A couple more indications for CB-839

That’s the case for Bristol-Myers Squibb (BMS) and biotechnology company Calithera Biosciences Inc., who announced in mid-May that they were expanding their collaboration to investigate Opdivo in combination with CB-839 into two new indications: non-small cell lung cancer (NSCLC) and melanoma.

The original agreement was announced on Dec. 21, 2016, when the companies shared news of a clinical trial collaboration to assess the two drugs as a combination therapy in patients with clear cell renal cell carcinoma (ccRCC). Specifically, BMS and Calithera are interested in evaluating whether this combination can target immune-suppressive cells in the tumor microenvironment and demonstrate improved, sustained efficacy in ccRCC patients whose cancer is stable or advancing on a PD-1 inhibitor therapy. No financial details were released.

“We are pleased to expand our collaboration with Calithera into NSCLC and melanoma, building upon our existing clinical study evaluating Opdivo and CB-839 in clear cell renal cell carcinoma,” said Dr. Fouad Namouni, senior vice president and head of oncology development at BMS.

CB-839 is an investigational, oral glutaminase inhibitor, and is presently in Phase 1/2 clinical trials. As Calithera explains on its website, “Genetically mandated alterations in the fundamental metabolic pathways of tumors often cause a dramatic rise in the uptake of the nutrients glucose and glutamine. Removal of glutamine leads to a substantial reduction in cell growth or induces cell death in certain types of cancer cells, indicating that these cells are dependent on, or ‘addicted’ to, glutamine. Normal cells do not show this pronounced dependence on glutamine. The enzyme glutaminase, which converts glutamine to glutamate, has been identified as a critical choke point in the utilization of glutamine by cancer cells. CB-839 is a potent, selective, reversible and orally bioavailable inhibitor of human glutaminase.”

Additionally, Calithera explains, “Inhibition of glutaminase also results in accumulation of glutamine in tumors. Glutamine, which is frequently depleted in the tumor microenvironment due to uptake by tumor cells, has been shown to be an important nutrient for T cell growth. CB-839 could potentially have an impact on the treatment of cancer by first starving the tumor cell, and second facilitating the activation of T cells in the nutrient-deprived tumor microenvironment.”

This could boost the effects of checkpoint inhibitors and reverse tumors’ resistance to such drugs. As Opdivo, a PD-1 immune checkpoint inhibitor, is engineered to overcome immune suppression and restore the immune system’s natural antitumor response, there is strong rationale for the potential efficacy of these two drugs when administered together.

CB-839 has shown antitumor activity in a number of different animal tumor models, as well as encouraging synergy with immunomodulatory agents and kinase inhibitors that target certain growth factor pathways, Calithera notes. Preclinical toxicology studies have shown that CB-839 is well tolerated in animals, even at doses above what is necessary to inhibit tumor growth.

“The expansion of this clinical collaboration with Bristol-Myers Squibb into NSCLC and melanoma is an important addition to our immunotherapy clinical strategy for CB-839,” Susan Molineaux, CEO of Calithera, commented in a press release. “This represents one of several strategies to develop CB-839, a glutaminase inhibitor, in combination with approved therapies with the hope of improving the treatment of patients with solid tumors.”

Calithera has had some early data to share on CB-839 lately, including a presentation in March at the Keystone Symposia on Tumor Metabolism. In the abstract of that presentation, the authors reported that in preclinical models, “CB-839 had a cytotoxic effect in 18 out of 23 tested RCC cell lines.” CB-839 was tested in combination with cabozantinib and everolimus, and it was found to synergize with both compounds. The presentation also noted that “The CB-839/everolimus combination showed greater anti-tumor activity, and tumor metabolomics showed evidence of oxidative stress in tumors treated with this combination. The combination of CB-839 and everolimus is currently being tested in patients with advanced RCC and is showing encouraging clinical activity.”