Reversing VEGF TKI resistance in ccRCC: Early data from the FIT-001 trial

New clinical data presented at the 2026 International Kidney Cancer Symposium (IKCS) Europe supports the potential of next-generation FTI darlifarnib, alone and in combination with cabozantinib, to overcome resistance and resensitize tumors to VEGFR TKI therapy in clear cell renal cell carcinoma (ccRCC)

FIT-001 (NCT 06026410), a first-in-human, multicenter, open-label phase 1a/b study, demonstrated encouraging clinical activity and a manageable safety profile in patients with advanced ccRCC.

In this interview, we spoke with Dr Adanma Ayanambakkam (Stephenson Cancer Center, University of Oklahoma, Norman, OK, USA) about early clinical data from the FIT-001 trial evaluating the next-generation farnesyl transferase inhibitor (FTI) darlifarnib plus cabozantinib in advanced ccRCC, and the potential of this combination strategy to overcome VEGF TKI resistance.

What clinical unmet need in cabozantinib-pretreated renal cell carcinoma led to the development of the FIT-001 trial?

Patients with advanced ccRCC who progress on VEGF TKIs such as cabozantinib have limited treatment options, and responses to subsequent therapies are often modest and not durable. A key challenge in this setting is the development of adaptive resistance mechanisms that allow tumors to bypass VEGF pathway inhibition. The phase 1a portion of FIT-001 enrolled a broader RCC population, including patients previously treated with immunotherapy, with or without prior VEGF TKI exposure. Within this group, a subset of patients had received prior cabozantinib, representing a particularly difficult-to-treat population. The activity observed in these patients is especially encouraging, as it suggests the potential to overcome resistance even after prior VEGF-targeted therapy. Emerging evidence points to mTORC1 signaling as an important driver of this resistance biology, and in this particular subset analysis of FIT-001, we were able to evaluate whether adding darlifarnib to cabozantinib could help restore sensitivity to the VEGF-targeted treatment used previously.

What is the mechanistic rationale for combining darlifarnib with cabozantinib to overcome VEGF TKI resistance?

Darlifarnib is a next-generation FTI that blocks the farnesylation of key signaling proteins, including RHEB, which is required for activation of mTORC1. In RCC, mTORC1 signaling has been implicated in tumor growth, angiogenesis, and the development of resistance to VEGF-targeted therapies. By inhibiting this pathway, darlifarnib may help suppress adaptive resistance mechanisms that emerge during VEGF TKI treatment. In addition, preclinical data suggest that darlifarnib can modulate signaling in tumor endothelial cells, which may enhance the antiangiogenic activity of agents like cabozantinib. In RCC models, the combination of darlifarnib and cabozantinib has demonstrated deeper and more durable tumor responses compared with either agent alone, including activity in tumors that had previously progressed on VEGF TKIs. These findings provide a strong mechanistic rationale for evaluating this combination as a strategy to restore or enhance sensitivity to VEGF-targeted therapy.

Can you briefly outline the FIT-001 study design and key eligibility criteria, particularly regarding prior therapies?

FIT-001 is an ongoing, first-in-human, multicenter, open-label phase 1a/b study evaluating darlifarnib as monotherapy and in combination in patients with advanced solid tumors. In the RCC cohort, darlifarnib is being evaluated in combination with cabozantinib, starting with a phase 1a dose-escalation portion followed by expansion. Patients are required to have received prior immunotherapy, and in phase 1a, prior VEGF TKI exposure was allowed but not required. The subset of data presented at IKCS focused on patients who had previously been treated with cabozantinib, representing a particularly heavily pretreated population.

The study has now advanced into a phase 1b expansion in ccRCC, which is designed to further characterize the safety and clinical activity of the combination. This portion of the study includes a cabozantinib control arm and is focused on patients who have received prior immunotherapy. While patients in this phase are required to be cabozantinib-naïve, we expect that many will have had prior exposure to other VEGF TKIs, as well as agents such as HIF-2α inhibitors, reflecting the current treatment landscape.

Importantly, patients treated on the cabozantinib control arm have the opportunity to cross over to the darlifarnib and cabozantinib combination if their disease progresses, which may provide additional insight into the potential of this approach in a resistant setting while allowing for a more controlled evaluation of the combination upfront.

Please summarize the key data presented so far, and what this might mean for this patient population?

In patients with cabozantinib-pretreated ccRCC, the combination of darlifarnib and cabozantinib has shown early evidence consistent with proof of mechanism. An objective response rate of 44% and a disease control rate of 94% were observed, with tumor shrinkage seen in the majority of patients.

Importantly, responses were observed in a heavily pretreated population, including patients whose disease had previously progressed on cabozantinib. Treatment durations ranged from approximately 2 months to over 12 months, with about one-third of patients remaining on treatment at the time of data cutoff. The combination has also demonstrated a manageable safety and tolerability profile across dose levels.

While these are early data, the activity seen in patients previously treated with cabozantinib suggests the potential to overcome resistance and restore sensitivity to VEGF-targeted therapy. If confirmed in larger studies, this approach could represent a meaningful advance for patients with limited options following progression on standard treatments.

Can you share further information on the ongoing trial, and how this combination could shape the future RCC treatment landscape?

The study is continuing in the phase 1b expansion in ccRCC, which includes patients who have received prior immunotherapy and is designed to better define the safety and consistency of the clinical activity in a more controlled setting. With the advent of newer combination approaches, such as lenvatinib plus belzutifan, and continued use of combinations like lenvatinib plus everolimus, patients are living longer and receiving multiple lines of therapy. As a result, the need for effective treatment options after progression remains significant.

From a clinical perspective, I do see a role for this combination – particularly in patients who have already been exposed to immunotherapy and VEGF-targeted therapies and whose disease has developed resistance. If the activity seen to date is confirmed, this approach could help extend the benefit of VEGF-targeted therapies by overcoming resistance. At the same time, given the mechanism, there may also be potential in patients who are earlier in their treatment course, including those who are TKI-naïve, by helping to delay or prevent the development of resistance. Phase 1a data also includes a portion of patients who are TKI-naïve, which we look forward to seeing in the 2H of this year.

Overall, this represents a promising strategy for patients whose disease has progressed following prior standard treatments, with potential to be explored more broadly as we better understand where it fits.