Derazantinib Yields 79% DCR in FGFR2+ Advanced Intrahepatic Cholangiocarcinoma

Derazantinib demonstrated promising disease control when given to patients with inoperable or advanced intrahepatic cholangiocarcinoma and FGFR2 gene fusions, according to results from an interim analysis of cohort 2 from the phase 2 FIDES-01 trial (NCT03230318).¹

The investigational, oral FGFR inhibitor yielded a disease control rate (DCR) of 79%, which included 1 patient who achieved a confirmed complete response, 1 with an unconfirmed partial response, and 9 who experienced a best response of stable disease at the time that the interim analysis was performed.

Moreover, at least 8 patients experienced a progression-free survival (PFS) of 3 months or more, meeting the primary end point of the trial. Although the median PFS was not yet mature at the time of the interim analysis and will need to be defined at a later time point, the positive data will allow the trial to progress to its next stage, which will enroll a total of 43 patients.

“We are very pleased with the positive interim results for this cohort of [patients with] intrahepatic cholangiocarcinoma with FGFR2 gene mutations or amplifications,” Marc Engelhardt, MD, chief medical officer at Basilea, stated in a press release. “The clinical benefit with derazantinib is similar to that reported for [patients with] intrahepatic cholangiocarcinoma with FGFR2 gene fusions earlier this year. This supports the relevance of derazantinib in a group of patients with intrahepatic cholangiocarcinoma where there has been very limited clinical evidence of successful treatment with other FGFR inhibitors and confirms the broad potential of derazantinib as a monotherapy for the treatment of [these] patients with diverse FGFR2 genetic aberrations.”

As FGFR kinases are a key driver of cell proliferation, differentiation, and migration, FGFR aberrations are thought to be an important therapeutic target in several tumor types, including intrahepatic cholangiocarcinoma.²

Derazantinib has previously showcased promising antitumor activity with favorable tolerability in patients with advanced or inoperable intrahepatic cholangiocarcinoma, according to data from a biomarker-driven phase 1/2 study (NCT03230318).³ In the population of 29 patients, the agent elicited an overall response rate (ORR) of 20.7%, as well as a DCR of 82.8%. Moreover, the estimated median PFS was 5.7 months (95% CI, 4.04-9.2) with the agent. Common any-grade treatment-related adverse effects (AEs) included asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade 3 or higher AEs occurred in 27.6% of patients.

The interim analysis of cohort 2 from the FIDES-01 trial focused on 14 evaluable patients who had 1 or more post-baseline tumor assessments. In the pivotal, open-label, single-arm study, investigators aimed to assess the anticancer activity of the agent in patients with inoperable or advanced FGFR2-positive intrahepatic cholangiocarcinoma who had received 1 or more prior regimens containing a systemic agent.⁴

To be eligible for enrollment, patients needed to be at least 18 years of age with histologically or cytologically confirmed locally advanced, inoperable disease and FGFR2 gene fusions. Patients need to have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 to 1. Additionally, patients needed to have acceptable organ function to participate.

Those who have received major surgery, locoregional therapy, or radiation therapy within 4 weeks of the first dose of derazantinib were excluded from the study, as were those who previously received treatment with an FGFR inhibitor, had clinically unstable central nervous system metastases, concurrent uncontrolled or active hepatobiliary disease, or untreated or ongoing complications following a laparoscopic procedure or stent.

Patients received derazantinib at a daily dose of 300 mg 1 hour prior, or 2 hours after, a meal.

The primary outcome measures of the study were ORR and PFS at 3 months. Key secondary outcome measures included safety, duration of response, PFS, overall survival, and health-related quality of life.

“This outcome is very encouraging and further strengthens the evidence for the differentiation of derazantinib vs other FGFR inhibitors both from the efficacy and safety perspective,” Engelhardt added in the release. “We are now progressing the study to the next stage and expect topline results for cohort 2 in the first half of 2022.”

Derazantinib is also under examination in the phase 1/2 FIDES-02 trial (NCT04045613). In the study, the agent is being assessed as both a monotherapy and in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) in patients with advanced urothelial carcinoma whose tumors have FGFR genetic abberations.⁵ Interim results from the phase 1b portion of the study have identified the recommended phase 2 dose (RP2D) of the combination to be 300 mg of oral derazantinib daily and 1200 mg of intravenous atezolizumab once every 3 weeks.

The RP2D corresponds to the single-agent derazantinib dose used in FIDES-01 and the standard does of atezolizumab monotherapy in this disease. Notably, no dose-limiting toxicities were observed with the regimen. The most common AEs associated with the regimen were asthenia or fatigue, nausea, and diarrhea.

Investigators are also evaluating the agent in patients with advanced gastric cancer with FGFR genetic aberrations as part of the phase 1/2 FIDES-03 study (NCT04604132).⁶ The multicohort trial will assess derazantinib as a single-agent, as well as in combination regimens, such as derazantinib plus atezolizumab.

References

1. Basilea reports positive interim results from phase 2 study 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 April 16, 2021. https://bit.ly/3soVMmR
2. Porta R, Borea R, Coelho A, et al. FGFR a promising druggable target in cancer: molecular biology and new drugs. Crit Rev Oncol Hematol. 2017;113:256-267. doi:10.1016/j.critrevonc.2017.02.018
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 April 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03230318
5. Basilea reports interim results from phase 1/2 study FIDES-02 exploring derazantinib in patients with advanced urothelial cancer. News release. Basilea Pharmaceutica Ltd. October 13, 2020. Accessed April 16, 2021. https://bit.ly/3wZEboZ
6. Basilea starts phase 1/2 study FIDES-03 with derazantinib in patients with gastric cancer. News release. Basilea Pharmaceutica Ltd. September 28, 2020. Accessed April 16, 2021. https://bit.ly/3aktt2N