Darlifarnib Plus Cabozantinib Displays Early Signals of Safety and Efficacy in RCC

The combination of darlifarnib and cabozantinib (Cabometyx) demonstrated promising efficacy with a tolerable safety profile in patients with renal cell carcinoma (RCC) in the phase 1a FIT-001 trial (NCT06026410), giving investigators hope that it could have a future role in multiple settings in the disease landscape, according to Adanma Ayanambakkam, MD, MS.¹

“Apart from the impressive objective response rates [ORRs], we also saw that these responses were pretty durable; the median progression-free survival [PFS] in this cabozantinib-naive population was [approximately 13 months, with at least 60% of these patients remaining on study at the 9-month data cutoff,” Ayanambakkam, the associate program director of hematology oncology fellowship and the director of infusion services at Stephenson Cancer Center at the University of Oklahoma Health Sciences Center in Oklahoma City, said in an interview with OncLive®. “Importantly, almost half of these patients were still on treatment when we did this data cut, so we’re hoping that that signal keeps improving. This [highlights] not only the safety and efficacy, but also the tolerability of this treatment, which translates to a durable treatment response.”

In the interview, Ayanambakkam discussed the rationale for initiating FIT-001, the latest data from the trial that were presented during the 2026 Kidney Cancer Research Summit, and the next steps for the combination in RCC.

OncLive: What was the rationale behind evaluating darlifarnib in combination with cabozantinib in RCC?

Ayanambakkam: This study evaluated darlifarnib, which is a next-generation farnesyltransferase inhibitor, in RCC in combination with cabozantinib. We know the role that TKIs play in RCC, and we know how important they are in blocking signaling pathways. We also know about the role of mTOR signaling in RCC and how important it is in tumor growth, angiogenesis, and disease progression, predominantly as a mechanism of resistance.

Darlifarnib can block RAS farnesylation, which results in selective mTORC1 inhibition. What that mTORC1 inhibition translates into is blocking the most important part of the mTOR signaling pathway, which is mTORC1, while not blocking the mTORC2 pathway. Most of the toxicity that we've seen with prior mTOR inhibitors has been predominantly from the mTORC2.

We're hoping that by targeting mTORC1, we'll be able to overcome some of the mechanisms of resistance but still retain the safety signals that we want to see.

Could you describe the study design and patient population?

FIT-001 was a phase 1A dose-escalation study. We initially evaluated a lower dose of cabozantinib at 40 mg, and we combined it with darlifarnib at 3, 5, and 8 mg. Initially, the study was open to both patients who had had prior cabozantinib and those who were cabozantinib-naive; we've expanded that to full-dose cabozantinib evaluated at 60 mg, in addition to darlifarnib at 3, 5, and 8 mg.^1,2

Importantly, with the higher doses of darlifarnib at 5 and 8 mg, with the full dose of cabozantinib at 60 mg, we restricted it to a cabozantinib-naive population. So, we had a good mix of both cabozantinib-naive and cabozantinib-exposed patients.

Overall, the study [enrolled] 72 patients. The median number of lines of [prior] treatment as about 2 [range, 1-7]. Sixty-seven percent of these patients had a prior IO-TKI and 38% had prior cabozantinib.

In our initial data presentation, we focused on the cabozantinib-exposed group. Recently, in our KCRS presentation, we focused on the cabozantinib-naive group. At this point, we’ve had a good mixture of patients on both cabozantinib-naive and exposed.

What safety data were presented from the study?

For the safety data, we looked at all patients, both cabozantinib-naive and cabozantinib-exposed. Fortunately, we did not see any worsening toxicity of TKI-based adverse effect [AE] profiles. There was no worsening diarrhea, stomatitis, or hand-foot syndrome.²

There were a few unique AEs that stood out, most importantly neutropenia. [Approximately] 65% of patients had grade 3 or higher AEs. [Approximately] 50% of those were attributed to darlifarnib monotherapy. Most of them predominantly were neutropenia, which we do know is an on-target toxicity due to the mechanism of action of darlifarnib, but fortunately it was manageable with just dose modifications or interruptions.

We did find more significant neutropenia in the initial dose-limiting toxicity periods where we did not allow granulocyte colony-stimulating factor [GCSF] prophylaxis. Subsequently, in later parts of the study where we have allowed patients to have GCSF prophylaxis, we have not seen as much neutropenia, so it has been more manageable. Overall, [it was] a very convincing, safe toxicity profile with expected AEs from cabozantinib-based TKIs.

What efficacy data have been observed with the darlifarnib and cabozantinib combination?

[In our KCRS presentation], we looked at the analysis of the cabozantinib-naive patients. Notably, [approximately] 50% of these patients, even though they were cabozantinib-naive, did get prior TKIs, including lenvatinib [Lenvima] and axitinib [Inlyta], so we had a population that was exposed to TKIs and we're looking at this in the second- or third-line setting.

ORRs ranged from 33% to 50%, and disease control rates ranged from 80% to 100%, which is pretty promising. When we looked at one of our cohorts of interest, which is the darlifarnib at 5 mg and cabozantinib at 60 mg, we saw an ORR of 50% [95% CI, 18.7%-81.3%].

The range of ORRs could be explained by the varying doses of darlifarnib and cabozantinib on the study, because some of these cabozantinib-naive patients in the initial parts of the study were just exposed to cabozantinib at 40 mg.

What are the next steps for the development of this combination?

We have expanded this into a phase 1b dose-expansion phase, where we are doing a 3-arm randomized study in a 1:1:1 fashion, where patients are being randomly assigned to either cabozantinib monotherapy at the full dose at 60 mg, or to cabozantinib 60 mg plus darlifarnib at both 5 and 8 mg.

Because we had those safety and efficacy signals in the cabozantinib-exposed population, we will allow patients who are randomized to the cabozantinib monotherapy arm to be enrolled into the subsequent cabozantinib plus darlifarnib combination [arm] to see if this is still a drug that we could use post-cabozantinib. That's an interesting twist to this design [and] we're waiting to see some promising data.

This [expansion] will help answer the question of how much of this synergistic efficacy are we seeing with darlifarnib and cabozantinib, rather than most of this benefit being driven by cabozantinib. Based on this, we're hopeful that we'll be able to design a larger prospective trial in this space.

What unmet needs in RCC could this combination potentially address?

The RCC landscape is very interesting because we are changing the whole framework pretty quickly with the recent studies looking at lenvatinib and everolimus [Afinitor], and also lenvatinib and belzutifan [Welireg], showing us that there is efficacy for a combination approach even in the second-line or second-line-and-higher [settings].

An approach like this with darlifarnib plus a TKI of interest would be reasonable to evaluate in this space. We also have that holy grail, which is the combination approach in the frontline strategy, where we've looked at multiple combinations of triplet therapy that we haven't breached, and then there is also data now showing us that there are efficacy signals of using combination approaches in the adjuvant [setting].

All of these are open avenues that we could evaluate with darlifarnib. But before we put the horse in front of the cart, we have to look at what the data shows from the expansion study. But there is a lot of promise in either the second-line or the third-line strategy, and maybe even thinking carefully about a frontline strategy in RCC.

References

1. Ayanambakkam A, Zakharia Y, Rosen LS, et al. Farnesyl transferase inhibitor (FTI) darlifarnib combined with cabozantinib in renal cell carcinoma (RCC): updated phase 1a results from FIT-001. Presented at: Kidney Cancer Research Summit; July 23-24, 2026; Boston, MA.
2. KO-2806 monotherapy and combination therapies in advanced solid tumors (FIT-001). ClinicalTrials.gov. Updated June 8, 2026. Accessed July 31, 2026. https://clinicaltrials.gov/study/NCT06026410