Dr Ayanambakkam on the FIT-001 Study in Renal Cell Carcinoma

“We’re hoping that by targeting mTOR1, we'll be able to overcome some of the mechanisms of resistance but still retain the safety signals that we want to see.”

Adanma Ayanambakkam, MD, MS, the associate program director of hematology oncology fellowship and the director of infusion services at Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, discussed the background of the phase 1a FIT-001 trial (NCT06026410) of darlifarnib plus cabozantinib (Cabometyx) in renal cell carcinoma (RCC).

FIT-001 is evaluating darlifarnib, a next-generation farnesyltransferase inhibitor, in combination with cabozantinib in patients with RCC, Ayanambakkam began. The rationale for the combination is based on the established importance of TKI therapy in RCC, as well as the role of the mTOR pathway in tumor growth, angiogenesis, disease progression, and treatment resistance, he continued.

Cabozantinib is being used to target signaling pathways that are important to RCC biology, building on the established role of TKIs in the disease, Ayanambakkam explained. He continued that at the same time, the investigators are attempting to address mechanisms of resistance through selective targeting of the mTOR pathway. mTOR signaling is particularly important in tumor growth and progression and can contribute to resistance to existing treatments, he added.

Darlifarnib is designed to inhibit farnesyltransferase. By blocking farnesylation, the agent is intended to produce selective inhibition of mTORC1, Ayanambakkam said. This approach is designed to target mTORC1 while avoiding inhibition of mTORC2, he said. The distinction between these two components of the pathway is central to the therapeutic rationale according to Ayanambakkam.

Toxicities associated with earlier mTOR inhibitors have been predominantly attributed to inhibition of mTORC2, Ayanambakkam said. Therefore, selectively targeting mTORC1 could potentially preserve the desired antitumor effects of mTOR pathway inhibition while reducing some of the toxicities associated with broader mTOR inhibition, he pointed out.

The combination of darlifarnib and cabozantinib is consequently being studied as a strategy to address both tumor signaling and potential mechanisms of treatment resistance in RCC, Ayanambakkam said. The goal is to determine whether selectively inhibiting mTORC1 alongside TKI therapy can produce meaningful activity while maintaining a favorable safety profile, he concluded.