FGFR2 rearrangement

He underwent an uncomplicated LDLT (including an uncomplicated donor surgery) and at one year follow-up is without evidence of disease recurrence. We believe this is the first report of LDLT for this indication.

Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Custom FGFR synthetic reference standards representing both single nucleotide variants (SNVs) and gene rearrangements were utilized at a range of variant frequencies and revealed a detection limit of 0.5% with sensitivities of 97.2% and 92.9% for SNVs and rearrangements, respectively. Furthermore, FGFR-Dx detected rearrangements and identified the intronic breakpoints from cfDNA collected from 13 of 15 patients with known FGFR fusions.

Our study further revealed the clinicopathological and genetic features of FGFR-altered iCCA and demonstrated that its occurrence may show regional or ethnic variability and is less common in the Chinese population. A significant number of LD-type iCCA cases also have FGFR alterations rather than the SD type.

The addition of durvalumab to a gemcitabine plus cisplatin regimen has significantly improved overall survival in the phase 3 TOPAZ-1 trial and is currently recommended as a standard first-line treatment. The phase 3 ABC-06 and phase 2b NIFTY trials have shown the benefit of second-line fluoropyrimidine plus oxaliplatin, and fluoropyrimidine plus nanoliposomal irinotecan, respectively...However, most patients eventually show resistance to the treatment, and tumor progression occurs within a year. Indeed, there should be further efforts to improve the outcomes of patients with advanced IHCCA.

P1/2, N=407, Completed, Taiho Oncology, Inc. | Active, not recruiting --> Completed

These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

P2, N=83, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=164 --> 83 | Trial completion date: Jan 2026 --> Nov 2024 | Trial primary completion date: Jan 2026 --> Nov 2024

P3, N=216, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

In contrast to some prior literature, this study reports detection of a wide variety of rearrangements in ctDNA. The prevalence of driver rearrangements in tissue and LBx was comparable when TF ≥1%. LBx presents a viable alternative when TBx is not available, and there may be less value in confirmatory testing when TF is sufficient.

The diverse population in this RWS is reflective of the heterogeneous CCA pt population in the US. These real-world overall response rates support the clinical benefit of pemi across racial and ethnic groups and complement the results of the clinical trial. >BL, baseline (date of 1st pemi prescription); CI, confidence interval; FGFR2, fibroblast growth factor receptor 2; P25-P75, 25-75th percentile; rwORR, real-world overall response rate; y, years.

FHNC include a morphological spectrum of carcinomas with squamous features and may occur in different HN locations, such as parotid gland and the sinonasal tract. Sinonasal cases can harbour FGFR2 rearrangement with or without associated high-risk HPV. Timely recognition of FHNC could help select patients potentially amenable to targeted therapy with FGFR inhibitors. Further studies are needed (1) to determine if FGFR2 rearranged/HPV-positive sinonasal carcinomas are biologically distinct from HMSC, and (2) to elucidate the biological and clinical significance of FGFR2 rearrangement in the context of high-risk HPV.

P3, N=216, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Sep 2023 --> Dec 2023 | Trial primary completion date: Sep 2023 --> Dec 2023

OBJECTIVES: To evaluate the cost-effectiveness of pemigatinib compared to oxaliplatin-L-folinic-acid and fluorouracil plus active symptom control (mFOLFOX+ASC) and ASC alone for the treatment of patients with advanced or metastatic cholangiocarcinoma (CCA) with a fibroblast growth factor receptor 2 (FGFR2) rearrangement or fusion who have progressed on at least one line of prior systemic therapy in Greece. Pemigatinib, a therapy covering the unmet medical need of patients with previously treated locally advanced or metastatic CCA with an FGFR2 fusion or rearrangement, was estimated to be cost-effective compared with mFOLFOX+ASC and ASC alone in Greece.

BTC mutation prevalence in TOPAZ-1 by primary tumour location and geographical region was consistent with other studies. Although pt numbers were low and the confidence intervals were broad, pts with clinically actionable alterations ( IDH1 , BRAF and BRCA1/2 mutations and FGFR2 rearrangements) appeared to benefit from D+GC. Previously presented at ESMO Asia Congress, FPN 680, Juan Valle et al.

FISH achieved satisfactory concordance with NGS, has potential value for FGFR2 screening for targeted therapies. FGFR2 detection should be prioritized for unique clinical subgroups in ICC, which features a histological small duct subtype, early clinical stage, and reduced mucus production.

These data indicate the primary metabolic pathways of futibatinib are O-desmethylation and glutathione conjugation, with cytochrome P450 enzyme-mediated desmethylation as the main oxidation pathway. C-futibatinib was well tolerated in this Phase 1 study.

Conclusions MBC patients with one or more DNA gene rearrangements and structural atypia had a significantly better prognosis. Further investigations of the prognostic and biological significance of these alterations in MBC patients are warranted.

These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches.

P1, N=169, Recruiting, Abbisko Therapeutics Co, Ltd | Not yet recruiting --> Recruiting | Initiation date: Dec 2022 --> Jun 2023

P2, N=120, Recruiting, Taiho Oncology, Inc. | Not yet recruiting --> Recruiting

On the other hand, the positive prognostic role of IDH1/2 mutation seems much more uncertain. In this scenario, better designed clinical trials in these subsets of iCCA patients are needed in order to get definitive conclusions on this issue.

Although family history seems not relevant in developing BTC in unselected population, in our experience a family and/or personal history of cancer was reported in a not negligible percentage of cases of EOBTC while the other known risk factor were less represented. This information, together with those given by an extensive molecular assessment, could help in identifying not only druggable but even genetic alterations involved in hereditary syndromes, and in selecting patients to address to a genetic counselling.

Furthermore, positive FGFR2 rearrangement occurred only in small duct type ICC and IDH1/2 was mutated mainly in small duct type ICC. The subclassification system was applicable and the ICC subtypes had distinct clinicopathological characteristics, prognostic outcome, and IDH1/2 mutation pattern.

P3, N=216, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Mar 2023 --> Sep 2023

Patients progressed to erdafitinib (n = 14), futibatinib (n = 4) or pemigatinib (n = 3)...In patient-derived models, erdafitinib combined with pictilisib was synergic in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination overcame bypass resistance mediated by EGFR activation.Conclusions We detected a high frequency of FGFR kinase domain mutations at progression to selective FGFR inhibitors in urothelial cancer. Unlike FGFR2-driven cholangiocarcinoma, polyclonality of FGFR3 kinase domain mutations does not seem to be a hallmark of FGFR-driven urothelial cancer. The identification of off-target events and the preclinical validation sustain the potential clinical applicability of combinatorial treatment strategies.

P2, N=120, Not yet recruiting, Taiho Oncology, Inc.

P3, N=216, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Apr 2028 --> Mar 2023 | Trial primary completion date: Apr 2027 --> Mar 2023

In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Gemcitabine/Cisplatin was given to 3 of 6 patients as first-line (1L) therapy, with median progression free survival of 4 months. MSI-H represents a small subset of patients with iCCA. High-TMB noted amongst MSI-H iCCA. Currently, MSI testing is not universally performed and may be necessary to identify and best treat these patients.

P1, N=169, Not yet recruiting, Abbisko Therapeutics Co, Ltd

This article reviews FGFR and its dysregulation in oncogenesis, FGFR inhibitors, especially pemigatinib, utilized in treatment of CCA, common adverse events associated with FGFR inhibitors, and future directions in the field of targeted drug development for CCA. FGFR inhibitors, including pemigatinib, have shown promise in the management of CCA with FGFR2 fusion or rearrangement; however, acquired resistance remains a major barrier in the field of FGFR inhibitors and requires further study.

P3, N=434, Recruiting, Incyte Corporation | Trial completion date: Feb 2028 --> Jul 2028 | Trial primary completion date: Mar 2027 --> Oct 2027

P2, N=34, Active, not recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Trial completion date: Jun 2022 --> Dec 2023 | Trial primary completion date: Jan 2021 --> Jun 2022

We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell-lines, and patient derived organoid and xenograft models.

The encouraging antitumor activity and favorable safety profile support the use of pemigatinib as a treatment in previously treated Chinese patients with cholangiocarcinoma and FGFR2 rearrangements.