Darlifarnib Plus Cabozantinib Shows Durable Activity in Advanced RCC

Updated phase 1a data from the ongoing FIT-001 trial (NCT06026410)¹ show that darlifarnib (KO-2806), an investigational farnesyltransferase inhibitor (FTI), combined with cabozantinib (Cabometyx) produced objective response rates (ORRs) of 33% to 50% across evaluated dose levels in patients with cabozantinib-naive, advanced clear cell renal cell carcinoma (ccRCC) who had received prior systemic therapy. Median progression-free survival (PFS) was 13 months across pooled dose cohorts. The findings were presented at the Kidney Cancer Research Summit (KCRS) in Boston, Massachusetts.²

The results, drawn from an efficacy-evaluable population of 34 patients, add to a growing dataset supporting darlifarnib as a combination partner for VEGFR-targeted therapies in RCC. Darlifarnib inhibits farnesylation of RHEB, a step required for mTOR complex 1 (mTORC1) activation, while sparing mTORC2, a selectivity profile the company says may allow it to enhance the antitumor activity of tyrosine kinase inhibitors (TKIs) such as cabozantinib without compounding overlapping toxicities.

Median duration of response was not estimable at most dose levels because a majority of responses remained ongoing at data cutoff, and more than half of the 34 patients remained on treatment. The combination's activity compared favorably with historical benchmarks for TKI and HIF-2α monotherapies in similarly pretreated populations. However, there was no head-to-head comparison, and cross-trial comparisons in oncology carry inherent limitations related to differences in patient selection, prior therapy exposure, and follow-up duration.

Safety Findings

In a safety population of 72 patients across the RCC cohorts, the combination's tolerability profile was described as manageable and generally consistent with the known safety profiles of darlifarnib and cabozantinib individually. Neutropenia emerged as a notable adverse event but was addressed through dose interruption or reduction and supportive care once the initial dose-limiting toxicity (DLT) observation period had concluded; supportive care for neutropenia was not permitted during the DLT assessment window itself.

“The response rates and progression-free survival observed with darlifarnib plus cabozantinib are encouraging in this refractory, pretreated, cabozantinib-naive population, particularly given the limited treatment options after prior immunotherapy, immune checkpoint inhibitors, and VEGFR-targeted therapy,” said Adanma Ayanambakkam, MD, MS, assistant professor of hematology oncology and assistant medical director of the Clinical Trials Office, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, in a news release. “Continued follow-up will further define the durability of benefit.”

Next Steps

Kura Oncology, the sponsor, is now enrolling patients in the US and the European Union in the randomized phase 1b dose-optimization portion of FIT-001, which is comparing darlifarnib plus cabozantinib with cabozantinib alone in cabozantinib-naive, refractory ccRCC. That portion is designed to establish a recommended phase 3 dose ahead of a planned registrational study the company has targeted for 2028.

REFERENCES

1. KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors (FIT-001). ClinicalTrials.gov. Updated June 8, 2026. Accessed July 27, 2026. https://clinicaltrials.gov/study/NCT06026410
2. Kura Oncology Reports Durable Clinical Activity of Darlifarnib Plus Cabozantinib in Cabozantinib-Naïve Clear Cell Renal Cell Carcinoma Patients at KCRS 2026. News release. Kura Oncology. July 27, 2026. Accessed July 27, 2026. https://tinyurl.com/yck2wr8d