Darlifarnib Plus Cabozantinib Active in ccRCC After Prior Cabozantinib

The combination of the farnesyl transferase inhibitor darlifarnib (KO-2806) and cabozantinib (Cabometyx) yielded antitumor activity in patients with advanced clear cell renal cell carcinoma (ccRCC) who received prior cabozantinib, according to findings from a subset analysis of the phase 1 FIT-001 trial presented at the 2026 International Kidney Cancer Symposium (IKCS).¹

Among 16 evaluable patients across all doses, the overall response rate (ORR) was 44% and the disease control rate (DCR) was 94% with the combination. Three-fourths (75%) of patients had at least some level of tumor shrinkage, ranging from 32% to 47% among responders.

Antitumor activity was observed across this heavily pretreated population, including in patients whose best response to prior cabozantinib had been stable disease. Responses were seen in patients who had received cabozantinib in the immediately preceding line of therapy, as well as in those who had been exposed to other TKIs beyond cabozantinib.

Durability signals were also encouraging; treatment durations ranged from 8 to 56 weeks, with 6 patients still receiving therapy at the time of data cutoff. The updated data announced today represent a meaningful update from data first disclosed at the 2025 ESMO Congress, where the combination had demonstrated ORRs of 33% to 50% in ccRCC and 17% to 50% in patients with prior cabozantinib exposure.

Regarding safety, the combination demonstrated a manageable safety profile across all RCC patients enrolled at multiple dose levels, including those treated at the full label dose of cabozantinib. This tolerability signal across the dose range—spanning darlifarnib doses of 3 mg, 5 mg, and 8 mg—is particularly relevant given concerns about additive toxicity in a patient population that has already received prior TKI therapy.

"These data highlight the potential of darlifarnib to overcome resistance to prior cabozantinib and enhance the activity of VEGF TKIs in patients with advanced RCC," Mollie Leoni, MD, chief medical officer, Kura Oncology, stated in a press release.¹ "We are highly encouraged by these results and are committed to advancing this combination to evaluate further its potential to deliver meaningful benefit for RCC patients."

FIT-001 Trial Design and Patient Characteristics

Researchers have hypothesized that the mechanism of action of darlifarnib may restore the sensitivity of tumors that have escaped VEGFR blockade, offering a mechanistically rational basis for re-challenging patients with cabozantinib in this combination context.

Accordingly, the open-label, nonrandomized FIT-001 study evaluated darlifarnib at once-daily oral doses of 3 mg, 5 mg, or 8 mg, administered on an alternating 7 days on/7 days off schedule, in combination with cabozantinib at once-daily doses of either 60 mg or 40 mg.

Regarding prior therapy, all patients enrolled in the RCC cohort were required to have received prior immunotherapy.² The ccRCC patient subset highlighted at IKCS had all also received cabozantinib.

Next Steps With Darlifarnib Plus Cabozantinib in RCC

The FIT-001 trial continues as an ongoing study, with the phase 1b dose expansion cohort now enrolling. The study is being conducted at 40 locations in the United States and Europe. The target enrollment is 300 patients and the estimated primary completion date is January 2027.

The company indicated that the dose expansion phase is designed to identify the optimal biologically active dose for the darlifarnib-cabozantinib combination, which would serve as the foundation for potential further development.

Cabozantinib currently has FDA-approved single-agent and combination indications for the treatment of patients with RCC.

References

1. Kura Oncology, Inc. Kura Oncology Reports Darlifarnib Plus Cabozantinib Demonstrates Robust Activity in Patients With Clear Cell Renal Cell Carcinoma Previously Treated With Cabozantinib [press release]. San Diego, CA and Paris, France: Kura Oncology; April 17, 2026. Available at: https://tinyurl.com/fnj854cc

2. KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors (FIT-001). ClinicalTrials.gov. Updated January 2, 2026. Accessed April 17, 2026. https://clinicaltrials.gov/study/NCT06026410