Adanma Ayanambakkam, MD, MS, highlights safety profile of darlifarnib/cabozantinib in ccRCC

In the following video, Adanma Ayanambakkam, MD, MS, discusses encouraging early findings from the phase 1 FIT-001 trial (NCT06026410) evaluating the investigational farnesyl transferase inhibitor darlifarnib in combination with cabozantinib (Cabometyx) for patients with advanced clear cell renal cell carcinoma (ccRCC). These data were presented at the 2026 International Kidney Cancer Symposium (IKCS): Europe in Paris, France.¹

Ayanambakkam is a medical oncologist at the Stephenson Cancer Center of the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma.

Ayanambakkam explained that darlifarnib is designed to inhibit farnesyl transferase, thereby preventing farnesylation of the Rheb protein and downstream activation of mTORC1. This mechanism may help restore sensitivity to VEGFR-targeted therapy and enhance the activity of cabozantinib, a tyrosine kinase inhibitor (TKI) widely used in renal cell carcinoma.

FIT-001 is a first-in-human, multicenter, open-label phase 1a/b study evaluating darlifarnib both as monotherapy and in combination with cabozantinib through dose-escalation and expansion cohorts. Primary end points include safety and tolerability, with secondary assessments of antitumor activity and pharmacokinetics.

The combination portion of the study tested darlifarnib at 3 mg, 5 mg, and 8 mg on an intermittent schedule alongside cabozantinib at 40 mg or 60 mg daily. The current data set highlighted at IKCS focused largely on patients with ccRCC who had prior exposure to cabozantinib or other TKIs, representing a population with limited treatment options after progression. Among 16 response-evaluable patients with prior cabozantinib exposure, the objective response rate was 43.8%, and the disease control rate was 93.8%. Notably, several responders had achieved only stable disease during prior cabozantinib treatment, suggesting the addition of darlifarnib may be contributing to renewed antitumor activity. The longest reported duration of response was 11.2 months.

Related: Darlifarnib plus cabozantinib shows early activity in ccRCC

Regarding safety, Ayanambakkam noted that the regimen has been manageable thus far and has not appeared to meaningfully worsen the known toxicity profile of cabozantinib. The most common treatment-emergent adverse event associated with darlifarnib was neutropenia, occurring in 41% of patients overall and at grade 3 or higher in 30%. Other common adverse events included fatigue (30%), diarrhea (26%), nausea (26%), and thrombocytopenia (21%). Ayanabakkam emphasized that cytopenias have generally been manageable with dose interruptions, modifications, reductions, and supportive care strategies such as prophylactic granulocyte colony-stimulating factor. Overall, he said the preliminary findings support continued development of the darlifarnib/cabozantinib combination for patients with previously treated ccRCC.

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