 2016;34(suppl; abstr 4568). meetinglibrary.asco.org/record/122796/abstract.
- Tannir NM, Fan AC, Lee RJ, et al. Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (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.
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