FGFR2 (Fibroblast growth factor receptor 2)

The responsiveness of gastrointestinal stromal tumors to imatinib requires validation via molecular testing. Patients diagnosed with pancreatic cancer may see enhanced survival rates by targeted therapy addressing microsatellite instability and BRCA mutations. In bile duct malignancies, especially intrahepatic cholangiocarcinoma of the small duct variant, the analysis of IDH1 mutations and FGFR2 fusions presents new treatment prospects.

In this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis shows clinically relevant potential as a noninvasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms.

In gallbladder and biliary tract cancers, we are mainly looking for IDH1 and IDH2 mutations, FGFR2 gene fusions and mutations, HER2 amplifications or mutations, as well as mutations of BRAF or BRCA1/2. All results should be discussed within the molecular tumor board.

The patient was treated with pemigatinib (a selective FGFR inhibitor) in combination with Gemcitabine and Cisplatin at our hospital. To the best of our knowledge, this is the first reported rare case of unresectable cHCC-CCA with FGFR2-PRDM16 fusion in a child successfully treated with a combination of pemigatinib and chemotherapy as a first-line regimen. This treatment combination may be effective and safe for patients with unresectable cHCC-CCAs.

P2, N=168, Completed, Taiho Oncology, Inc. | Active, not recruiting --> Completed

These findings broaden the current spectrum of gene rearrangements in head and neck carcinomas and support the utility of clinical NGS in identifying unusual, actionable alterations in diagnostically challenging cases.

Sorafenib is a targeted therapy for unresectable canine HCC...Differentially expressed genes (DEGs) between canine HCC and normal liver were explored based on previously reported molecular-targeted agents for human tumours. PARP3, DNMT1, FGF19, FGF23, and RET DEGs were upregulated, whereas KIT, FGFR2, and FGF21 DEGs were downregulated.

We constructed an AI-assisted genetic alteration screening system which is predictable to ICC actionable targets and has potential to assist precise targeted treatment of advanced ICC.

P2, N=63, Active, not recruiting, Eisai Co., Ltd. | Trial completion date: Sep 2024 --> Mar 2026 | Trial primary completion date: Sep 2024 --> Mar 2026

Characterizing unresectable, metastatic, or recurrent GC with positive CLDN18.2 expression and evaluating intratumoral heterogeneity and prognostic implications of various therapeutics help advance treatment strategies and develop new therapies for patients with GC.

The metabolites accounting for >10% of infigratinib were BHS697 and CQM157. The PK profiles of infigratinib and its metabolites in Chinese patients with GC or GEJ were largely consistent with known PK profiles of infigratinib from global populations.

The epithelial alternatively spliced FGFR2 IIIb isoform was significantly enriched in ER+ breast cancer, while the mesenchymal FGFR2 IIIc isoform was significantly prevalent in HER2+ cancer. Increased levels of FGFR2 and IIIb splice isoforms are associated with less aggressive breast cancer phenotypes, while decreased levels of FGFR2 and increased IIIc splice isoform are associated with more aggressive phenotypes.

Overall, more than half of the UCs had potentially druggable genetic alterations. The proposed NGS panel permits comprehensive and cost-efficient analysis of UC-specific molecular targets and may be considered in clinical routine.

Additionally, by coupling the molecular analysis with an interactome investigation, we hypothesized a potential functional interplay between the Ca2+ channel Transient Receptor Potential Ankyrin 1 (TRPA1) and FGFR2c, mediated by 16E5 during the establishment of the oncogenic signaling. These findings will help to elucidate the actual relevance of 16E5 in the early progression of anal lesions and contribute to determine its potential as target for future preventive approaches for HPV16-positive SCCA.

DICER1MUT and DICER1WT tumors showed different mRNA expression profiles. The FOXL2 mutation is less common in these tumors and is mutually exclusive with the DICER1 mutation.

For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

P3, N=507, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.

This study underscores the critical role of gene fusions as biomarkers in cancer, extending beyond fusion-driven malignancies to encompass all cancer types. Gene fusions serve as both diagnostic markers and tumor-agnostic therapeutic targets within the current cancer treatment paradigm. Our insights into the prevalence of oncogenic drivers and novel targets expand the understanding of gene fusions, shedding new light on their mechanisms and clinical implications.

This review provides practical insights for advanced practice providers on the management of these common AEs associated with selective FGFR inhibitors in the real-world setting, focusing on pemigatinib and futibatinib. Impacts of renal or hepatic impairment, drug-drug interactions, and drug-food interactions are discussed. Also presented are practical recommendations for prophylaxis and supportive care measures, and resources for health-care professionals and patients.

Molecular docking was performed to investigate the possible binding modes of 18i within the binding site of FGFR2. These results suggest that compound 18i is a promising candidate for further drug discovery.

P2, N=202, Recruiting, Abbisko Therapeutics Co, Ltd | Not yet recruiting --> Recruiting

We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1.

The FGFR and IDH-1 pathways are the primary targets for therapy, with FGFR-2 and IDH-1 inhibitors, such as Pemigatinib and Ivosidenib respectively, already available on the market. This prospective study validates the prevalence of mutations documented in the literature and underscores the significance of NGS in presenting supplementary therapeutic avenues. Moreover, we demonstrated the role of other potential targets co-expressed with FGFR2 or IDH1 which could represent a crucial opportunity for novel combinations or sequences therapies.

Our results seem to confirm the negative prognostic role in terms of PFS of GA in BAP1 and CDKN2A genes in patients affected by locally advanced or metastatic FGFR2-positive CCA treated with pemigatinib in a real-world setting.

Our study provides an example of implementation of molecular profiling in an academic pre-screening program. Further analysis will investigate treatment matching rates, drug access schemes, and their impact on treatment efficacy and survival.

Among pts with EMP available, 64.2% had intrahepatic cholangiocarcinoma and 69.8% received CT1 (36.1% cisplatinum-gemcitabine). Despite a broader availability of EMP in advanced BTC in recent years, access to TT remains suboptimal even in referral Institutions. Our results demonstrate TT administration as a pivotal positive prognostic factor in a real-world setting, whilst FGFR2 or IDH1 alterations did not act as prognostic determinants per-se. Therefore, strategies aiming at improving the rate of patients receiving TT are warranted.

FGFR2 fusion should be assessed for advanced iCCA patients. We recommend DNA + RNA-based NGS as the preferred option to supply all possible therapeutic targets. FISH should be preferred if the tumor sample is insufficient for NGS or if the patient is inclined to receive FGFR inhibitors promptly. Although IHC is not the preferred method to identify FGFR2 fusion, it might be used as preliminary screening for FGFR2 alterations if the hospital cannot offer NGS or FISH, and the results need to be validated before FGFR2 inhibitors treatment.

Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now...Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC...This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC.

While delineating tumour types among the FGFR2-fused glioneuronal tumour spectrum, by histopathology or DNA-methylation profiling, remains challenging, neuroimaging data revealed two distinct patterns that could correlate to PLNTY and ganglioglioma. However, more series including extensive histo-radio-molecular data are needed to confirm this hypothesis.

Real-world evidence in our Caucasian patient population confirmed that a significant number of intrahepatic CCAs showcase MDM2 amplification, qualifying for a personalized therapy option with Brigimadlin. MDM2 amplification must therefore be considered in the context of personalized molecular testing in CCA.

Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

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.

This review explores the multifaceted genetic, epigenetic and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.

P1, N=35, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Mar 2024

AFP, the targeted, breakpoint/fusion partner agnostic panel, outperformed 3 other established panels using real-world, fusion-driven thyroid cancers by an average detection frequency of 39%. Such findings demonstrate the importance in sequencing panel selection for fusion-driven thyroid cancer detection, and the potential downstream consequences for diagnostic utility and therapeutic intervention.

Fusion detection using ctDNA CGP showed high concordance to tissue tests and high accuracy in predicting therapeutic response in NSCLC patients. The ctDNA CGP is expected to provide an important diagnostic option for fusion detection.

Fusion detection using ctDNA CGP showed high concordance with tissue tests and accuracy in predicting therapeutic responses in patients with non-small cell lung cancer. ctDNA CGP may provide an important diagnostic tool for fusion detection.

In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.

Mechanistically, RPPH1 protects IGF2BP2 from ubiquitination-induced degradation, stabilizes N6-methyladenosine (m6A)-modified FGFR2 mRNA, and activates the PI3K/AKT pathway. Our research unveils the role of RPPH1 in breast cancer metastasis and highlights its potential as a therapeutic target.

Conclusions Our highly integrated infrastructure allows us to collect and integrate unprecedented longitudinal multiomic molecular data from HR+/HER2- mBC patients. A combination of genomic, transcriptomic, and epigenetic analyses will provide a more accurate characterization of primary and acquired resistance mechanisms to CDK4/6i.