Early results from the FIT-001 phase 1 trial show that combining the farnesyltransferase inhibitor KO-2806 with cabozantinib is feasible in renal cell carcinoma, with manageable toxicity and preliminary signs of clinical activity.
The dose-escalation study enrolled patients with several tumor types but reported data were primarily in clear cell RCC. Cabozantinib was tested at 40 mg and 60 mg combined with escalating KO-2806 doses of 3 mg, 5 mg and 8 mg to evaluate safety, tolerability and early efficacy.
Hematologic toxicity, particularly neutropenia, was the most notable KO-2806–related adverse event and occurred more frequently than typically seen with cabozantinib alone. Grade 3 neutropenia was observed in about 40% of patients at the 5 mg KO-2806 dose and roughly 50% at the 8 mg dose, indicating a dose-dependent effect. These events were managed with treatment interruptions, dose reductions and granulocyte colony-stimulating factor support, and clinical and radiographic responses were maintained despite dose modifications.
Other adverse events—including fatigue, gastrointestinal symptoms and hand-foot syndrome—were consistent with the known cabozantinib safety profile. Early hematologic effects appeared somewhat more frequent and earlier in onset, but overall toxicity remained manageable using standard tyrosine kinase inhibitor management strategies.
Evidence of activity was seen in patients previously resistant to cabozantinib. KO-2806 selectively inhibits mTORC1 by blocking protein farnesylation, a mechanism that may prevent mTOR pathway reactivation while sparing mTORC2 and limiting additional toxicity. This profile could help overcome or delay resistance, a possibility supported by preclinical data and observed clinical responses.
Preliminary efficacy signals indicated higher objective response rates in cabozantinib‑naïve patients (about 50%) compared with cabozantinib‑exposed patients (about 33%), while disease control rates were high in both groups. These results are informing phase 2 expansion plans that will include cohorts of cabozantinib‑exposed patients.
KO-2806 is also being explored beyond RCC, including in KRAS‑mutant and HRAS‑mutant tumors, underscoring the broader potential of farnesyltransferase inhibitor–based combination strategies.
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