Darlifarnib plus cabozantinib shows early activity in ccRCC

Adding the investigational farnesyl transferase inhibitor darlifarnib (previously KO-2806) to cabozantinib (Cabometyx) demonstrated promising antitumor activity in patients with advanced clear cell renal cell carcinoma (ccRCC) who had received prior immunotherapy-based treatment, according to preliminary data from a subset analysis of the phase 1 FIT-001 trial.¹

The results were presented at the 2026 International Kidney Cancer Symposium (IKCS): Europe in Paris, France.

“Patients with advanced ccRCC whose disease progresses on cabozantinib have limited treatment options,” explained Adanma Ayanambakkam, MD, MS, who is an assistant professor of hematology/oncology and director of genitourinary medical oncology research at the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, in a news release on the results.² “The tumor shrinkage and high disease control rate observed with darlifarnib in combination with cabozantinib suggest this approach may offer meaningful clinical benefit in a refractory setting or in patients with disease progression after therapy.”

About FIT-001

The FIT-001 trial (NCT06026410) is an open-label first-in-human phase 1 study evaluating darlifarnib alone and in combination regimens across advanced solid tumors. The trial includes a cohort assessing the safety and preliminary efficacy of the combination in patients with locally advanced or metastatic ccRCC with prior cabozantinib exposure.

Related: Early FIT-001 results highlight activity of KO-2806 in RCC

To be eligible for enrollment in the ccRCC cohort, patients needed to have received at least 1 prior immunotherapy-based treatment and a Karnofsky performance score of 70 or higher. Participants received darlifarnib at once-daily 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 40 mg or 60 mg daily in 28-day cycles. The primary end points were safety and tolerability, antitumor activity, and pharmacokinetics.

At the time of data report, 18 patients had been enrolled and treated in the trial. More than half (56%; 10 of 18) of patients had received cabozantinib as the immediate prior line of therapy, 67% (12 of 18) had prior exposure to other TKIs, and 56% (10 of 18) had discontinued prior cabozantinib because of disease progression.

Efficacy data

Efficacy data were available for 16 patients. Antitumor activity with observed across all dose levels, which included an objective response rate of 44%. The disease control rate was 94%, with 15 of 16 patients achieving a response of partial response or stable disease.

Tumor shrinkage was observed in 75% of patients, with reductions ranging from 32% to 47% among responders. Six patients remained on treatment at the time of data cutoff, with treatment durations ranging from 8 to 56 weeks and durations of response ranging from 8 to 32 weeks. Among responders, 57% had received cabozantinib as the immediate prior line of therapy and 71% had received other tyrosine kinase inhibitors in addition to cabozantinib. Additionally, 71% of responders had a best overall response of stable disease on prior treatment with cabozantinib.

According to the authors, “Activity of the combination in a post-cabo setting is suggestive of darlifarnib’s contribution to antitumor activity in this patient population.”

Safety profile

The authors described the safety profile as manageable across dose levels, including in cabozantinib-exposed ccRCC patients. Across RCC patients treated in the combination cohorts, the overall dose-limiting toxicity (DLT) rate was 6%.

Neutropenia was the most commonly reported darlifarnib-related grade 3 or higher adverse event, occurring in 21 patients (30%). Darlifarnib dose interruptions were reported more frequently when paired with cabozantinib 60 mg compared with 40 mg, although relatively few patients required permanent discontinuation (6%; 4 of 70) or dose reduction (13%; 9 of 70). Investigators further stated that the safety profile of cabozantinib in the combination was generally consistent with prior experience using cabozantinib monotherapy.

“There has been [preclinical] evidence to show that [darlifarnib] resensitizes the tumors that have previously progressed on cabozantinib,” Ayanambakkam noted in correspondence with Urology Times®. “It's nice that what we saw in a preclinical test environment is being reproduced in the patient population [from this trial].”

Based on these results, the FIT-001 trial has advanced into the phase 1b dose expansion phase.

Ayanambakkam concluded, “The study is going to move on to the expansion phase, where it has started enrollment at multiple sites looking at patients who are cabozantinib-naïve. Hopefully we'll be able to look at a [drug with a new] mechanism of action to add to the portfolio of kidney cancer drugs that we have [available].”

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