Darlifarnib plus cabozantinib showed preliminary activity and safety across dose levels in cabozantinib-treated ccRCC.
Darlifarnib (KO-2806) in combination with cabozantinib (Cabometyx) demonstrated a manageable safety profile and promising activity in patients with clear cell renal cell carcinoma (ccRCC) who received prior cabozantinib, according to data from the phase 1a/1b FIT-001 trial (NCT06026410) presented during the 2026 International Kidney Cancer Symposium (IKCS): Europe.1
Preliminary results from FIT-001, presented in a poster, showed that cabozantinib-exposed patients who received darlifarnib across dose levels plus cabozantinib (n = 16) achieved an overall response rate (ORR) of 44% (95% CI, 19.8%-70.1%). The disease control rate (DCR) was 94% (95% CI, 69.8%-99.8%). Moreover, the combination displayed a manageable safety profile across all dose levels; dose-limiting toxicities occurred in 6% of patients with renal cell carcinoma (RCC; n = 70).
“Darlifarnib is a next-generation farnesyltransferase inhibitor that has shown promising preclinical efficacy,” Adanma Ayanambakkam, MD, MS, said in an exclusive interview with OncLive®. “By blocking farnesylation of that protein, it can prevent mTOR1 activation, predominantly through mTOR1 inhibition. We have looked at mTOR inhibition in renal cell carcinoma, [and] we’ve had good success with everolimus [Afinitor] and other drugs in the kidney [cancer] landscape. But the difference between darlifarnib and other drugs inhibiting the mTOR complex is that it is very specific to mTOR1 inhibition, and thus it has a better safety and tolerability profile.”
Ayanambakkam is the associate program director of hematology oncology fellowship and the director of infusion services at the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center in Oklahoma City, and a coauthor of FIT-001.
FIT-001 was a multicenter, open-label, first-in-human study of darlifarnib alone and in combination with cabozantinib in adult patients with advanced solid tumors, including patients with locally advanced or metastatic ccRCC.1,2 Patients with ccRCC were required to have received at least 1 prior immunotherapy-based regimen and have a Karnofsky performance score of at least 70. Patients with non-ccRCC needed to be treatment naive or have received any prior systemic treatment.
Oral darlifarnib was administered at 3 mg, 5 mg, or 8 mg on days 1 to 7 and 15 to 21 in combination with continuous oral cabozantinib at 40 mg or 60 mg given daily in 28-day cycles.
The primary end point was safety.1 Secondary end points included antitumor activity and pharmacokinetic measures.
At baseline, the median age in the overall population (n = 18) was 67 years (range, 48-82). Most patients were male (67%), had a Karnofsky performance score of 80 to 100 (100%), had distant metastases (94%), received cabozantinib as their immediate prior line of treatment (56%), and received a tyrosine kinase inhibitor in any prior line of treatment (67%).
Additional findings from FIT-001 revealed that patients with cabozantinib-exposed ccRCC who received darlifarnib at 3 mg and cabozantinib at 40 mg (n = 5) experienced an ORR of 40% (95% CI, 5.3%-85.3%) and a DCR of 100% (95% CI, 47.8%-100%). Those treated with darlifarnib at 5 mg and cabozantinib at 40 mg (n = 6) experienced an ORR and DCR of 33% (95% CI, 4.3%-77.7%) and 100% (95% CI, 54.1%-100%), respectively. The ORR and DCR were both 50% (95% CI, 1.3%-98.7%) among patients who received darlifarnib at 8 mg and cabozantinib at 40 mg (n = 2). Patients who received darlifarnib at 3 mg and cabozantinib at 60 mg (n = 3) achieved an ORR of 67% (95% CI, 9.4%-99.2%) and a DCR of 100% (95% CI, 29.2%-100%).
In terms of safety, among all patients with RCC, any-grade treatment-emergent adverse events (TEAEs) occurred in 83%; grade 3 or higher TEAEs were reported in 50%. The most common any-grade TEAEs included neutropenia (41%), fatigue (30%), diarrhea (26%), nausea (26%), and thrombocytopenia (21%). Serious adverse effects (SAEs) related to darlifarnib (9%), any-grade cabozantinib-related TEAEs (93%), grade 3 or higher cabozantinib-related TEAEs (46%), and SAEs related to cabozantinib (13%) were all reported. Darlifarnib dose reductions, interruptions, or discontinuations occurred in 13%, 60%, and 6% of patients, respectively. Cabozantinib dose reductions or interruptions were reported in 26% and 71% of patients, respectively.
“The study is moving forward into the dose-expansion phase, where it's focusing on ccRCC [and] looking at cabozantinib-naive patients. We are actively accruing that patient population, and hopefully we'll see promising responses like we have [here], but there is a lot of unmet need,” Ayanambakkam said.
Disclosures: Ayanambakkam reported consulting or advisory roles with AVEO, Pfizer/Astellas, Johnson & Johnson, and Kura Oncology. He received travel, accommodations, and/or expenses from Kura Oncology and research funding from Regeneron.
