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

In this video, Adanma Ayanambakkam, MD, MS, discusses preliminary results from the FIT-001 phase 1 trial evaluating the next-generation farnesyl transferase inhibitor (FTI) KO-2806 in combination with cabozantinib in renal cell carcinoma (RCC).¹ Ayanambakkam is an assistant professor of hematology oncology and an adjunct assistant professor of urology, associate program director of the OUHSC Hematology Oncology Fellowship Program, medical director of the Genitourinary Medical Oncology Research & SCC Infusion Center at Stephenson Cancer Center, University of Oklahoma Health Sciences Center.

Although the trial includes multiple tumor types, the presented data focus on RCC, predominantly clear cell disease. The study employed a dose-escalation design, testing cabozantinib at 40 mg and 60 mg in combination with escalating doses of KO-2806 (3 mg, 5 mg, and 8 mg) to assess safety, tolerability, and early efficacy.

Neutropenia emerged as the most notable KO-2806–related toxicity, occurring more frequently than typically observed with cabozantinib alone. Grade 3 neutropenia was reported in approximately 40% of patients at the 5-mg dose and 50% at the 8-mg dose, suggesting a dose-dependent effect. Importantly, these events were manageable with treatment interruptions, dose reductions, and granulocyte colony-stimulating factor support. Durable clinical and radiographic responses were observed despite dose modifications, supporting the feasibility of maintaining efficacy while optimizing tolerability.

Beyond hematologic toxicity, other adverse events—including fatigue, gastrointestinal effects, and hand-foot syndrome—were largely consistent with the known cabozantinib safety profile. Early hematologic effects appeared somewhat more frequent and earlier in onset, but overall toxicity was manageable with standard TKI management strategies.

A particularly compelling finding was evidence of activity in patients previously resistant to cabozantinib. KO-2806 selectively inhibits mTORC1 by blocking farnesylation, potentially preventing mTOR pathway reactivation while sparing mTORC2 and limiting additional toxicity. This mechanism may help overcome or delay resistance, a hypothesis supported by preclinical data and the observed clinical responses.

Preliminary efficacy signals suggest higher objective response rates in cabozantinib-naïve patients (~50%) compared with cabozantinib-exposed patients (~33%), though disease control rates were high in both groups. These findings are informing plans for phase 2 expansion, including cohorts of cabozantinib-exposed patients. Beyond RCC, KO-2806 is also being explored in KRAS-mutant cancers and HRAS-mutant tumors, highlighting the broader potential of FTI-based combination strategies.

REFERENCE

1. Ayanambakkam A, Rosen LS, Garmezy B, et al. Farnesyltransferase Inhibitor (FTI) KO-2806 in combination with cabozantinib (cabo) in renal cell carcinoma (RCC): Preliminary results from FIT-001 phase 1 trial. Ann Oncol. 2025; 36, Supplement 2S1397-S1398