Dr Ayanambakkam on the Mechanism of Action of Darlifarnib in ccRCC

“The difference between darlifarnib and other drugs inhibiting the mTOR complex is that it is very specific to mTOR1 inhibition, and thus it has a better safety and tolerability profile.”

Adanma Ayanambakkam, MD, MS, the associate program director of hematology oncology fellowship and the director of infusion services at the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, discussed the mechanism of action of darlifarnib (KO-2806) for the treatment of patients with clear cell renal cell carcinoma (ccRCC).

Darlifarnib is a next-generation farnesyltransferase inhibitor that has shown promising preclinical efficacy, Ayanambakkam began. By blocking the farnesylation of farnesyltransferase, the agent is able to prevent mTOR1 activation, predominantly through mTOR1 inhibition, he continued.

mTOR inhibition has previously shown activity in renal cell carcinoma with drugs such as everolimus (Afinitor), Ayanambakkam said. However, darlifarnib distinguishes itself from other mTOR inhibitors by being highly specific for mTOR1, he explained. Because of this high specificity, the drug has a better safety and tolerability profile compared with approved mTOR inhibitors, he concluded.

Darlifarnib in combination with cabozantinib (Cabometyx) was evaluated in the phase 1a/1b FIT-001 trial (NCT06026410). Preliminary data from FIT-001 were shared during the 2026 International Kidney Cancer Symposium: Europe.

FIT-001 was the first-in-human study evaluating darlifarnib alone and in combination with cabozantinib in adult patients with advanced solid tumors. To be eligible for enrollment, patients with ccRCC were required to have received at least 1 prior immunotherapy-based regimen and have a Karnofsky performance score of at least 70. Patients with non-ccRCC needed to be treatment naive or have received any prior systemic treatment.

Disclosures: Ayanambakkam reported consulting or advisory roles with AVEO, Pfizer/Astellas, Johnson & Johnson, and Kura Oncology. He received travel, accommodations, and/or expenses from Kura Oncology and research funding from Regeneron.