Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/ FGFR Aberrations: A Phase I Dose-Expansion Study

Abstract

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy. SIGNIFICANCE: This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1-4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.This article is highlighted in the In This Issue feature, p. 275.

Figure 1.

Phase I expansion study design. ^aIntrahepatic (n = 61) and extrahepatic (n = 3) CCA. ^bSarcoma (n = 6); colorectal cancer (n = 5); endometrial cancer (n = 3); esophageal cancer (n = 3); gallbladder cancer (n = 3); head and neck cancer (n = 2); adrenal cortical cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, and thyroid cancer (n = 1 each); and primary unknown (n = 3). ^cBreast cancer, gallbladder cancer, primary CNS cancer, sarcoma, urothelial cancer, and thyroid cancer (n = 1 each), and primary unknown (n = 2). iCCA, intrahepatic CCA; QD, once daily.

Figure 2.

Individual response and treatment outcome by tumor type in patients who received futibatinib 20 mg once daily. This figure shows individual treatment outcomes organized by tumor type, color coded for FGFR aberration in patients who received futibatinib 20 mg once daily (n = 170). RECIST v1.1 criteria were used for tumor response assessment for all tumor types except CNS tumors, for which RANO criteria were used to assess tumor response. Several patients (n = 14; indicated with a–f) had more than one type of FGF/FGFR aberration. In addition to the FGF/FGFR aberration indicated by the color-coded bars, patients had (a) FGFR2 F/R, (b) FGF3/4/19 amp, (c) FGFR3 F/R, (d) FGFR3 mut, (e) FGF3/19 amp, or (f) FGFR2/3 amp. amp, amplification; FGFRi, FGFR inhibitor; F/R, fusion/rearrangement; mut, point mutation; NE, not evaluable; PD, progressive disease.

Figure 3.

Individual response and treatment outcome by FGFR aberration in patients who received futibatinib 20 mg once daily. The figure shows individual treatment outcomes organized by FGFR aberration type, color coded for tumor type in patients who received futibatinib 20 mg once daily. RECIST v1.1 criteria were used for tumor response assessment for all tumor types except for CNS tumors, for which RANO criteria were used. Several patients (n = 14) had more than one type of FGF/FGFR aberration and are represented in each relevant FGFR aberration category. These patients are indicated with the letters a–n, with each letter representing an individual patient.

Figure 4.

Time on treatment by best response in patients with CCA who received (A) futibatinib 20 mg once daily or (B) futibatinib 16 mg once daily. Time on treatment (color coded by best overall response) of each patient with CCA who received futibatinib at (A) 20 mg once daily (n = 64) or (B) 16 mg once daily (n = 19). NE, not evaluable; PD, progressive disease; QD, once daily.