Darlifarnib plus cabozantinib showed durable responses and manageable safety in cabozantinib-naive advanced clear cell RCC.
Darlifarnib, an investigational farnesyltransferase inhibitor (FTI), combined with cabozantinib (Cabometyx) produced objective responses in cabozantinib-naive patients with clear cell renal cell carcinoma (ccRCC), according to updated data from the phase 1a FIT-001 trial (NCT06026410) presented at the
Across cabozantinib 60-mg cohorts combined with darlifarnib at 3 mg, 5 mg, or 8 mg, and a cabozantinib 40-mg/darlifarnib 8-mg cohort, objective response rates (ORR) ranged from 33% to 50%, with a median progression-free survival (PFS) of 13 months (95% CI, 7.1-not estimable [NE]) and a median duration of response that was NE. Data were reported in patients who had received prior immuno-oncology (IO)–based therapy but no prior cabozantinib.
FIT-001 was a phase 1a dose-escalation study of darlifarnib, administered orally once daily on days 1 to 7 and 15 to 21, plus cabozantinib administered orally once daily in 28-day cycles, in adults 18 years and older with histologically or cytologically confirmed RCC.¹ Patients with ccRCC were required to have received at least 1 prior systemic IO-based therapy; patients with non-clear cell histology could be treatment-naive or have received any prior systemic therapy. Eligibility also required a Karnofsky performance status of 70 or higher and no active central nervous system metastases.1,2
As of the May 8, 2026, data cutoff, 72 patients with RCC had been treated with the combination across dose-escalation cohorts (both cabozantinib-naive and cabozantinib-experienced), with 27 remaining on treatment and a median follow-up of 8.8 months (range, 0.9-20.6).¹ The population was heavily pretreated: median age was 67 years (range, 24-83), 76% were male, 81% had clear cell histology, and the median number of prior therapy lines was 2 (range, 1-7), with 67% having received prior IO plus TKI combination therapy and 38% having received cabozantinib at any line.
Among response-evaluable cabozantinib-naive patients with ccRCC, ORR (complete response plus partial response) was 33% (95% CI, 4.3%-77.7%) with darlifarnib 8 mg plus cabozantinib 40 mg (n = 6); 33% (95% CI, 4.3%-77.7%) with darlifarnib 3 mg plus cabozantinib 60 mg (n = 6); 50% (95% CI, 18.7%-81.3%) with darlifarnib 5 mg plus cabozantinib 60 mg (n = 10); and 33% (95% CI, 9.9%-65.1%) with darlifarnib 8 mg plus cabozantinib 60 mg (n = 12).¹ Disease control rates ranged from 80% to 100% and clinical benefit rates from 33% to 83% across the 4 dose cohorts.
At a median follow-up of 9.4 months (95% CI, 6.9-12.8) among cabozantinib-naive patients, PFS rates were 74% (95% CI, 55.0%-86.4%) at 6 months and 60% (95% CI, 38.4%-76.2%) at 9 months. More than half of patients remained on treatment at the data cutoff.
Among all 72 treated patients, the most common any-grade treatment-emergent adverse effects (TEAEs) occurring in at least 30% of patients were diarrhea (64%; grade ≥3, 8%), fatigue (50%; grade ≥3, 10%), neutropenia (47%; grade ≥3, 38%), nausea (44%; grade ≥3, 0%), decreased appetite (36%; grade ≥3, 0%), stomatitis (33%; grade ≥3, 1%), and palmar-plantar erythrodysesthesia syndrome (31%; grade ≥3, 1%). TEAEs of any grade occurred in 99% of patients (grade ≥3, 76%), and serious TEAEs occurred in 40%. Four deaths (6%) were reported, due to cardiac arrest (n = 2), pneumonia (n = 1), and septic shock (n = 1); investigators attributed 1 death (pneumonia) to darlifarnib and 1 (cardiac arrest) to cabozantinib. Dose-limiting toxicities occurred in 4 patients (6%), comprising neutropenia (2 grade 3, 1 grade 4) and increased aspartate aminotransferase (1 grade 3); supportive care for neutropenia was not permitted during the dose-limiting toxicity period but was used afterward alongside dose interruption or reduction to manage the adverse effect (AE).
Investigators concluded that darlifarnib plus cabozantinib demonstrated durable antitumor activity in both cabozantinib-naive and cabozantinib-experienced patients with ccRCC, with a safety profile manageable through dose modification and consistent with the known AE profiles of the individual agents.
