Agent That Starves Tumor Cells May Improve Survival in Metastatic RCC

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.

The combination with CB-839 is being investigated in the randomized, phase II CANTATA study (NCT03428217). The study is enrolling participants with measurable clear cell RCC who have received 1 or 2 prior lines of therapies, including at least 1 antiangiogenic therapy or nivolumab (Opdivo) combined with ipilimumab (Yervoy).

“[The trial] will bring a first-in-its-class glutaminase-targeted drug as an addition to our armamentarium to treat this disease,” said Nizar M. Tannir, MD, professor and deputy chairman in the department of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center in Houston. 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 in the frontline setting and as a second-line treatment following prior TKI therapy.

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

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 is decreased, and cell proliferation is blocked.¹

Figure. CB-839 in Patients with Clear Cell RCC

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.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.

In preclinical studies, CB-839 has been shown to kill or halt the growth of cancer cells across several solid tumor types.² Prior studies have also demonstrated that CB-839 has strong synergy with cabozantinib in patients with RCC. One study noted that CB-839 treatment of RCC cells causes decreases in glutamine-derived metabolites, mTOR pathway signaling, and cellular proliferation, and that combining the drug with cabozantinib enhances antitumor activity in xenograft mouse models.³

A phase I trial (NCT02071862) demonstrated that CB-839 is safe and effective in patients with RCC, either as a monotherapy or in combination with everolimus (Afinitor). Of the 21 evaluable patients who received CB-839 monotherapy, there was 1 partial response (PR) and 10 patients achieved stable disease. The disease control rate was 52%, and the drug was well tolerated.⁴

The most common adverse events (AEs) observed in the monotherapy arm of the phase I trial were fatigue (33%), nausea (26%), and constipation (15%). The study authors noted that the AEs were easily manageable and reversible.⁴

Updated results from this study demonstrated that when CB-839 was combined with cabozantinib, the combination led to a 40% overall response rate in patients with clear cell RCC (33% for all histologies) and a 100% disease control rate. There were 4 PRs for all patients with RCC, and 8 patients achieved stable disease.⁵ Tannir noted that they also determined the recommended phase II dose to be 800 mg administered orally twice a day.

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.

References

1. 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.
2. Glutaminase inhibitor CB-839. Calithera website. Accessed June 12, 2018. calithera.com/glutaminase-inhibitor-cb-839/.
3. 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.
4. 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.
5. 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.