Darlifarnib plus cabozantinib shows encouraging antitumor activity in ccRCC

Updated phase 1a findings from the ongoing FIT-001 trial (NCT06026410) showed that the investigational farnesyl transferase inhibitor darlifarnib in combination with cabozantinib (Cabometyx) demonstrated preliminary antitumor activity with a manageable safety profile in patients with advanced renal cell carcinoma (RCC), including those previously exposed to cabozantinib.¹

The data, presented at the 2026 Kidney Cancer Research Summit (KCRS), support continued evaluation of the regimen in the randomized phase 1b portion of the study.

How was the FIT-001 trial designed?

FIT-001 (NCT06026410) is a first-in-human, multicenter, open-label phase 1a/1b trial evaluating darlifarnib across advanced solid tumors. The RCC dose-escalation cohort evaluated oral darlifarnib at doses of 3 mg, 5 mg, or 8 mg administered on days 1 to 7 and 15 to 21 of each 28-day cycle in combination with cabozantinib at either 40 mg or 60 mg daily. Primary end points included safety and tolerability, while secondary end points assessed pharmacokinetics and preliminary antitumor activity.

At the March 25, 2026, data cut-off, 72 patients with RCC had received combination therapy, including 58 patients with ccRCC. Patients represented a heavily pretreated population: 53% had received at least 2 prior systemic therapies, 65% had previously received an immune checkpoint inhibitor plus VEGFR tyrosine kinase inhibitor (TKI), and 38% had prior exposure to cabozantinib, including 17% whose most recent therapy had been cabozantinib.

What were the key findings from FIT-001 presented at KCRS?

With a median follow-up of 7.8 months, 42% of patients remained on treatment at the time of analysis. Among cabozantinib-naïve patients with ccRCC treated with darlifarnib plus full-dose cabozantinib (60 mg), objective response rates (ORRs) varied by darlifarnib dose. Patients receiving darlifarnib 5 mg achieved an ORR of 50% (95% CI, 18.7 to 81.3), whereas those receiving the 8-mg dose had an ORR of 33% (95% CI, 9.9 to 65.1). Disease control rates ranged from 80% to 100%, and median progression-free survival (PFS) had not yet matured in several cohorts. The median PFS across pooled dose levels was 13 months.

Median duration of response also remained not estimable in most groups because multiple responses were ongoing.

Activity was also observed among patients previously treated with cabozantinib. Investigators reported that 6 of 19 response-evaluable patients with prior cabozantinib exposure achieved an objective response, including 3 patients whose immediately preceding therapy had been cabozantinib.

The combination also appeared tolerable across the evaluated dose levels. The most common treatment-emergent adverse events (TEAEs) of any grade were diarrhea (64%), fatigue (50%), neutropenia (47%), and nausea (43%). Grade 3 or higher neutropenia occurred in 36% of patients and represented the only grade 3 or higher TEAE reported in at least 10% of participants. Four dose-limiting toxicities were observed, primarily grade 3 or 4 neutropenia. One on-treatment death due to respiratory failure occurred in a patient with pulmonary lesions and was reported during the study. Darlifarnib dose interruptions occurred in 58% of patients, dose reductions in 18%, and permanent discontinuations in 3%.

“The response rates and progression-free survival observed with darlifarnib plus cabozantinib are encouraging in this refractory, pretreated, cabozantinib-naïve population, particularly given the limited treatment options after prior immunotherapy, immune check point inhibitors, and VEGFR-targeted therapy,” said presenting author Adanma Ayanambakkam, MD, MS, assistant professor of hematology oncology and assistant medical director clinical trials office at the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, in a news release on the findings.² “Continued follow-up will further define the durability of benefit.”

Enrollment is ongoing in the randomized phase 1b portion of FIT-001, which is comparing darlifarnib plus cabozantinib with cabozantinib alone in cabozantinib-naïve patients with refractory ccRCC in the US and EU. The study is intended to identify the optimal dose combination for subsequent phase 3 evaluation planned for 2028.

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