Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion.

BACKGROUND/AIM: Cholangiocarcinoma (CCA) is an aggressive tumor with limited treatment options especially in 2nd line or later treatments. Targeting fibroblast growth factor receptor (FGFR) 2 has recently emerged as a promising treatment option for patients with CCA harboring FGFR2-fusion. This study investigated the antitumor activities of tasurgratinib as an orally available FGFR1-3 inhibitor, in preclinical FGFR2-driven CCA models. MATERIALS AND METHODS: Antitumor activities of tasurgratinib were examined in vitro and in vivo using NIH/3T3 cells expressing FGFR2-fusion as FGFR2-driven CCA models, and in vivo using a CCA patient-derived xenograft model. The molecular mechanism of action of tasurgratinib was elucidated through co-crystal structure analysis with FGFR1, manual complex model analysis with FGFR2, and binding kinetics analysis with FGFR2. Furthermore, the cell-based inhibitory activities against acquired resistant FGFR2 mutations in patients with CCA treated with FGFR inhibitors were evaluated. RESULTS: Tasurgratinib showed antitumor activity in preclinical FGFR2-driven CCA models by inhibiting the FGFR signaling pathway in vitro and in vivo. Furthermore, cell-based target engagement assays indicated that tasurgratinib had potent inhibitory activities against FGFR2 mutations, such as N549H/K, which are the major acquired mutations in CCA. We also confirmed that tasurgratinib exhibited fast association and slow dissociation kinetics with FGFR2, binding to the ATP-binding site and the neighboring region, and adopting an Asp-Phe-Gly (DFG)-"in" conformation. CONCLUSION: These data demonstrate the therapeutic potential of tasurgratinib in FGFR2-driven CCA and provide molecular mechanistic insights into its unique inhibitory profile against secondary FGFR2 resistance mutations in patients with CCA treated with FGFR inhibitors.

State-of-the-art and trends in fibroblast growth factor receptor-directed therapies in gastro-intestinal malignancies.

PURPOSE OF REVIEW: This review is timely and relevant due to the increasing recognition of the significance of the fibroblast growth factor receptor (FGFR) family in cancer biology. Understanding the role of FGFRs and their dysregulation in various cancers is crucial for developing targeted therapies and improving patient outcomes. RECENT FINDINGS: The review highlights the importance of the FGFR family in cellular processes such as growth, proliferation, and survival. It discusses how abnormalities in FGFR2, including overexpression, gene amplification, and other genetic alterations, contribute to cancer progression, particularly in gastro-intestinal cancers. The paper also emphasizes the promising results of FGFR-targeted therapies, especially tyrosine kinase inhibitors, in certain cancers such as cholangiocarcinoma and oesophagogastric cancers. SUMMARY: The findings underscore the potential of FGFR-targeted therapies in treating cancers with FGFR dysregulation. However, the review also addresses the challenges associated with these therapies, including toxicities and mechanisms of resistance. Understanding these complexities is essential for optimizing the efficacy of FGFR-targeted treatments and improving patient outcomes in clinical practice and research efforts.

Discovery of LHQ490 as a highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor.

Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

The combination of gemcitabine plus an anti-FGFR inhibitor can have a synergistic antitumor effect on FGF-activating cholangiocarcinoma.

Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50 = 19.3, 22.6 mg/dl, p = 0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50 = 7.18,7.60 nM, p = 0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.

FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

A Phase I Study of KIN-3248, an Irreversible Small-molecule Pan-FGFR Inhibitor, in Patients with Advanced FGFR2/3-driven Solid Tumors.

PURPOSE: Despite efficacy of approved FGFR inhibitors, emergence of polyclonal secondary mutations in the FGFR kinase domain leads to acquired resistance. KIN-3248 is a selective, irreversible, orally bioavailable, small-molecule inhibitor of FGFR1-4 that blocks both primary oncogenic and secondary kinase domain resistance FGFR alterations. EXPERIMENTAL DESIGN: A first-in-human, phase I study of KIN-3248 was conducted in patients with advanced solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). The primary objective was determination of MTD/recommended phase II dose (RP2D). Secondary and exploratory objectives included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular response by circulating tumor DNA (ctDNA) clearance. RESULTS: Fifty-four patients received doses ranging from 5 to 50 mg orally daily across six cohorts. Intrahepatic cholangiocarcinoma (48.1%), gastric (9.3%), and urothelial (7.4%) were the most common tumors. Tumors harbored FGFR2 (68.5%) or FGFR3 (31.5%) alterations-23 (42.6%) received prior FGFR inhibitors. One dose-limiting toxicity (hypersensitivity) occurred in cohort 1 (5 mg). Treatment-related, adverse events included hyperphosphatemia, diarrhea, and stomatitis. The MTD/RP2D was not established. Exposure was dose proportional and concordant with hyperphosphatemia. Five partial responses were observed; 4 in FGFR inhibitor naïve and 1 in FGFR pretreated patients. Pretreatment ctDNA profiling confirmed FGFR2/3 alterations in 63.3% of cases and clearance at cycle 2 associated with radiographic response. CONCLUSION: The trial was terminated early for commercial considerations; therefore, RP2D was not established. Preliminary clinical data suggest that KIN-3248 is a safe, oral FGFR1-4 inhibitor with favorable pharmacokinetic parameters, though further dose escalation was required to nominate the MTD/RP2D. SIGNIFICANCE: KIN-3248 was a rationally designed, next generation selective FGFR inhibitor, that was effective in interfering with both FGFR wild-type and mutant signaling. Clinical data indicate that KIN-3248 is safe with a signal of antitumor activity. Translational science support the mechanism of action in that serum phosphate was proportional with exposure, paired biopsies suggested phospho-ERK inhibition (a downstream target of FGFR2/3), and ctDNA clearance may act as a RECIST response surrogate.

Derazantinib alone and with atezolizumab in metastatic urothelial carcinoma with activating FGFR aberrations.

BACKGROUND: This Phase 1b/2 study assessed the efficacy in terms of objective response rate (ORR) of the FGFR1/2/3 kinase inhibitor derazantinib as monotherapy or in combination with atezolizumab in patients with metastatic urothelial cancer (mUC) and FGFR1-3 genetic aberrations (FGFR1-3GA). METHODS: This multicenter, open-label study comprised 5 substudies. In Substudies 1 and 5, patients with mUC with FGFR1-3GA received derazantinib monotherapy (300 mg QD in Substudy 1, 200 mg BID in Substudy 5). In Substudy 2, patients with any solid tumor received atezolizumab 1200 mg every 3 weeks plus derazantinib 200 or 300 mg QD. In Substudy 3, patients with mUC harboring FGFR1-3GA received derazantinib 200 mg BID plus atezolizumab 1200 mg every 3 weeks. In Substudy 4, patients with FGFR inhibitor-resistant mUC harboring FGFR1-3GA received derazantinib 300 mg QD monotherapy or derazantinib 300 mg QD plus atezolizumab 1200 mg every 3 weeks. RESULTS: The ORR for Substudies 1 and 5 combined was 4/49 (8.2%, 95% confidence interval = 2.3% to 19.6%), which was based on 4 partial responses. The ORR in Substudy 4 was 1/7 (14.3%, 95% confidence interval = 0.4% to 57.9%; 1 partial response for derazantinib 300 mg monotherapy, zero for derazantinib 300 mg plus atezolizumab 1200 mg). In Substudy 2, derazantinib 300 mg plus atezolizumab 1200 mg was identified as a recommended dose for Phase 2. Only 2 patients entered Substudy 3. CONCLUSIONS: Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC. Clinicaltrials.gov NCT04045613, EudraCT 2019-000359-15.

The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations.

PURPOSE: FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 and FGFR3 alterations are most prevalent in intrahepatic cholangiocarcinoma (ICC) and bladder cancers, respectively, and multiple selective reversible and covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved in these contexts. However, resistance, often due to acquired secondary mutations in the FGFR2/3 kinase domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different mutations that most frequently affect the molecular brake and gatekeeper residues (N550 and V565 in FGFR2). EXPERIMENTAL DESIGN: Here, we characterize the activity of the next-generation covalent FGFR inhibitor, KIN-3248, in preclinical models of FGFR2 fusion+ ICC harboring a series of secondary kinase domain mutations, in vitro and in vivo. We also test select FGFR3 alleles in bladder cancer models. RESULTS: KIN-3248 exhibits potent selectivity for FGFR1-3 and retains activity against various FGFR2 kinase domain mutations, in addition to being effective against FGFR3 V555M and N540K mutations. Notably, KIN-3248 activity extends to the FGFR2 V565F gatekeeper mutation, which causes profound resistance to currently approved FGFR inhibitors. Combination treatment with EGFR or MEK inhibitors potentiates KIN-3248 efficacy in vivo, including in models harboring FGFR2 kinase domain mutations. CONCLUSIONS: Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

Inhibition of FGFR2 enhances chemosensitivity to gemcitabine in cholangiocarcinoma through the AKT/mTOR and EMT signaling pathways.

AIM: To investigate the oncogenic role of FGFR2 in carcinogenesis in cholangiocarcinoma (CCA) cells. In addition, the feasibility of using FGFR inhibitors in combination with standard chemotherapy was also explored for the chemosensitizing effect in CCA cells. MAIN METHODS: Five CCA cell lines were used to screen FGFR2 expression by Western immunoblotting. Two CCA cell lines, KKU-100 and KKU-213A, were knocked down of the FGFR2 gene using siRNA. Cell viability was assessed by the MTS cell proliferation assay. Reproductive cell death was assessed by clonogenic assay. The effects on cell migration and invasion were analyzed by the Transwell chamber method. Cell cycle analysis was performed by flow cytometry. Cell angiogenesis was assessed by HUVEC tube formation and human angiogenesis antibody array analysis. Proteins associated with proliferative and metastatic properties were evaluated by Western blotting. KEY FINDINGS: Knockdown of FGFR2 suppressed cell growth and colony formation in CCA cells in association with G2/M cell cycle arrest and downregulation of STAT3, cyclin A and cyclin B1. Silencing FGFR2 enhanced the suppressive effect of gemcitabine (Gem) on cell migration and invasion. The combination of infigratinib, an FGFR inhibitor, and Gem, interrupted cell growth, migration, and invasion via downregulation of FGFR/AKT/mTOR pathways and the EMT-associated proteins vimentin and slug. Moreover, the combination also suppressed tube formation together with decreased expression of the proangiogenic factor VEGF. SIGNIFICANCE: Inhibition of FGFRs by infigratinib enhanced the antitumor effect of Gem in CCA cells through downregulation of the FGFR/AKT/mTOR, FGFR/STAT3 and EMT signaling pathways.

FGFR blockade by pemigatinib treats naïve and castration resistant prostate cancer.

Prostate cancer (PCa) is a leading cause of cancer mortality in the male population commonly treated with androgen deprivation therapy (ADT) and relapsing as aggressive and androgen-independent castration-resistant prostate cancer (CRPC). In PCa the FGF/FGFR family of growth factors and receptors represents a relevant mediator of cancer growth, tumor-stroma interaction, and a driver of resistance and relapse to ADT. In the present work, we validate the therapeutic efficacy the FDA-approved FGFR inhibitor pemigatinib, in an integrated platform consisting of human and murine PCa cells, and the transgenic multistage TRAMP model of PCa that recapitulates both androgen-dependent and CRPC settings. Our results show for the first time that pemigatinib causes intracellular stress and cell death in PCa cells and prevents tumor growth in vivo and in the multistage model. In addition, the combination of pemigatinib with enzalutamide resulted in long-lasting tumor inhibition and prevention of CRPC relapse in TRAMP mice. These data are confirmed by the implementation of a stochastic mathematical model and in silico simulation. Pemigatinib represents a promising FDA-approved FGFR inhibitor for the treatment of PCa and CRPC alone and in combination with enzalutamide.

A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor.

Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.

Derazantinib: an investigational drug for the treatment of cholangiocarcinoma.

INTRODUCTION: This review evaluates the clinical role of fibroblast growth factor receptor 2 (FGFR2) inhibition with derazantinib in patients with intrahepatic cholangiocarcinoma (iCCA) harboring actionable oncogenic FGFR2 fusions/rearrangements, mutations and amplifications. FGFR inhibitors such as derazantinib are currently being evaluated to address the unmet medical need of patients with previously treated, locally advanced or metastatic iCCA harboring such genetic aberrations. AREAS COVERED: We summarize the pharmacokinetics, and the emerging safety and efficacy data of the investigational FGFR inhibitor derazantinib. We discuss the future directions of this novel therapeutic agent for iCCA. EXPERT OPINION: Derazantinib is a potent FGFR1‒3 kinase inhibitor which also has activity against colony stimulating factor-1‒receptor (CSF1R) and vascular endothelial growfth factor receptor‒2 (VEGFR2), suggesting a potentially differentiated role in the treatment of patients with iCCA. Derazantinib has shown clinically meaningful efficacy with durable objective responses, supporting the therapeutic potential of derazantinib in previously treated patients with iCCA harboring FGFR2 fusions/rearrangements, mutations and amplifications. The clinical safety profile of derazantinib was well manageable and compared favorably to the FGFR inhibitor class, particularly with a low incidence of drug-related hand-foot syndrome, stomatitis, retinal and nail toxicity. These findings support the need for increased molecular profiling of cholangiocarcinoma patients.

Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy.

Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates FGF signaling. Various FGFR2 alterations are detected in breast cancer, yet it remains unclear if activation of FGFR2 signaling initiates tumor formation. In an attempt to answer this question, a mouse model berrying an activation mutation of FGFR2 (FGFR2-S252W) in the mammary gland is generated. It is found that FGF/FGFR2 signaling drives the development of triple-negative breast cancer accompanied by epithelial-mesenchymal transition that is regulated by FGFR2-STAT3 signaling. It is demonstrated that FGFR2 suppresses BRCA1 via the ERK-YY1 axis and promotes tumor progression. BRCA1 knockout in the mammary gland of the FGFR2-S252W mice significantly accelerated tumorigenesis. It is also shown that FGFR2 positively regulates PD-L1 and that a combination of FGFR2 inhibition and immune checkpoint blockade kills cancer cells. These data suggest that the mouse models mimic human breast cancers and can be used to identify actionable therapeutic targets.

Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer.

PURPOSE: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. EXPERIMENTAL DESIGN: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. RESULTS: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%-4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number. CONCLUSIONS: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.

Noninvasive Detection of Polyclonal Acquired Resistance to FGFR Inhibition in Patients With Cholangiocarcinoma Harboring FGFR2 Alterations.

PURPOSE: Fibroblast growth factor receptor (FGFR) 2 alterations, present in 5%-15% of intrahepatic cholangiocarcinomas (IHC), are targets of FGFR-directed therapies. Acquired resistance is common among patients who respond. Biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. We studied circulating tumor DNA (ctDNA) as a less invasive means of potentially identifying genomic mechanisms of resistance to FGFR-targeted therapies. MATERIALS AND METHODS: Serial blood samples were collected from eight patients with FGFR-altered cholangiocarcinoma for ctDNA isolation and next-generation sequencing (NGS) throughout treatment and at resistance to anti-FGFR-targeted therapy. ctDNA was sequenced using a custom ultra-deep coverage NGS panel, incorporating dual index primers and unique molecular barcodes to enable high-sensitivity mutation detection. RESULTS: Thirty-one acquired mutations in FGFR2, 30/31 located in the kinase domain, were identified at resistance in six of eight patients with detectable ctDNA. Up to 13 independent FGFR2 mutations were detected per patient, indicative of striking genomic concordance among resistant subclones. CONCLUSION: ctDNA could be an effective means to longitudinally monitor for acquired resistance in FGFR2-altered IHC. The numerous acquired genetic alterations in FGFR2 suggest frequent polyclonal mechanisms of resistance that cannot be detected from single-site tissue biopsies.

Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.

Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound 38 (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles. Pemigatinib has received accelerated approval from the U.S. Food and Drug Administration for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. Additional clinical trials are ongoing to evaluate pemigatinib in patients with FGFR alterations.

Infigratinib: First Approval.

Infigratinib (TRUSELTIQTM), a fibroblast growth factor receptor (FGFR)-specific tyrosine kinase inhibitor, is being co-developed by QED Therapeutics and Helsinn for the treatment of cholangiocarcinoma, urothelial carcinoma and other FGFR-driven conditions. Infigratinib was recently approved in the USA for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by a test approved by the US Food and Drug Administration. This article summarizes the milestones in the development of infigratinib leading to this first approval for advanced cholangiocarcinoma.