Derazantinib Demonstrates Efficacy, Tolerability for Intrahepatic Cholangiocarcinoma With FGFR2 Aberrations

Mitesh Borad, MD, Mayo Clinic Cancer Center, Rochester, MN, reviews the results from the single-arm, open-label phase 2 FIDES-01 study, evaluating the fibroblast growth factor receptor (FGFR)1-3 inhibitor, derazantinib in patients with intrahepatic cholangiocarcinoma and FGFR2 fusions, mutations, or amplifications, who had previously been treated with at least 1 chemotherapy regimen.

Dr Borad explains that derazantinib was well tolerated and demonstrated meaningful clinical benefit in patients with FGFR2 genetic aberrations, including FGFR2^F and FGFR2^MA.

Transcript:

Hi, I'm Professor Mitesh Borad at the Mayo Clinic College of Medicine and Science. I also serve as the co-director of the Precision Cancer Therapeutics Program at Mayo Clinic Center for Individualized Medicine, and the program leader for Gene and Virus Therapy program at the Mayo Clinic Comprehensive Cancer Center. Today I will give you an overview of the FIDES-01 study that utilized derazantinib in patients with cholangiocarcinoma.

As a brief background, derazantinib is a selective inhibitor of the FGFR family of receptor tyrosine kinases, primarily FGFR1, FGFR2, and FGFR3, and being even more selective for FGFR2 amongst these three. The study was a single-arm, open-label, pivotal study for derazantinib in patients with cholangiocarcinoma. There were two cohorts: Cohort 1 examined the use of the drug in patients with FGFR2 fusions or rearrangements, and Cohort 2 explored the utility of the medication in patients with mutations or amplifications in FGFR2. And the drug was dosed at 300 mg on a daily basis.

The study was designed statistically so that Cohort 1 would exceed a 10% upper-bound of a presumed response rate of 10% in patients who would have received other therapies, for example. And Cohort 2, utilizing the mutations and amplifications, was designed to show improvement in progression-free survival with 45% of patients exceeding that boundary at 3 months as the assumption, and a change being noted if more than 65% of patients exceeded that 3-month boundary.

As I mentioned, this was a single-arm, a pivotal study with these 2 cohorts. In the first cohort response rate was the primary end point. In the second cohort, the progression-free survival parameter that I described was the primary end point. Secondary end points for both cohorts were other efficacy parameters, such as progression-free survival, overall survival, safety profiling, toxicity, and preliminary correlations with specific mutations and efficacy in the mutation and amplification cohort.

The responses were assessed by independent review for this study, and as such, it had that level of rigor. As far as the results go, these were reported on several occasions with the most recent report being at ESMO 2022. And in this report, in Cohort 1, 103 patients were enrolled into the study. The response rate noted was 22.3% confirmed by independent review. The progression-free survival for these patients was 7.8 months, and the overall survival was 17.2 months. The disease control rate, which would also account for patients with stable disease, was approximately 76%. For the patients in Cohort 2, with mutations or amplifications, there were 44 patients enrolled. The response rate was 6.8%. The progression-free survival was 8.3 months, and the overall survival was 15.9 months. The disease control rate was approximately 64%.

Across both cohorts, in terms of the toxicity profile, what was notable was that there was a low rate of events that are typically seen in small molecule, FGFR tyrosine kinase inhibitors that hit multiple kinases like I described, and lead to nail skin and ocular events. From that perspective, the proportion of these events were, nail events were 7.5%. Stomatitis was at 2%, retinal events at 1.4%, and hand-foot syndrome events at 1.4%. These are significantly lower than what have been reported with other agents, including FDA-approved agents such as pemigatinib and infigratinib, and most recently futibatinib. This could provide a distinguishing future for this drug in terms of its tolerability on a long-term basis.

What are the implications for the results from this study? This provides data for yet another FGFR inhibitor in this space. While the response rates are numerically lower than what have been reported for other agents, at 22.3%, one can note that on the waterfall plot, the percentage of patients having tumor shrinkage is comparable to the other agents and the disease control rate and progression-free survival numbers are very much in line with all the other agents. Perhaps using response rate as the only measure does not do full justice to agents that do cause tumor shrinkage and lead to prolonged stable disease such as derazantinib.

This trial also provides data in a robust fashion for 44 patients in this mutation and amplification cohort. And these are also patients that are identified when next generation sequencing is routinely done. It's in the 3% to 5% range of all patients with intrahepatic cholangiocarcinoma in particular. That adds almost 1/3 to 1/2 as many patients as are identified with fusions and rearrangements. This study was therefore important from that perspective, that it provided data in this group of patients. While the response rate is low, 6.8%, one can see from the fairly robust progression-free survival of 8.3 months that this likely results in meaningful clinical benefit. And again, here the disease control rate was 64%, which accounts for both response and stable disease; that is meaningful.

Lastly, given the toxicity and safety profile, this could provide another avenue for patients if they do experience toxicities and have to discontinue use of available agents such as pemigatinib, infigratinib, or futibatinib. Perhaps an agent like derazantinib could provide efficacy in those settings where there isn't resistance conferred by one of the mutations that could lead to resistance, but could continue providing efficacy with a more favorable toxicity profile.

These are the key takeaways from this study and we'll see what transpires in terms of future work with this agent. Thank you for attention today.

Source:

Borad M, Javle M, Shaib WL, et al. 59P Efficacy of derazantinib in intrahepatic cholangiocarcinoma (iCCA) patients with FGFR2 fusions, mutations or amplifications. Annals Oncol. 2022;33:S567-568. doi:10.1016/j.annonc.2022.07.087