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Futibatinib in Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Rearrangements: Primary Results of FOENIX-CCA2 Presented at AACR 2021

June/July 2021, Vol 2, No 2

The primary results of the phase 2 FOENIX-CCA2 clinical trial of futibatinib in patients with previously treated intrahepatic cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements were presented by Lipika Goyal, MD, MPhil, Assistant Professor of Medicine, Massachusetts General Hospital, Boston, at the 2021 Annual Meeting of the American Association for Cancer Research (AACR).1

In contrast to other FGFR inhibitors, futibatinib demonstrates covalent, irreversible binding to an FGFR kinase domain P-loop,2 and robust inhibition of the FGFR2 kinase domain mutations that are resistant to reversible ATP-competitive inhibitors (Figure 1).2-4

Figure 1

In a phase 1 study, futibatinib demonstrated tolerability and antitumor activity in patients with advanced FGFR-aberrant tumors, including FGFR2-rearranged intrahepatic CCA.5 These data formed the basis for the pivotal phase 2 FOENIX-CCA2 study, the final results of which were presented at the 2021 AACR Annual Meeting.

The Pivotal Phase 2 FOENIX-CCA2 Study

The study enrolled patients with unresectable or metastatic intrahepatic CCA with an FGFR fusion or other rearrangement, who had received previous gemcitabine plus platinum–based chemotherapy but no previous FGFR inhibitor.1 Patients received futibatinib 20 mg orally once daily, continuously over 21-day cycles, until disease progression, drug intolerance, withdrawal of consent, or death.

The primary end point of the study was objective response rate (ORR) as confirmed by independent review. Secondary end points included duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Survival follow-up was for up to 18 months after enrollment of the last patient.

The median age of the patients was 58 years, with 56% female. Approximately 50% of the patients had 1 previous regimen and 50% had ≥2 previous regimens. FGFR2 fusions were noted in 78% of the patients, with 22% having FGFR rearrangements.

Early, Durable Results

In the 103 patients enrolled in the study, the ORR was 41.7% (95% confidence interval [CI], 32.1-51.9), with 1 patient having a complete response and 42 patients with partial responses (Figure 2).

Figure 2

The responses occurred early and were durable, with a median time to response of 2.5 months and a median DOR of 9.7 months (95% CI, 7.6-17.0). The disease control rate was 82.5% (95% CI, 73.8-89.3), with the majority of patients who had stable disease having tumor shrinkage. The median PFS was 9 months (95% CI, 6.9-13.1), and the median OS was 21.7 months (95% CI, 14.5-not reached), but the OS data are still immature, and further follow-up is ongoing.

Adverse Events Profile

Serious treatment-related adverse events (TRAEs) were noted in 10% of patients (7% were grade ≥3). The most common TRAEs were hyperphosphatemia (91% all grades; grade 3, 31%), nail toxicities (47%; grade 3, 2%), increased liver function tests (27%; grade 3, 12%), palmar-plantar erythrodysesthesia syndrome (21%; grade 3, 5%), rash (9%; no grade 3), and retinal disorders, including chorioretinopathy, detachment of retinal pigment epithelium, maculopathy, serous retinal detachment, and subretinal fluid (8%; no grade 3).

No grade 4 adverse events were noted, except for 1% elevated alanine transaminase. TRAEs resulted in dosing interruption in 50% of the patients, dose reduction in 54% of patients, and drug discontinuation in 2%. There were no treatment-related deaths reported.

Exploratory Analyses

Exploratory analyses of molecular correlates showed that the responses occurred in patients with BICC1 as well as non-BICC1 fusion partners. Responses were also seen in patients with co-occurring genomic alterations in tumor suppressor genes, including in TP53 (Figure 3).

Figure 3

The ORR was 43.8% and 38.5% in patients with unaltered and altered TP53, respectively; the median PFS was 9 months and 7 months in TP53 unaltered and altered, respectively.

Of the 4 patients harboring FGFR as well as IDH1 alterations, 2 patients had centrally confirmed partial responses.

Martin Birkhofer, MD, Chief Medical Officer at Taiho Oncology, suggested that the pivotal phase 2 FOENIX-CCA2 study showed that second-line therapy with futibatinib of patients with intrahepatic CCA resulted in a numerically higher ORR and DOR than that reported with any other FGFR inhibitor, with a manageable safety profile and rare discontinuations.

“This is the best response for patients with intrahepatic CCA reported to date,” Dr Birkhofer said. He expressed his thanks to the patients, their caregivers, and the investigators in the FOENIX-CCA2 clinical trial for their wonderful efforts under challenging circumstances associated with the COVID-19 pandemic.

Breakthrough Therapy Designation

On April 1, 2021, the FDA granted a breakthrough therapy designation for futibatinib for the treatment of patients with previously treated, locally advanced or metastatic CCA harboring FGFR2 gene rearrangements, including gene fusions.6


  1. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Primary results of phase 2 FOENIX-CCA2: the irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (CCA) with FGFR2 fusions/rearrangements. Presented at the Annual Meeting of the American Association for Cancer Research; April 10-15, 2021. Abstract CT010.
  2. Sootome H, Fujita H, Ito K, et al. Futibatinib is a novel irreversible FGFR 1-4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors. Cancer Res. 2020;80:4986-4997.
  3. Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019;9:1064-1079.
  4. Sootome H, Kato S, Aoyagi Y, et al. Acquired resistance to ATP-competitive and irreversible FGFR inhibitors: a library-based approach. Presented at the Annual Meeting of the American Association for Cancer Research; April 10-15, 2021. Abstract CT1117.
  5. Bahleda R, Meric-Bernstam F, Goyal L, et al. Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors. Ann Oncol. 2020;31:1405-1412.
  6. US Food and Drug Administration. FDA grants breakthrough therapy designation for Taiho Oncology’s futibatinib for treatment of advanced cholangiocarcinoma. April 1, 2021. Accessed April 16, 2021.

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