Derazantinib Continues to Elicit Encouraging Responses in FGFR2 Gene Fusion–Positive Intrahepatic Cholangiocarcinoma

Marc Engelhardt, MD

Derazantinib continued to induce encouraging responses in patients with FGFR2 gene fusion–positive intrahepatic cholangiocarcinoma, according to updated data from cohort 1 of the phase 2 FIDES-01 trial (NCT03230318).¹

Topline data from the cohort were presented in February 2021 and showed that the orally administered FGFR inhibitor elicited an objective response rate (ORR) of 20.4%, with a disease control rate (DCR) of 72.8% in patients with intrahepatic cholangiocarcinoma whose tumors harbored FGFR2 gene fusions and who had previously received at least 1 chemotherapy regimen.² The median progression-free survival (PFS) at the time was 6.6 months.

Data from the updated analysis showed, that at a data cutoff of April 2021, the ORR, DCR, and PFS achieved with the agent in this population all increased to 21.4%, 74.8%, and 7.8 months, respectively. These data serve to further support the efficacy of single-agent derazantinib in this indication, according to Basilea Pharmaceutica Ltd.

“We are very pleased with the more mature results from the first fully-enrolled patient cohort of the FIDES-01 study. The PFS of 7.8 months is in the upper range reported for this end point with FGFR inhibitors in this patient population,” Marc Engelhardt, MD, chief medical officer of Basilea Pharmaceutica Ltd., stated in a press release. “Derazantinib also continues to show a well-manageable safety profile, with low rates of retinal [adverse] effects [AEs], stomatitis, hand–foot syndrome, and nail toxicity. Overall, these results underscore the favorable benefit to risk profile of derazantinib as a monotherapy in bile duct cancer.”

Derazantinib is an investigational, orally-administered, small molecule FGFR inhibitor that has been shown to have strong activity against FGFR1, FGFR2, and FGFR3; the agent also inhibits the CSF1R kinase.

Previously, the agent has demonstrated encouraging antitumor activity and acceptable tolerability in patients with advanced or inoperable intrahepatic cholangiocarcinoma in a biomarker-driven phase 1/2 study (NCT03230318).³ Results indicated that the FGFR inhibitor induced an ORR of 20.7% and a DCR of 82.8% in 29 patients. The estimated median PFS in these patients was 5.7 months (95% CI, 4.04-9.2). Any-grade treatment-related toxicities reported with the agent included asthenia/fatigue (69.0%), ocular toxicity (41.4%), and hyperphosphatemia (75.9%).

The phase 2 FIDES-01 trial is examining the antitumor activity of derazantinib in 103 patients with inoperable or advanced intrahepatic cholangiocarcinoma and confirmed FGFR2 gene fusions. Patient enrollment to cohort 1 of the trial was completed in July 2020.

In the trial, study participants are given oral derazantinib at a daily dose of 300 mg. The primary efficacy end point of the trial for cohort 1 is ORR and it has been evaluated through an independent central radiology review. Secondary end points include safety, duration of response, PFS, overall survival, and health-related quality of life.⁴

Additional safety data from the initial analysis of cohort 1 showed that treatment-related AEs (TRAEs) included hyperphosphatemia, asthenia/fatigue, increased liver enzymes, nausea, dry mouth, dry eye, diarrhea, and dysgeusia. The percentage of those who reported TRAEs pertaining to nail toxicities was just 6%. Moreover, incidence of retinopathy, stomatitis, or hand–foot syndrome was low (1% each).

Data from cohort 1 provided proof of concept for derazantinib monotherapy in patients with FGFR2 gene fusion–positive intrahepatic cholangiocarcinoma. As such, cohort 2 of the trial is examining the agent in patients with intrahepatic cholangiocarcinoma whose tumors harbor FGFR2 gene mutations or amplifications.

Data from the interim analysis of cohort 2 were shared in March 2021 and were based on a total of 14 evaluable patients who had at least 1 post-baseline tumor assessment available. In this cohort, the agent resulted in a PFS of at least 3 months in 8 patients, meeting the primary end point of the trial.⁵

The agent was also found to induce a DCR of 79%, which included 1 patient with a confirmed complete response, 1 patient with an unconfirmed partial response, and 9 patients with a best response of stable disease at the time that the analysis was completed.

The positive data from the interim analysis allowed for the study to advance to the next stage in which the enrollment of 43 total patients is planned.

“We are also making good progress in cohort 2 of the study, which is enrolling [patients with] intrahepatic cholangiocarcinoma [and] FGFR2 gene mutations or amplifications. We have achieved about 50% of target enrollment and are aiming to report topline results in the first half of 2022,” Engelhardt added. “If the encouraging results from the recently reported interim [analysis] are confirmed upon completion of the study, this will further strengthen the evidence of a differentiated efficacy and safety profile for derazantinib in bile duct cancer.”

Derazantinib is also under investigation in the phase 1/2 FIDES-02 trial (NCT04045613), where it is being evaluated as a single agent and in combination with atezolizumab (Tecentriq) in patients with advanced solid tumors.⁶ The trial is comprised of several substudies:

• Substudy 1 (phase 2) is examining derazantinib at a once-daily dose of 300 mg in the second-line or later treatment of patients with metastatic urothelial carcinoma whose tumors harbor FGFR genetic aberrations.
• Substudy 2 (phase 1b) is evaluating 2 dose levels of the agent plus atezolizumab in patients with solid tumors. Those receiving dose level 1 will be administered a daily 200-mg dose of derazantinib with a 1200-mg dose of atezolizumab every 3 weeks. Those who are receiving dose level 2 will be given derazantinib at a daily dose of 300 mg and atezolizumab at 1200 mg every 3 weeks.
• Substudy 3 (phase 2) is examining derazantinib at a daily dose of 300 mg as a first-line treatment in patients with cisplatin-ineligible, PD-L1–low, FGFR-mutated metastatic urothelial cancer compared with the recommended phase 2 dose (RP2D) of derazantinib/atezolizumab.
• Substudy 4 (phase 2) is comparing the efficacy of single-agent derazantinib at a daily dose of 300 mg in patients with FGFR inhibitor–resistant, FGFR-mutated metastatic urothelial cancer vs the RP2D of derazantinib/atezolizumab.

The primary end point of substudies 1, 3, and 4 is to examine the antitumor activity of derazantinib monotherapy and in combination with atezolizumab via ORR per central radiology review and RECIST v1.1 criteria. The primary end point for substudy 2 is to identify the RP2D of derazantinib plus atezolizumab, which will be done by evaluating the proportion of those experiencing dose-limiting toxicities, AEs, preliminary pharmacokinetics, and efficacy data.

Basilea announced that based on the interim efficacy data observed in the ongoing cohort of patients with FGFR inhibitor–naïve urothelial cancer receiving derazantinib monotherapy at a daily dose of 300 mg as a second-line or later treatment, the cohort will not be further expanded. Now, efforts will be focused on examining an intensified dose of 400 mg daily in this patient population based on available data.

“Derazantinib monotherapy at a dose of 300 mg per day has shown to be efficacious and safe in patients with intrahepatic cholangiocarcinoma and has also provided signs of clinical benefit in the ongoing FIDES-02 urothelial cancer study,” Engelhardt explained. “The unmet medical need in advanced metastatic urothelial cancer remains high…Derazantinib dose levels above 300 mg per day have previously been studied and we believe that the intensified dose regimen of 400 mg per day could provide additional overall clinical benefit in advanced urothelial cancer.”

References

1. Basilea provides updates on efficacy data with derazantinib in bile duct cancer and on ongoing clinical programs in urothelial and gastric cancer. News release. Basilea Pharmaceutica Ltd. May 31, 2021. Accessed June 2, 2021. https://bit.ly/3icpgmp
2. Basilea reports positive topline results from phase 2 study FIDES-01 for derazantinib in FGFR2 gene fusion-positive patients with bile duct cancer (iCCA). News release. Basilea Pharmaceutica Ltd. February 10, 2021. Accessed June 2, 2021. https://bit.ly/3gks66v
3. Mazzaferro V, El-Rayes BF, Dit Busset MD, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120(2):165-171. doi:10.1038/s41416-018-0334-0
4. Derazantinib in subjects with FGFR2 gene fusion-, mutation-, or amplification-positive inoperable or advanced intrahepatic cholangiocarcinoma (FIDES-01). ClinicalTrials.gov. Updated February 1, 2021. Accessed June 2, 2021. https://clinicaltrials.gov/ct2/show/NCT03230318
5. Basilea reports positive interim results from phase 2 study of FIDES-01 for derazantinib in FGFR2 gene mutation- or amplification-positive patients with bile duct cancer (iCCA). News release. Basilea Pharmaceutica Ltd. March 24, 2021. Accessed June 2, 2021. https://bit.ly/3g6tFoo
6. Abdul-Karim RM, Chaudhry A, Patrikdou A, et al. Derazantinib (DZB) in combination with atezolizumab (AZB) in patients with solid tumors: results from the dose-finding phase 1b substudy of FIDES-02. J Clin Oncol. 2021;39(suppl 6):437. doi:10.1200/JCO.2021.39.6_suppl.437