Futibatinib Induces Durable Responses in FGFR2+ Intrahepatic Cholangiocarcinoma

Futibatinib (TAS-120) demonstrated efficacy and tolerability when administered to patients with intrahepatic cholangiocarcinoma (iCCA) who harbor FGFR2 fusions/rearrangements, according to results of an interim analysis of the FOENIX-CCA2 trial (NCT02052778) presented in a poster during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.¹

Investigators recorded an objective response rate (ORR) of 37.3% (95% CI, 25.8-50.0) in this analysis of 67 patients with at least 6 months of follow-up. One patient (1.5%) had a complete response and 24 (35.8%) had partial responses.

Futibatinib is an oral, small molecule inhibitor of FGFR1-4. FGFR2 fusions occur in 10% to 20% of patients with iCCA, with an expected 5-year survival rate of 24%. Currently, there is no standard treatment for advanced disease after first-line chemotherapy.²

Responses were durable, lasting a median of 8.3 months, and 37% of patients remained on treatment at the median follow-up of 11.4 months. Investigators observed objective responses across patient subgroups, regardless of the number of prior treatment regimens and in patients with co-occurring genetic alterations in TP53, IDH1, and PI3K genes.

The disease control rate was 82.1% ­(95% CI, 70.8%-90.4%). Median time to response was 2.5 months (range, 1.4-2.7). The median duration of response (DOR) was 8.3 months (95% CI, 6.2 to not evaluable).

The median progression-free survival (PFS) was 7.2 months (95% CI, 4.0-15.2). At 6-months, the PFS rate was 61% (95% CI, 47.5%-72.0%) and the overall survival (OS) rate was 86% (95% CI, 74.7%-92.4%).

The targeted agent is being explored in an ongoing, global, open-label phase 2 study of patients with unresectable locally advanced or metastatic iCCA harboring an FGFR2 fusion or rearrangement. A total of 103 patients were enrolled across 36 international sites from April 2018 to November 2019. Median follow-up in this planned analysis (database lock March 30, 2020) was 11.4 months. Investigators identified FGFR2 fusion in 55 patients (82%).

The primary end point was ORR as assessed by independent central radiological review per RECIST 1.1, confirmed by a second tumor assessment 4 to 6 weeks after the initial response. DOR, disease control rate (DCR), PFS, and safety were secondary end points.

Investigators noted the safety profile observed was consistent with this drug class. All patients experienced treatment-related adverse effects (TRAE) and 38 (57%) experienced a grade 3 TRAE.

Seven patients (10%) reported serious TRAEs. Migraine was the only serious TRAE reported in more than 1 patient (n = 2). Overall, 44 patients (66%) had a dosing modification because of a TRAE. There were 37 patients (55%) who required dosing interruption and 34 (51%) with dose reductions.

Eighteen patients (27%) experienced grade 3 or higher hyperphosphatemia. All cases resolved with medication and no patients discontinued treatment because of hyperphosphatemia.

Thirty-six patients (54%) discontinued because of clinical or radiological disease progression; no patients died while on treatment. Four patients discontinued treatment because AEs.

This trial also included a phase 1 dose-escalation phase, which established 20 mg once daily futibatinib as the maximum tolerated dose.³ Antitumor activity of futibatinib was also demonstrated across patients with various advanced tumor types (including cholangiocarcinoma) with a range of FGFR alterations.

The phase 3 FOENIX-CCA3 (NCT04093362) trial of futibatinib versus gemcitabine/cisplatin in the first-line setting is underway. This is an open-label, multinational, 2-arm parallel, randomized study of patients with advanced, metastatic, or recurrent unresectable iCCA harboring FGFR2 gene rearrangements. The trial is estimated for enrollment of 216 patients. The primary end point is PFS, with secondary outcome measures of ORR, DCR, OS, safety, and tolerability.

Futibatinib is also being studied in a phase 2 trial (NCT04024436) in patients locally advanced/metastatic breast cancer harboring FGFR gene amplifications. This is an open-label, nonrandomized trial that will recruit 168 patients and assess ORR, clinical benefit rate, and 6-month PFS.

_References:

_{1. Bridgewater JA, Meric-Bernstam F, Hollebecque A, Valle JW, et al. Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/other rearrangements: Subgroup analyses of a phase II study (FOENIX-CCA2). Poster. European Society of Medical Oncology (EMSO) Virtual Congress 2020; September 17-21, 2020. Abstract #4493.}

_{2. Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, et al. FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. J Clin Oncol. 2020;38(15):108. doi: 0.1200/JCO.2020.38.15_suppl.108}

_{3. Bahleda R, Meric-Bernstam F, Goyal L, Tran B, 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;S0923-7534(20)39928-2. doi:10.1016/j.annonc.2020.06.018.}