12 Farnesyl Transferase Inhibitor (FTI) Darlifarnib Combined with Cabozantinib in Renal Cell Carcinoma (RCC): Updated Phase 1a Results from FIT-001

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Abstract Background VEGFR- and IO-targeted therapies for metastatic RCC have limitations that can lead to disease progression, highlighting the need for well-tolerated and effective combination strategies. VEGFR-TKI resistance occurs through multiple escape mechanisms, with the mTOR pathway playing a central role in sustaining tumor survival and therapeutic resistance. Darlifarnib–a potent next-generation FTI–selectively inhibits mTORC1 signaling by blocking RHEB farnesylation, sparing toxicity burden associated with mTORC2 inhibition. Preclinical studies show that darlifarnib can enhance the antitumor and antiangiogenic effects of and also resensitize tumors to cabozantinib and other VEGFR TKIs. These data support clinical investigation of darlifarnib+cabozantinib to potentially improve outcomes, overcome resistance, and restore sensitivity to cabozantinib. Here, we report updated safety and preliminary antitumor activity of darlifarnib+cabozantinib from the overall RCC cohort of the FIT-001 trial. Methods FIT‑001 (NCT06026410) is an ongoing, first-in-human, multicenter, open-label, Ph1a/b dose-escalation/expansion study evaluating darlifarnib in advanced solid tumors. In the Ph1a RCC cohort, darlifarnib 3, 5, or 8 mg QD was orally administered on Days 1–7 and 15–21 with cabozantinib 40 or 60 mg QD in 28‑day cycles. Primary objectives are safety and tolerability; secondary objectives include preliminary antitumor activity, pharmacokinetics. Results As of 25March2026, 72 RCC (58 clear cell [cc] RCC) patients received darlifarnib 3, 5, or 8 mg plus cabozantinib 40 or 60 mg in dose escalation. Across all RCC patients, median age was 67 years (range 24–83), 76% male, 75% White. Patients were heavily pre-treated: 53% had received ≥2 prior lines of therapy (65% prior IO+TKI combination, 31% prior IO only, 38% prior cabozantinib [17% as immediate prior line]). Darlifarnib+cabozantinib was well-tolerated in patients with RCC across all dose levels assessed: most common (≥25% of patients) any-grade TEAEs were diarrhea (64%), fatigue (50%), neutropenia (47%), nausea (43%). The only grade ≥3 TEAE occurring in ≥ 10% of patients was neutropenia (36%), a previously reported effect of FTIs. One on-treatment death occurred (respiratory failure in a patient with lung lesions). Four dose-limiting toxicities were reported with darlifarnib, primarily grade 3 or 4 neutropenia. Darlifarnib-related TRAEs leading to darlifarnib dose interruptions, reductions, and discontinuations occurred in 58% (42/72), 18% (13/72), and 3% (2/72) of patients, respectively. In all RCC patients, median follow-up was 7.8 months (range 0.9–19.2), with 30 patients (42%) remaining on treatment at data cutoff. Antitumor activity was observed across dose levels assessed in cabozantinib-naive and cabozantinib-exposed ccRCC (Table). In 22 cabozantinib-naive ccRCC patients treated with darlifarnib 5 or 8 mg plus cabozantinib 60 mg, ORRs (95%CIs) were 50% (18.7–81.3) and 33% (9.9–65.1), DCRs (95%CIs) were 80% (44.4–97.5) and 100% (73.5–100), median PFS (95%CI; still evolving) was 11.2 months (1.8–NE) and NE (3.7–NE), and median DORs (95%CIs) were NE months (6.2–NE) and NE (3.4–NE), respectively. 6/19 response-evaluable ccRCC patients with prior cabozantinib exposure responded to the combination; 3/6 of these responders had immediate prior cabozantinib exposure. Across all RCC patients, darlifarnib demonstrated approximately dose-proportional exposures (Cmax/AUC) with no accumulation from C1D1 to C2D1, and similar darlifarnib exposures for monotherapy and the cabozantinib combination. Conclusions In the ongoing FIT‑001 trial, darlifarnib+cabozantinib was well-tolerated, demonstrating a manageable safety profile. Encouraging antitumor activity was seen in patients with ccRCC, including both cabozantinib-naive and cabozantinib-exposed populations. In cabozantinib-naive ccRCC patients, ORRs were 50% and 33% with darlifarnib 5 and 8 mg plus cabozantinib 60 mg. These results support further evaluation of the combination in ccRCC. FIT-001 Ph1b is ongoing and enrolling cabozantinib-naive ccRCC patients, with randomization across darlifarnib 5 and 8 mg plus cabozantinib 60 mg and a cabozantinib monotherapy arm, with potential to cross over to a combination arm upon progression.

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