Futibatinib, an Irreversible FGFR1-4 Inhibitor for the Treatment of FGFR-Aberrant Tumors.

Implications for Practice

Patients with FGFR -altered cancers have limited treatment options in advanced stages. Promising responses have been observed with FGFR inhibitors; however, acquired resistance is an emerging concern. This review summarizes data surrounding futibatinib, the only second-generation FGFR1-4 inhibitors in phase II/III clinical development. Futibatinib has shown durable efficacy and tolerability in cholangiocarcinoma with FGFR2 fusions/rearrangements, and recently received approval from the US Food and Drug Administration for this indication. Futibatinib has demonstrated antitumor activity across several FGFR -aberrant tumors, spurring the initiation of several phase II trials of futibatinib or futibatinib-containing combinations in other tumor types.

Introduction

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play an integral role in regulating a wide range of biological processes 1 and dysregulation of the FGFR pathway is associated with oncogenesis. 2-7 Approximately 7% of all cancers harbor FGFR aberrations, with type and prevalence varying widely. 8 Thus, FGFR has emerged as an important therapeutic target. Most FGFR inhibitors in development are ATP-competitive, reversible inhibitors, which are associated with acquired resistance. 9 , 10 Futibatinib, an irreversible FGFR1-4 inhibitor, is the most advanced covalent inhibitor in clinical development for multiple cancer types. 11 Here, we briefly describe the role of FGFR and FGFR inhibitors in cancer and discuss recent data supporting futibatinib as a clinically meaningful, second-generation FGFR inhibitor.

FGFR as an Oncologic Target

The FGFR pathway includes a family of 22 FGF ligands, which primarily convey cellular signals through 4 transmembrane tyrosine kinase receptors (FGFR1-4). 12 , 13 Typically, FGFR activation induces cell proliferation and migration, 14 but it can also drive cell differentiation or negatively regulate proliferation. 15 , 16 Aberrant FGFR signaling (generally constitutive FGFR activation) can promote tumorigenesis, support tumor survival, and confer resistance to chemotherapy through anti-apoptotic signaling, 2-7 , 17 , 18 rendering FGFR- altered tumors difficult to treat. 19

Analysis of 17 different cancer types showed that 7% had FGFR aberrations, found most commonly in urothelial, breast, endometrial, and squamous cell lung cancer ( Fig. 1 ). Gene amplifications, mutations, and rearrangements accounted for 66%, 26%, and 8% of FGFR aberrations identified, respectively. 8 These findings suggest FGFR inhibition as a potential therapeutic strategy in multiple tumor types.

Selective, Small-Molecule FGFR Inhibitors

FGFR inhibitors mostly target the FGFR kinase domain, inhibiting FGFR signaling. Although several therapeutic modalities are being investigated for FGFR inhibition (reviewed elsewhere 39 ), small-molecule FGFR inhibitors remain the most widely investigated. These inhibitors vary in their selectivity (specific to FGFR or multikinase) and mode of binding to the FGFR kinase domain (type I, type II, reversible, or irreversible). 40 Reversible ATP-competitive FGFR inhibitors currently under investigation, including derazantinib, erdafitinib, pemigatinib, and infigratinib ( Table 1 ; Supplementary Table S1 ), engage primarily in noncovalent interactions with amino acids in the hinge and surrounding regions of the ATP-binding pocket in the FGFR kinase domain. Irreversible inhibitors, such as PRN1371, futibatinib, and fisogatinib, form a covalent bond, generally with a conserved cysteine in the FGFR kinase domain. 40 , 54

Selective FGFR inhibitors have shown promising activity in various FGFR -aberrant cancer types. To date, the US Food and Drug Administration (FDA) has approved erdafitinib in patients with metastatic urothelial carcinoma harboring FGFR2/3 aberrations who were previously treated, 55 and pemigatinib and infigratinib for second- or later-line treatment of unresectable cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements. 49 , 55 An emerging concern with these inhibitors is acquired resistance, which leads to disease progression. 9 , 56 , 57 One mechanism of acquired resistance is the development of secondary “gatekeeper” mutations in the FGFR kinase domain that “block” FGFR inhibitor binding through steric hindrance. 9 , 39 , 56 , 58 Reversible inhibitors, such as erdafitinib, infigratinib, and pemigatinib, are largely ineffective against these mutations. 56 Second-generation inhibitors that retain activity against these mutations and have a lower susceptibility to resistance are sorely needed.

Futibatinib, a Potent, Irreversible FGFR1-4 Inhibitor

Futibatinib is a structurally novel, highly selective, and potent FGFR inhibitor, 11 which binds covalently and irreversibly to a conserved cysteine residue in the FGFR kinase domain within the ATP-binding pocket 54 ( Fig. 2 ). As this cysteine residue is conserved across all FGFR receptors, futibatinib inhibits the kinase activity of all 4 FGFR isoforms. The distinct binding site and irreversible binding render futibatinib less susceptible to drug resistance mutations than reversible, ATP-competitive inhibitors.

Preclinical Development

In vitro characterization of futibatinib against a panel of 296 kinases demonstrated high selectivity and potent inhibition of all 4 FGFR isoforms with half-maximal inhibitory concentration values ranging from 1.4 nmol/L to 3.7 nmol/L. 11 Futibatinib selectively inhibited cancer cell lines of diverse tissue origins (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring a variety of FGFR aberrations. Additionally, futibatinib treatment led to significant dose-dependent tumor reductions and sustained FGFR kinase inhibition in FGFR -aberrant human tumor xenograft mice models.

In vitro futibatinib treatment of gastric cancer cells was associated with a lower risk of developing drug resistance due to FGFR escape mutations than the reversible FGFR inhibitor AZD4547. 11 Futibatinib also demonstrated greater inhibition of secondary FGFR2 kinase domain drug-resistant mutations, including the gatekeeper mutation V565I/L, than AZD4547, infigratinib, pemigatinib, or erdafitinib. 11

In an unbiased library-based analysis, the activity of futibatinib and other FGFR inhibitors were examined against drug-resistant FGFR2 kinase domain mutations generated by random mutagenesis 59 and transfected in a Ba/F3 cell system dependent on FGFR2 signaling for growth. Futibatinib showed the most robust inhibition of drug-resistant FGFR2 kinase domain mutations (also clinically relevant 9 , 56 , 57 , 60 ) as well as the lowest propensity for emergence of resistant clones with prolonged treatment.

Futibatinib Early Clinical Data: Dose Selection and Pharmacology

A first-in-human, phase I dose-escalation study ( NCT02052778 ) evaluated futibatinib safety and pharmacokinetics/pharmacodynamics in 86 patients with advanced solid tumors (83% with FGF/FGFR aberrations) who were heavily pretreated. 61 Futibatinib was administered on daily (QD) continuous dosing (4-24 mg QD; n = 44) and 3 times a week (TIW) intermittent dosing (8-200 mg TIW; n = 42) schedules. Dose-limiting toxicities (DLTs), all related to liver enzyme elevations, occurred in 3 patients receiving futibatinib 24 mg QD. No DLTs were observed with TIW dosing. All QD doses tested showed dose-proportional pharmacokinetics, whereas TIW dosing was associated with saturation between 80 mg and 200 mg TIW. As renal handling of phosphorus is mediated by FGF23 signaling, 62 serum phosphorus levels were evaluated as an on-target effect and chosen as a pharmacodynamic marker. While serum phosphorus levels correlated positively with futibatinib dose and exposure for both QD and TIW dosing, this correlation was stronger with QD vs. TIW dosing. Similar data were observed in a phase I dose-escalation study in patients with advanced solid tumors from Japan (JapicCTI-142552). 63 Based on these data, futibatinib 20 mg QD was selected as the recommended phase II dose.

Futibatinib showed a manageable safety profile. 61 The most common treatment-emergent adverse events were hyperphosphatemia, diarrhea, and constipation. In addition, encouraging preliminary antitumor activity was observed in this heavily pretreated population, particularly in those with intrahepatic CCA (iCCA). Across cohorts, 5 patients (6%) experienced partial responses (PRs) and 48% ( n = 41) achieved stable disease (SD). Most patients with PRs or SD had tumors harboring FGF/FGFR aberrations; those with PRs included 3 patients with iCCA, all harboring FGFR2 fusions, and 2 patients with FGFR1 -mutant brain tumors. Among patients with CCA, 75% (18/24) experienced a PR or SD.

Futibatinib pharmacokinetics were evaluated in healthy adult volunteers in multiple open-label, phase I studies. An absorption, distribution, metabolism, and excretion study with [ 14 C]-futibatinib identified futibatinib as the most abundant component circulating in plasma; other metabolites accounted for 9%-13% of circulating components. 64 [ 14 C]-futibatinib was mainly excreted through the fecal route after metabolism, and no unmetabolized futibatinib was detected in the feces or urine.

In a food-effect and drug-drug interaction (DDI) study with a proton pump inhibitor (PPI; lansoprazole), consuming a high-fat, high-calorie meal slightly lowered futibatinib oral bioavailability, and delayed time to futibatinib maximum plasma concentration, but the differences were not clinically meaningful. Coadministration of lansoprazole had no clinically relevant effect on futibatinib pharmacokinetics, indicating that futibatinib can be coadministered with PPIs. 64 , 65

Other phase I studies in healthy adult volunteers evaluated the involvement of futibatinib in the common drug metabolizing CYP3A pathway. 66 DDIs were assessed between futibatinib and midazolam (a sensitive CYP3A substrate), itraconazole (a strong dual inhibitor of CYP3A and P-gp), and rifampin (a strong dual inducer of CYP3A and P-gp). 65 Multiple doses of futibatinib did not affect the pharmacokinetics of midazolam; therefore, futibatinib is not expected to affect the exposure of concomitant medications metabolized via CYP3A. However, itraconazole coadministration resulted in higher peak plasma concentrations and significant increases in plasma exposure of futibatinib compared with futibatinib alone, and coadministration of rifampin decreased futibatinib exposure. Thus, coadministering futibatinib with strong dual inhibitors or inducers of CYP3A and P-gp should be avoided because of potential significant DDIs.

Activity of Futibatinib in CCA

Based on results from the phase I dose escalation study, 61 the phase I dose expansion study evaluated futibatinib in a larger population of patients with advanced solid tumors harboring FGF / FGFR aberrations, including a sizeable CCA population. 67 Among 64 patients with FGFR -altered CCA who received futibatinib 20 mg QD, the objective response rate (ORR) was 15.6%, and in the subgroup of patients with iCCA harboring FGFR2 fusions/rearrangements ( n = 42), the ORR was 16.7%. Median duration of response (DOR) was 5.3 months and 6.9 months, respectively, and disease control rate (DCR) was 72% and 79%, respectively. In patients with FGFR2 fusion/rearrangement–positive iCCA treated with either futibatinib 20 mg or 16 mg QD, the overall ORR was 25.4% (15/59). These data formed the basis for further study of futibatinib in patients with FGFR2 -rearrangement–positive iCCA.

The pivotal phase II FOENIX-CCA2 study investigated futibatinib in 103 patients with advanced unresectable iCCA harboring FGFR2 fusions or rearrangements after one or more lines of systemic chemotherapy. 48 FOENIX-CCA2 surpassed its primary endpoint target with an ORR of 41.7% (43/103; 95% CI, 32.1-51.9), as assessed by independent central review ( Fig. 3A ). Responses were rapid and durable: median time to response was 2.5 months (range, 0.7-7.4), median DOR was 9.7 months (95% CI, 7.6-17.0), and 72% (31/43) of responders had responses lasting at least 6 months ( Fig. 3B ). Objective responses were consistent across subgroups, including patients with poor prognostic factors, such as patients 65 years and older or who were heavily pre-treated (≥3 prior therapies). Preliminary survival data were promising; after a median follow-up of 17.1 months, median progression-free survival (PFS) was 9.0 months (95% CI, 6.9-13.1) and median overall survival (OS) was 21.7 months ( Fig. 3C , 3D ). The 1-year OS rate was 72%. Results were similar at extended follow-up (median 25.0 months) with a confirmed ORR of 41.7%, mature median OS of 20.0 months (12-month OS rate, 73%), and median PFS of 8.9 months. 68 Based on these data, futibatinib was granted accelerated approval by the FDA for patients with previously treated, unresectable, locally advanced, or metastatic FGFR2 -fusion/rearrangement-positive iCCA. 69

Genomic Profiling of Futibatinib Clinical Activity in CCA

Exploratory molecular profiling analyses from FOENIX-CCA2 examined futibatinib activity by FGFR aberration type or in the context of co-occurring genomic alterations ( Fig. 3A ). 48 Futibatinib response did not appreciably vary with fusion partner type: ORRs were 41.7% and 44.6% in patients with BICC1 and non- BICC1 fusions, respectively.

ORRs were consistent regardless of the presence of co-alterations in TP53 (ORR, 38.5%; 43.8% with unaltered TP53 ), CDKN2A (40.0%; 43.8% with unaltered CDKN2A ), and CDKN2B (43.8%; 42.9% with unaltered CDKN2B ) ( Fig. 3A ). 48 Median PFS with futibatinib was 7.0 and 9.0 months in TP53 -altered and unaltered populations, respectively, 4.9 and 9.7 months in CDKN2A -altered and unaltered populations, respectively, and 4.8 and 11.0 months in CDKN2B -altered and unaltered populations, respectively. 48 While cross-trial comparisons should be made with caution, a similar analysis of pemigatinib treatment in patients with CCA harboring FGFR2 fusions/rearrangements found no response to pemigatinib treatment and a lower median PFS (2.8 months) in patients with TP53 co-alterations, while patients without TP53 co-alterations experienced an ORR of 38.8% and a median PFS of 9.0 months. 57 Patients with CDKN2A /B alterations treated with either pemigatinib or futibatinib had a lower median PFS, and those treated with pemigatinib experienced a lower ORR, than patients without alterations. 48 , 57 These data provide interesting information about the activity of these treatments in the context of the CCA genetic landscape; however, the findings are limited by the small number of patients with co-alterations and the post hoc exploratory nature of these analyses.

Response to Futibatinib in Patients With iCCA With Prior FGFR Inhibitor Treatment

Preliminary data suggest that futibatinib showed antitumor activity in patients with iCCA with progression after previous FGFR inhibitor treatment. In the dose-escalation study, one responder had a history of disease progression on prior infigratinib before receiving futibatinib treatment for 15.6 months. 61 In the dose expansion study, 5 of 28 patients with prior FGFR inhibitor therapy (17.9%) experienced objective responses with futibatinib. 67 Duration of response ranged from 3.5 months (with response ongoing at data cutoff) to 20.4 months. Of the 5 responders, 3 had FGFR2 fusions, 1 a FGFR2 mutation, and 1 a FGFR2 amplification/rearrangement. An additional 15 patients previously treated with an FGFR inhibitor had stable disease. Of note, mechanisms of acquired resistance to prior FGFR inhibitor therapy were not captured because immediate pretreatment and post-progression biopsies were not required in the study.

In a separate analysis, clonal dynamics using cell-free circulating tumor DNA (ctDNA) were evaluated in 4 patients from a single site within the phase I patient population. 60 These patients received prior infigratinib or Debio 1347, and each experienced clinical benefit with futibatinib (2 PR, 2 SD) with SD or PR lasting 5.1-17.2 months. In 3 patients, analysis of ctDNA at progression on the prior FGFR inhibitor indicated the development of acquired resistance mutations: E566A, H683L, K660M, K715R, M538I, N550H, N550K, N550T, and V565F. 60 Analyses of ctDNA at the start of futibatinib treatment and upon subsequent progression in all 4 patients suggested that futibatinib had differential activity against individual FGFR2 secondary mutations compared with the prior FGFR inhibitors. The mutation allele frequency of V565F increased upon futibatinib treatment, whereas levels of E566A and N550K were unchanged. These results suggest that the spectrum of acquired resistance mutations varies and may influence choice of therapy. In follow-up experiments, futibatinib retained activity against FGFR2 kinase domain mutations in preclinical iCCA models. The investigators concluded that these preliminary investigations support the clinical utility of futibatinib in patients with acquired resistance to ATP-competitive reversible FGFR inhibitors.

These analyses were consistent with preclinical experiments showing superior activity of futibatinib against acquired resistance mutations. 11 , 59 However, data on mechanisms of futibatinib resistance remain limited and further research is needed to understand the role of futibatinib after progression on FGFR inhibitors.

Activity of Futibatinib in Tumor Types Other Than CCA

In addition to CCA, futibatinib activity has been observed in at least 7 other tumor types harboring 10 different categories of FGFR1-4 aberrations ( Table 2 ). Among 19 patients with urothelial cancer in the phase I expansion study, 67 3 patients had PRs (16% ORR), all with FGFR1/3 -mutant tumors. The ORR in this urothelial cohort was numerically lower than that in trials of other selective FGFR inhibitors, 46 , 71 possibly because these patients were heavily pretreated: 58% received ≥3 prior regimens, with 42% previously treated with an FGFR inhibitor. Based on these data, a phase II study ( NCT04601857 ) was initiated to study futibatinib in combination with pembrolizumab in patients with advanced or metastatic urothelial cancer. 72

Futibatinib showed activity in gastric cancer in 2 phase I studies. In the phase I expansion study, 2 of 9 patients achieved a PR (ORR 22%). 67 One responder had an FGFR2 amplification and the other had an FGFR3 fusion. In the Japanese phase I dose-expansion study, patients with gastric cancer harboring an FGFR2 amplification with a copy number ≥10 experienced an ORR of 36.4% and DCR of 54.5% vs. 0% and 10% in those with FGFR2 amplification copy number <10. 63

Responses to futibatinib were also observed in primary central nervous system (CNS), breast, and head and neck tumors ( Table 2 ). 67 In the phase I dose-escalation study, 2 patients with primary CNS tumors (glioblastoma and anaplastic oligodendroglioma) harboring FGFR1 mutations experienced PRs, 61 while in the phase I expansion study, 1 patient with glioblastoma harboring an FGFR1 fusion experienced a PR. A patient with triple-negative breast cancer with FGFR2 amplification from the phase I expansion study (16-mg cohort) and another with FGFR2 -amplified breast cancer from the phase I study in Japan experienced durable responses with futibatinib. 63 , 67 In a compassionate use program, a patient with an FGFR1 -rearranged myeloid neoplasm treated with futibatinib had complete hematologic and cytogenetic remission. 70 Notably, these phase I trials helped to identify previously uncharacterized FGFR aberrations and tumor types as potential FGFR inhibitor targets, including FGF -amplified and FGFR1 -mutated urothelial carcinoma and FGFR -fusion positive head and neck cancer.

Altogether, these data support further investigation of futibatinib in multiple FGFR -aberrant tumor types and as a disease-agnostic treatment for patients with FGFR -altered advanced solid tumors.

Futibatinib Safety and Tolerability

Safety data in the 2 largest populations of patients who received futibatinib 20 mg QD, the phase I expansion 20-mg cohort ( n = 170) 67 and the phase II iCCA study ( n = 103), 48 indicated a manageable safety profile for futibatinib consistent with that of other FGFR inhibitors. 43 , 44 , 46 , 51 , 73 Adverse events (AEs) were common in both studies (reported in >98% of patients), including hyperphosphatemia, diarrhea, constipation, fatigue, dry mouth, and alopecia ( Table 3 ). In the phase I expansion and phase II iCCA studies, any-cause grade ≥3 AEs were reported in 72% and 77% of patients, respectively; grade ≥3 treatment-related AEs (TRAEs) occurred in 43% and 57% of patients, respectively, with grade 3 hyperphosphatemia most commonly reported in ≥10% of patients (phase I expansion, 22%; phase II, 30%). One grade 4 TRAE was reported in each study (increased gamma glutamyl-transferase and increased alanine aminotransferase). Serious TRAEs were reported in 6% and 10% of patients in the phase I expansion and phase II iCCA studies, respectively; no treatment-related deaths occurred in either study.

The most common AE across studies was hyperphosphatemia ( Table 3 ) 48 , 59 , 63 , 67 similar to findings with pemigatinib and infigratinib. 49 , 51 , 74 Hyperphosphatemia is an on-target effect of FGFR inhibition because decreased FGF23–FGFR1 signaling leads to increased phosphate reabsorption and hyperphosphatemia in proximal tubules. 62 The numerically higher rates of hyperphosphatemia reported with futibatinib vs. pemigatinib and infigratinib 49 , 51 , 74 may be related to between-study differences in dosing schedules, safety assessments, and grade definitions. Hyperphosphatemia was not defined in the National Cancer Institute Common Criteria for Adverse Events version 4.03, the version used for safety assessments in these trials. In the futibatinib studies, hyperphosphatemia was graded by serum phosphate levels regardless of symptoms, 48 , 67 which was not the case for the pemigatinib trial. 49 , 51 , 74 In the 2 futibatinib studies, hyperphosphatemia was managed with phosphate binders (75%-78%), dose interruptions (17%-20%), or dose reductions (8%-20%). All grade 3-4 events of hyperphosphatemia resolved, except in 2 patients in the phase I expansion study in whom resolution could not be assessed as they discontinued the study because of disease progression and withdrawal of consent.

Eye and nail toxicities are also considered AEs of special interest for FGFR inhibitors. 48 , 49 Similar to agents targeting the MAPK pathway, FGFR inhibitors can cause central serous retinopathy (CSR)/retinal pigment epithelial dystrophy (RPED). Patients with CSR/RPED can be asymptomatic; however, more severe cases manifest with acute central vision decrease/loss and metamorphopsia. 75 In the phase I expansion study, 26% of patients had eye-related AEs, most commonly dry eye (9%), and blurred vision (6%). All but 2 cases (grade 3 cataract [treatment-related]; grade 3 macular fibrosis/grade 4 ocular ischemic syndrome [unrelated]) were grade 1-2. Seven patients experienced grade 1-2 central serous retinopathy. 67 In the phase II iCCA study, retinal disorders were reported in 8% of patients (grade 1-2 events). 48 In the phase I expansion study, 20% of patients had nail toxicities, all but one (grade 3 onychalgia) grade 1 or 2. In the phase II study, 47% of patients developed nail toxicities (including nail disorder, onycholysis, nail discoloration, and paronychia), with grade 3 cases in 2%. 48 Similar data on eye and nail-related toxicities have been reported with other FGFR inhibitors. 76 , 77

Palmar-plantar erythrodysesthesia syndrome, clinically not­able in patients treated with FGFR inhibitors, was reported in 13% (grade ≥3, 4%) and 21% (grade ≥3, 5%) of patients in the phase I expansion and phase II studies, respectively. No grade 5 AEs of special interest were reported in either study.

AEs were mostly managed with dosing interruption and reductions. In the phase I expansion study, TRAEs led to dosing modifications in 44% of patients and treatment discontinuation in 4% of patients. In the phase II study, TRAEs led to dose interruption, dose reduction, or treatment discontinuation in 50%, 54%, and 2% of patients, respectively.

An integrated analysis of futibatinib safety in 318 patients across the global phase I/II and Japanese phase I studies showed a consistent safety profile: grade ≥3 hyperphosphatemia occurred in 23% of patients, but nearly all grade ≥3 events resolved and only 3% discontinued because of TRAEs. 78

Collectively, these results indicate a monitorable and manageable safety profile for futibatinib, rarely requiring treatment discontinuation due to AEs.

Quality of Life with Futibatinib Treatment

Across therapies for iCCA, little data are available on how treatment affects patient quality of life (QoL). 79 The phase II study of futibatinib in patients with iCCA harboring FGFR2 fusions/rearrangements was among the first to report patient-reported outcomes (PROs) with an FGFR inhibitor. PROs were measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and Euro QoL Visual analog scale (EQ-VAS). 48 Ninety-two of 103 patients (89%) had PRO data with at least one follow-up assessment, with 48 patients (47%) having PRO data at cycle 13 (final cycle assessed). Through 9 months of futibatinib treatment, patient global health status was maintained, with no clinically meaningful changes in individual functional measures (physical, role, cognitive, emotional, and social). Individual symptom measures on the EORTC QLQ-C30 were also stable except for constipation, which met criteria for a clinically meaningful change at cycle 4 only. Mean EQ-VAS scores were sustained and the status across all EQ-5D-3L dimensions remained the same or improved over this period. Most patients (82%-95%) maintained the same or better Eastern Cooperative Oncology Group performance status score relative to baseline. Overall, these data suggest patient QoL was not negatively impacted by AEs while on futibatinib treatment.

Ongoing Studies and Future Directions for Development of Futibatinib

Based on phase I data, phase II studies are examining the safety and activity of futibatinib in various FGFR- aberrant cancer types including metastatic breast cancer and urothelial cancer ( Table 4 ). A tumor-agnostic phase II study will investigate futibatinib as a disease-agnostic treatment option for patients with FGFR- rearranged advanced solid tumors. Building on the phase II iCCA study results, an ongoing open-label, randomized phase III study will assess futibatinib as a first-line treatment vs. gemcitabine–cisplatin for patients with FGFR2 fusion/rearrangement-positive iCCA.

Futibatinib combination studies are another important future prospect. The combination of FGFR inhibitors with immunotherapy is supported by preclinical evidence, 80 and phase II trials are evaluating futibatinib combined with pembrolizumab in metastatic urothelial carcinoma ( NCT04601857 ) and metastatic hepatocellular carcinoma ( NCT04828486 ). In preclinical models, futibatinib combined with cytotoxic chemotherapy, MEK inhibitors, or PI3K pathway inhibitors induced synergistic tumor regression 81-83 ; trials evaluating the combination of futibatinib with AKT and MEK inhibitors are ongoing (JapicCTI-194864; NCT04965818 ). There is also rationale for the combination of FGFR ­inhibitors with VEGF inhibitors. 84 Future exploration of futibatinib combined with other treatments could yield additional clinical benefits, particularly to combat tyrosine kinase inhibitor resistance.

Summary

FGFR dysregulation drives oncogenesis across a broad range of tumor types. Although many FGFR inhibitors are currently in clinical development, futibatinib has a unique mechanism of action as an irreversible FGFR1-4 inhibitor with potential activity against acquired secondary FGFR kinase domain mutations. In early studies, futibatinib demonstrated activity in diverse tumor types harboring various FGFR aberrations. Based on durable responses and manageable safety in the phase II FOENIX-CCA2 study futibatinib was approved for patients with iCCA harboring FGFR2 fusions/rearrangements. These data, combined with the unique irreversible mechanism of action, set futibatinib apart as a leading second-generation FGFR inhibitor, while both preclinical evidence and exploratory clinical results suggest a role for futibatinib after failure of prior FGFR inhibitor treatment. Further studies are required to assess mechanisms of futibatinib resistance and combination therapy approaches using this agent.

Supplementary Material

Click here for additional data file.

Acknowledgments

Editorial and medical writing assistances were provided under the direction of authors by Meredith Kalish, MD, Vasupradha Vethantham, PhD, and Kathleen Blake, PhD, Ashfield MedComms, an Inizio company, funded by Taiho Oncology, Inc.

Conflict of Interest

Milind Javle reported consulting fees from QED, Incyte, Taiho, Merck, EMD Serono, Basilea, Oncosil, BMS, and AstraZeneca; fees for promotional services from Incyte; institutional research funding from Bayer, Koo Foundation, Sanofi, Cyclacel; and advisory/consulting relationships with Tempus Inc, Pfizer, QED, and Novartis. Gentry King reported institutional funding from Bayer, Koo Foundation, Sanofi, and Cyclacel, and advisory/consulting relationships with Tempus Inc, Pfizer, QED, and Novartis.. Kristen Spencer reported advisory board member with QED Therapeutics and Caris Life Sciences. Mitesh Borad reported stock and other ownership interests with AVEO, Gilead Sciences, Intercept Pharmaceuticals, and Spectrum Pharmaceuticals; consulting or advisory role with Agios (Inst), ArQule (Inst), Celgene (Inst), De Novo Pharmaceuticals, Exelixis, Fujifilm (Inst), G1 Therapeutics, Genentech, Halozyme (Inst), Immunovative Therapies, Imvax, Inspyr Therapeutics, Insys Therapeutics (Inst), Klus Pharma, Lynx Group, Merck, Novartis (Inst), Pieris Pharmaceuticals (Inst), Taiho Pharmaceutical (Inst), and Western Oncolytics; research funding from Adaptimmune (Inst), Agios (Inst), ARIAD (Inst), AstraZeneca (Inst), Basilea (Inst), BiolineRx (Inst), Boston Biomedical (Inst), Celgene (Inst), Dicerna (Inst), Eisai (Inst), EMD Serono (Inst), Halozyme (Inst), ImClone Systems (Inst), Incyte (Inst), Isis Pharmaceuticals (Inst), MedImmune (Inst), Merck Serono (Inst), miRNA Therapeutics (Inst), Puma Biotechnology (Inst), QED Therapeutics (Inst), RedHill Biopharma (Inst), Senhwa Biosciences (Inst), Sillajen (Inst), Sun Biopharma (Inst), Taiho Pharmaceutical (Inst), Threshold Pharmaceuticals (Inst), and Toray Industries (Inst).

Author Contributions

All authors contributed to the conception, design, data ­analysis, interpretation, manuscript writing, and final ­approval of ­manuscript.

Data Availability

No new data were generated or analyzed for this manuscript.

References

1. Touat M , Ileana E , Postel-Vinay S , André F , Soria J-C. Targeting FGFR signaling in cancer . Clin Cancer Res . 2015 ; 21 ( 12 ): 2684 - 2694 . 10.1158/1078-0432.CCR-14-2329 . 26078430

2. Arai Y , Totoki Y , Hosoda F , et al . Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma . Hepatology . 2014 ; 59 ( 4 ): 1427 - 1434 . 10.1002/hep.26890 . 24122810

3. Jain A , Borad MJ , Kelley RK , et al . Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype . JCO Precis Oncol. 2018 ; 2 : 1 - 12 . 10.1200/PO.17.00080 . 35135097

4. Ardizzone A , Scuderi SA , Giuffrida D , et al . Role of fibroblast growth factors receptors (FGFRS) in brain tumors, focus on astrocytoma and glioblastoma . Cancers (Basel) . 2020 ; 12 ( 12 ): 3825 . 10.3390/cancers12123825 . 33352931 PMC7766440

5. André F , Bachelot T , Campone M , et al . Targeting FGFR with dovitinib (tki258): preclinical and clinical data in breast cancer . Clin Cancer Res . 2013 ; 19 ( 13 ): 3693 - 3702 . 10.1158/1078-0432.ccr-13-0190 . 23658459

6. Jang JH , Shin KH , Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers . Cancer Res . 2001 ; 61 ( 9 ): 3541 - 3543 . 11325814

7. Xie L , Su X , Zhang L , et al . FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547 . Clin Cancer Res . 2013 ; 19 ( 9 ): 2572 - 2583 . 10.1158/1078-0432.CCR-12-3898 . 23493349

8. Helsten T , Elkin S , Arthur E , et al . The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing . Clin Cancer Res . 2016 ; 22 ( 1 ): 259 - 267 . 10.1158/1078-0432.CCR-14-3212 . 26373574

9. Goyal L , Saha SK , Liu LY , et al . Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma . Cancer Discov . 2017 ; 7 ( 3 ): 252 - 263 . 10.1158/2159-8290.CD-16-1000 . 28034880 PMC5433349

10. Krook MA , Reeser JW , Ernst G , et al . Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance . Br J Cancer . 2021 ; 124 ( 5 ): 880 - 892 . 10.1038/s41416-020-01157-0 . 33268819 PMC7921129

11. 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 ( 22 ): 4986 - 4997 . 10.1158/0008-5472.CAN-19-2568 . 32973082

12. Zhang X , Ibrahimi OA , Olsen SK , et al . Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family . J Biol Chem . 2006 ; 281 ( 23 ): 15694 - 15700 . 16597617 10.1074/jbc.M601252200 PMC2080618

13. Turner N , Grose R. Fibroblast growth factor signalling: from development to cancer . Nat Rev Cancer . 2010 ; 10 ( 2 ): 116 - 129 . 10.1038/nrc2780 . 20094046

14. De Moerlooze L , Spencer-Dene B , Revest JM , et al . An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis . Development . 2000 ; 127 ( 3 ): 483 - 492 . 10.1242/dev.127.3.483 . 10631169

15. Yu K , Xu J , Liu Z , et al . Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth . Development . 2003 ; 130 ( 13 ): 3063 - 3074 . 10.1242/dev.00491 . 12756187

16. Colvin JS , Bohne BA , Harding GW , McEwen DG , Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 . Nat Genet . 1996 ; 12 ( 4 ): 390 - 397 . 10.1038/ng0496-390 . 8630492

17. Pardo OE , Lesay A , Arcaro A , et al . Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells . Mol Cell Biol . 2003 ; 23 ( 21 ): 7600 - 7610 . 10.1128/MCB.23.21.7600-7610.2003 . 14560006 PMC207633

18. Pardo OE , Wellbrock C , Khanzada UK , et al . Fgf-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2 . EMBO J . 2006 ; 25 ( 13 ): 3078 - 3088 . 10.1038/sj.emboj.7601198 . 16810323 PMC1500980

19. Zhou Y , Wu C , Lu G , et al . FGF/FGFR signaling pathway involved resistance in various cancer types . J Cancer . 2020 ; 11 ( 8 ): 2000 - 2007 . 10.7150/jca.40531 . 32127928 PMC7052940

20. Simon R , Richter J , Wagner U , et al . High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer . Cancer Res . 2001 ; 61 ( 11 ): 4514 - 4519 . 11389083

21. Churi CR , Shroff R , Wang Y , et al . Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications . PLoS One . 2014 ; 9 ( 12 ): e115383 . 10.1371/journal.pone.0115383 . 25536104 PMC4275227

22. Farshidfar F , Zheng S , Gingras MC , et al ; Cancer Genome Atlas Network . Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles . Cell Rep . 2017 ; 19 ( 13 ): 2878 - 2880 . 10.1016/j.celrep.2017.06.008 . 28658632 PMC6141445

23. Courjal F , Cuny M , Simony-Lafontaine J , et al . Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups . Cancer Res . 1997 ; 57 ( 19 ): 4360 - 4367 . 9331099

24. Knowles MA , Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity . Nat Rev Cancer . 2015 ; 15 ( 1 ): 25 - 41 . 10.1038/nrc3817 . 25533674

25. Heist RS , Mino-Kenudson M , Sequist LV , et al . FGFR1 amplification in squamous cell carcinoma of the lung . J Thorac Oncol . 2012 ; 7 ( 12 ): 1775 - 1780 . 10.1097/JTO.0b013e31826aed28 . 23154548 PMC3500511

26. Schultheis AM , Bos M , Schmitz K , et al . Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer . Mod Pathol . 2014 ; 27 ( 2 ): 214 - 221 . 10.1038/modpathol.2013.141 . 23887299

27. Singh D , Chan JM , Zoppoli P , et al . Transforming fusions of FGFR and TACC genes in human glioblastoma . Science . 2012 ; 337 ( 6099 ): 1231 - 1235 . 10.1126/science.1220834 . 22837387 PMC3677224

28. Su X , Zhan P , Gavine PR , et al . FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study . Br J Cancer . 2014 ; 110 ( 4 ): 967 - 975 . 10.1038/bjc.2013.802 . 24457912 PMC3929881

29. Liu YJ , Shen D , Yin X , et al . HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma . Br J Cancer . 2014 ; 110 ( 5 ): 1169 - 1178 . 10.1038/bjc.2014.61 . 24518603 PMC3950883

30. Hur JY , Chao J , Kim K , et al . High-level FGFR2 amplification is associated with poor prognosis and lower response to chemotherapy in gastric cancers . Pathol Res Pract . 2020 ; 216 ( 4 ): 152878 . 10.1016/j.prp.2020.152878 . 32089408

31. Dutt A , Salvesen HB , Chen TH , et al . Drug-sensitive FGFR2 mutations in endometrial carcinoma . Proc Natl Acad Sci USA . 2008 ; 105 ( 25 ): 8713 - 8717 . 10.1073/pnas.0803379105 . 18552176 PMC2438391

32. Chesi M , Brents LA , Ely SA , et al . Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma . Blood . 2001 ; 97 ( 3 ): 729 - 736 . 10.1182/blood.v97.3.729 . 11157491

33. Rosty C , Aubriot MH , Cappellen D , et al . Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation . Mol Cancer . 2005 ; 4 ( 1 ): 15 . 10.1186/1476-4598-4-15 . 15869706 PMC1131920

34. Hernandez S , de Muga S , Agell L , et al . FGFR3 mutations in prostate cancer: association with low-grade tumors . Mod Pathol . 2009 ; 22 ( 6 ): 848 - 856 . 10.1038/modpathol.2009.46 . 19377444

35. von Loga K , Kohlhaussen J , Burkhardt L , et al . FGFR1 amplification is often homogeneous and strongly linked to the squamous cell carcinoma subtype in esophageal carcinoma . PLoS One . 2015 ; 10 ( 11 ): e0141867 . 10.1371/journal.pone.0141867 . 26555375 PMC4640518

36. Gött H , Uhl E. FGFR3-TACCs3 fusions and their clinical relevance in human glioblastoma . Int J Mol Sci . 2022 ; 23 ( 15 ): 8675 . 10.3390/ijms23158675 . 35955806 PMC9369421

37. Jogo T , Nakamura Y , Shitara K , et al . Circulating tumor DNA analysis detects FGFR2 amplification and concurrent genomic alterations associated with FGFR inhibitor efficacy in advanced gastric cancer . Clin Cancer Res . 2021 ; 27 ( 20 ): 5619 - 5627 . 10.1158/1078-0432.CCR-21-1414 . 34376535 PMC9401460

38. Yaeger R , Chatila WK , Lipsyc MD , et al . Clinical sequencing defines the genomic landscape of metastatic colorectal cancer . Cancer Cell . 2018 ; 33 ( 1 ): 125 - 136.e3 . 10.1016/j.ccell.2017.12.004 . 29316426 PMC5765991

39. Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology . Nat Rev Clin Oncol . 2019 ; 16 ( 2 ): 105 - 122 . 10.1038/s41571-018-0115-y . 30367139

40. Dai S , Zhou Z , Chen Z , Xu G , Chen Y. Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors . Cells . 2019 ; 8 ( 6 ): 614 . 10.3390/cells8060614 . 31216761 PMC6627960

41. Aggarwal C , Redman MW , Lara PN Jr , et al . SWOG S1400D ( NCT02965378 ), a phase II study of the fibroblast growth factor receptor inhibitor AZD4547 in previously treated patients with fibroblast growth factor pathway-activated stage iv squamous cell lung cancer (lung-map substudy) . J Thorac Oncol . 2019 ; 14 ( 10 ): 1847 - 1852 . 10.1016/j.jtho.2019.05.041 . 31195180 PMC6901020

42. Chae YK , Hong F , Vaklavas C , et al . Phase II study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: results from the NCI-MATCH trial (EAY131) subprotocol W . J Clin Oncol . 2020 ; 38 ( 21 ): 2407 - 2417 . 10.1200/JCO.19.02630 . 32463741 PMC7367548

43. Mazzaferro V , El-Rayes BF , Droz Dit Busset M , et al . Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma . Br J Cancer . 2019 ; 120 ( 2 ): 165 - 171 . 10.1038/s41416-018-0334-0 . 30420614 PMC6342954

44. Voss MH , Hierro C , Heist RS , et al . A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor debio 1347 in patients with advanced solid tumors harboring FGFR gene alterations . Clin Cancer Res . 2019 ; 25 ( 9 ): 2699 - 2707 . 10.1158/1078-0432.CCR-18-1959 . 30745300 PMC9014845

45. Park JO , Feng Y-H , Chen Y-Y , et al . Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations . J Clin Oncol . 2019 ; 37 ( 15_suppl ): 4117 - 4117 . 10.1200/jco.2019.37.15_suppl.4117 .

46. Loriot Y , Necchi A , Park SH , et al ; BLC2001 Study Group . Erdafitinib in locally advanced or metastatic urothelial carcinoma . N Engl J Med . 2019 ; 381 ( 4 ): 338 - 348 . 10.1056/NEJMoa1817323 . 31340094

47. Kim RD , Sarker D , Meyer T , et al . First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma . Cancer Discov . 2019 ; 9 ( 12 ): 1696 - 1707 . 10.1158/2159-8290.CD-19-0555 . 31575541

48. Goyal L , Meric-Bernstam F , Hollebecque A , et al . Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma . N Engl J Med . 2023 ; 388 ( 3 ) 228 - 239 . 10.1056/NEJMoa2206834 . 36652354

49. Javle M , Roychowdhury S , Kelley RK , et al . Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: Mature results from a multicentre, open-label, single-arm, phase 2 study . Lancet Gastroenterol Hepatol. 2021 ; 6 ( 10 ): 803 - 815 . 10.1016/S2468-1253(21)00196-5 . 34358484

50. Pal SK , Rosenberg JE , Hoffman-Censits JH , et al . Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations . Cancer Discov . 2018 ; 8 ( 7 ): 812 - 821 . 10.1158/2159-8290.CD-18-0229 . 29848605 PMC6716598

51. Abou-Alfa GK , Sahai V , Hollebecque A , et al . Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study . Lancet Oncol . 2020 ; 21 ( 5 ): 671 - 684 . 10.1016/S1470-2045(20)30109-1 . 32203698 PMC8461541

52. Necchi A , Pouessel D , Leibowitz-Amit R , et al . Interim results of fight-201, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with metastatic or surgically unresectable urothelial carcinoma (UC) harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations (GA) . Ann Oncol . 2018 ; 29 ( Supp. 8 ): viii319VIII319 - viii319viii320 . 10.1093/annonc/mdy283.109 .

53. Schuler M , Cho BC , Sayehli CM , et al . Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study . Lancet Oncol . 2019 ; 20 ( 10 ): 1454 - 1466 . 10.1016/S1470-2045(19)30412-7 . 31405822

54. Kalyukina M , Yosaatmadja Y , Middleditch MJ , et al . TAS-120 cancer target binding: defining reactivity and revealing the first fibroblast growth factor receptor 1 (FGFR1) irreversible structure . ChemMedChem . 2019 ; 14 ( 4 ): 494 - 500 . 10.1002/cmdc.201800719 . 30600916

55. Cleary JM , Raghavan S , Wu Q , et al . FGFR2 extracellular domain in-frame deletions are therapeutically targetable genomic alterations that function as oncogenic drivers in cholangiocarcinoma . Cancer Discov . 2021 ; 11 ( 10 ): 2488 - 2505 . 10.1158/2159-8290.CD-20-1669 . 33926920 PMC8690974

56. Krook MA , Lenyo A , Wilberding M , et al . Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma . Mol Cancer Ther . 2020 ; 19 ( 3 ): 847 - 857 . 10.1158/1535-7163.MCT-19-0631 . 31911531 PMC7359896

57. Silverman IM , Hollebecque A , Friboulet L , et al . Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib . Cancer Discov . 2021 ; 11 ( 2 ): 326 - 339 . 10.1158/2159-8290.CD-20-0766 . 33218975

58. Chen H , Ma J , Li W , et al . A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases . Mol Cell . 2007 ; 27 ( 5 ): 717 - 730 . 10.1016/j.molcel.2007.06.028 . 17803937 PMC2094128

59. Sootome H , Kato S , Aoyagi Y , et al . Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi's): a library-based approach . Cancer Res . 2021 ; 81 ( Supp 13 ): 1117 . 10.3389/fnhum.2015.00181 .

60. 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 ( 8 ): 1064 - 1079 . 10.1158/2159-8290.CD-19-0182 . 31109923 PMC6677584

61. 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 ( 10 ): 1405 - 1412 . 10.1016/j.annonc.2020.06.018 . 32622884 PMC9743148

62. Wohrle S , Bonny O , Beluch N , et al . FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone . J Bone Miner Res . 2011 ; 26 ( 10 ): 2486 - 2497 . 10.1002/jbmr.478 . 21812026

63. Doi T , Shitara K , Kojima T , et al . Phase I study of the irreversible fibroblast growth factor receptor 1-4 inhibitor futibatinib in Japanese patients with advanced solid tumors . Cancer Sci . 2023 ; 114 : 574 - 585 . 10.1111/cas.15486 . 35838190 PMC9899610

64. Yamamiya I , Hunt A , Yamashita F , et al. Phase 1, open-label studies of futibatinib excretion, metabolic profiling, and food effects in healthy adult volunteers . Poster Presented at: American Society for Clinical Pharmacology and Therapeutics conference, March 8–12 and 15-17, 2021 ; Virtual. https://metaballcreative.com/TAGS/wp-content/uploads/2021/02/Yamamiya_ASCPT2021_ADME_foodeffect_poster_2.11.21.pdf . Accessed January 12, 2023 .

65. Yamamiya I , Laabs J , Hunt A , et al . Evaluation of potential drug–drug interactions (DDIs) between futibatinib and cyp3a inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs) . Cancer Res . 2021 ; 81 ( 13_Supplement ): CT125 - CT125 . 10.1158/1538-7445.am2021-ct125 .

66. McDonnell AM , Dang CH. Basic review of the cytochrome p450 system . J Adv Pract Oncol . 2013 ; 4 ( 4 ): 263 - 268 . 10.6004/jadpro.2013.4.4.7 . 25032007 PMC4093435

67. Meric-Bernstam F , Bahleda R , Hierro C , et al . Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study . Cancer Discov . 2022 ; 12 ( 2 ): 402 - 415 . 10.1158/2159-8290.CD-21-0697 . 34551969 PMC9762334

68. Goyal L , Meric-Bernstam F , Hollebecque A , et al . Updated results of the FOENIX-CCA2 trial: Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements . J Clin Oncol . 2022 ; 40 ( 16_suppl ): 4009 - 4009 . 10.1200/jco.2022.40.16_suppl.4009 .

69. Lytgobi (futibatinib) tablets, for oral use [prescribing information] . Princeton, NJ : Taiho Oncology, Inc .; 2022 .

70. Kasbekar M , Nardi V , Dal Cin P , et al . Targeted FGFR inhibition results in a durable remission in an FGFR1-driven myeloid neoplasm with eosinophilia . Blood Adv . 2020 ; 4 ( 13 ): 3136 - 3140 . 10.1182/bloodadvances.2020002308 . 32649766 PMC7362377

71. Nogova L , Sequist LV , Perez Garcia JM , et al . Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: Results of a global phase i, dose-escalation and dose-expansion study . J Clin Oncol . 2017 ; 35 ( 2 ): 157 - 165 . 10.1200/JCO.2016.67.2048 . 27870574 PMC6865065

72. Futibatinib and pembrolizumab combination in the treatment of advanced or metastatic urothelial carcinoma. ClinicalTrial.gov identifier NCT04601857 . Bethesda, MD : U.S. National Library of Medicine , October 26 2020. https://clinicaltrials.gov/ct2/show/NCT04601857 . Accessed October 28, 2021 .

73. Javle M , Lowery M , Shroff RT , et al . Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma . J Clin Oncol . 2018 ; 36 ( 3 ): 276 - 282 . 10.1200/JCO.2017.75.5009 . 29182496 PMC6075847

74. Javle MM , Roychowdhury S , Kelley RK , et al . Final results from a phase ii study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement . J Clin Oncol . 2021 ; 39 ( 3_suppl ): 265 - 265 . 10.1200/jco.2021.39.3_suppl.265 .33503392

75. King G , Javle M. FGFR inhibitors: clinical activity and development in the treatment of cholangiocarcinoma . Curr Oncol Rep . 2021 ; 23 ( 9 ): 108 . 10.1007/s11912-021-01100-3 . 34269915

76. Kommalapati A , Tella SH , Borad M , Javle M , Mahipal A. FGFR inhibitors in oncology: insight on the management of toxicities in clinical practice . Cancers . 2021 ; 13 ( 12 ): 2968 . 10.3390/cancers13122968 . 34199304 PMC8231807

77. Lacouture ME , Sibaud V , Anadkat MJ , et al . Dermatologic adverse events associated with selective fibroblast growth factor receptor inhibitors: overview, prevention, and management guidelines . Oncologist . 2021 ; 26 ( 2 ): e316 - e326 . 10.1002/onco.13552 . 33021006 PMC7873330

78. Meric-Bernstam F , Furuse J , Oh D-Y , et al . Pooled analysis safety profile of futibatinib in patients with advanced solid tumors, including intrahepatic cholangiocarcinoma . Ann Oncol . 2021 ; 32 ( Supp 5 ): S378S376 - S378S381 . 10.1016/j.annonc.2021.08.330 .

79. Cho Y , Chadwick C , Barrett S , et al . Health-related quality-of-life in patients with cholangiocarcinoma: results of a systematic literature review . J Clin Oncol . 2019 ; 37 ( 15_suppl ): e15623 - e15623 . 10.1200/jco.2019.37.15_suppl.e15623 .

80. Palakurthi S , Kuraguchi M , Zacharek SJ , et al . The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity . Cancer Immunol Res. 2019 ; 7 ( 9 ): 1457 - 1471 . 10.1158/2326-6066.CIR-18-0595 . 31331945

81. Iwasaki J , Kuramoto T , Komori T , Saito H , Hirai H. Abstract 661: synergistic antitumor activity of futibatinib, an FGFR1-4 inhibitor, and TAS-117, a selective AKT inhibitor, in FGFR-deregulated cancer models . Cancer Res . 2020 ; 80 ( 16_Supplement ): 661 - 661 . 10.1158/1538-7445.am2020-661 .

82. Sootome H , Miura A , Komori T , Hirai H. Abstract 564: Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various FGFR-deregulated cancer cell lines and xenograft models . Cancer Res . 2020 ; 80 ( 16_Supplement ): 564 - 564 . 10.1158/1538-7445.am2020-564 .

83. Miura A , Sootome H , Komori T , Ochiiwa H , Hirai H. Abstract 659: synergistic antitumor activity of futibatinib (TAS-120), a FGFR1-4 inhibitor, and PI3K pathway inhibitors . Cancer Res . 2020 ; 80 ( 16_Supplement ): 659 - 659 . 10.1158/1538-7445.am2020-659 .31831463

84. Lieu C , Heymach J , Overman M , Tran H , Kopetz S. Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis . Clin Cancer Res . 2011 ; 17 ( 19 ): 6130 - 6139 . 10.1158/1078-0432.CCR-11-0659 . 21953501 PMC5562355