FGFR1 fusion

However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

No abstract available

P2, N=46, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> May 2024

P1/2, N=47, Terminated, Basilea Pharmaceutica | Phase classification: P1b/2 --> P1/2

FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

The Oncomine Myeloid Assay is a fast, robust, and reproducible solution for comprehensive genomic profiling of myeloid malignancies. We describe the mutational spectrum of DNA variants and RNA fusions in a range of clinical research samples. (For research use only.

Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.

Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

Moreover, compound (S)-23 exhibited favorable pharmacokinetic properties, low potential for drug-drug interactions, and very potent antitumor activity in MFE-296 xenograft mouse models with a TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that compound (S)-23 is a potential therapeutic agent for FGFR mutant tumors.

P2, N=109, Active, not recruiting, The Hospital for Sick Children | Recruiting --> Active, not recruiting

P2, N=20, Active, not recruiting, Washington University School of Medicine | Trial completion date: Dec 2023 --> Dec 2024

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

The study provided insights into MAPK-altered gliomas in Kuwait highlighting the differences among paediatric and adult patients and providing a framework for planning therapeutic polices.

P2, N=46, Active, not recruiting, National Cancer Center, Japan | Recruiting --> Active, not recruiting

No abstract available

Tasurgratinib (E7090) is an orally available selective inhibitor of FGFR 1–3; the recommended dose is 140 mg per day per the dose-escalation part of a first-in-human phase 1 study...FGFR2 gene fusion was confirmed by fluorescence in situ hybridization performed in central laboratories; ≥ 1 prior chemotherapy regimen including a gemcitabine-based combination was required; pts treated with FGFR2 inhibitors were excluded... Tasurgratinib had promising antitumor activity in pts with CCA harboring FGFR2 gene fusion and who received ≥ 1 prior chemotherapy regimen. The primary endpoint (ORR) met the study’s predefined success criteria. Tasurgratinib had a manageable safety profile consistent with previous reports and with the known pharmacological profile of FGFR inhibitors.

FGFR kinase inhibitorshave the potential to be an effective targeted therapy in pancreas cancer. Additionally, telemedicine is a novel tool that can aid in the study of ultra-rare cancers and reduce barriers to patient participation in clinical trials.

"Our study shows population-based frequencies of novel ALL subtypes, including both recurrent and novel genetic aberrations. This data widens our knowledge on the interplay between molecular aberrations and clinical course of the disease and provides clues for diagnostics optimization."

"Not for use in diagnostic procedures. )"

Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

The overall survival in FGFR1- and BRAF V600E-mutant DMGs was not statistically improved when compared with those that were wildtype. However, the possibility of targeted therapy argues for comprehensive sequencing of H3K27-altered gliomas.

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.

We present the second detailed case of an intraventricular presentation in the MC EVN. Our findings broaden the spectrum of MC EVN and have implications in terms of diagnosis, therapy and terminology.

Here, we report a very unusual case of myeloid/lymphoid neoplasm with ETV6::FLT3 fusion with a nodal presentation without associated eosinophilia. Our case draws attention to diagnostic pitfalls in these rare entities.

We emphasise that caution should be taken when novel fusions are found and that the appearance of new gene fusions should always be interpreted in the molecular context of the respective disease.

Patients with symptomatic residual tumors (N=6, 46%) were treated with targeted therapies (Erdafitinib=3, Trametinib=1, Ponatinib / Everolimus=1, Dasatinib=1) and two patients received Radiation therapy. In summary, cortical tumors bearing FGFR alterations present with refractory seizures and are eminently treatable with surgical resection. Targeted therapy with FGFR specific inhibitors is tolerated well and updated response assessment of our patients will be presented in the meeting.

In HGG (glioblastoma, n=25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n=24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). No treatment-related deaths occurred.ConclusionsErda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.

In basket trials, new treatments are tested on various types of cancer, regardless of their location in the body; instead, researchers focus on specific abnormalities in the cancer cells. Basket trials offer hope that we can find personalized treatments that are more effective for each individual battling cancer.

Three HER2-negative patients were prescribed anti-HER2 therapy for ERBB2 amplification, one patient was prescribed entrectinib for NTRK fusion, and three patients participated in clinical trial for ERBB2 mutation and FGFR1 rearrangement. If ESCAT ranking beyond I/II and recommended therapy from FoundationOne report (e.g Abemaciclib for CCND1 amplification, Everolimus for PTEN loss)are added, 64 pts (60.1%) were considered these treatments, and 19 pts (18.1%) actually received these treatment...Low accessibility of ESCAT ranking I/II MT may be because, in Japan, CGP testing is available only for patients who have completed or are expected to complete standard therapy. Early use of CGP testing and an increase in clinical trials will be desirable in Japan.

Several new FGFR1 fusion partner genes, including C14orf93, CCDC6, and ETV6 were identified with NGS and PCR profiling. Pemigatinib treatment resulted in marked decreases in the percentages of cells with the FGFR1 rearrangement on FISH, as well as 2–3 log reductions in FGFR1 fusion transcripts in patients with MLNFGFR1. Further investigations are ongoing to determine the relationship between pemigatinib dose intensity and the depth and durability of molecular response.

A robust low-noise RNA fusion detection assay coupled us DNA alterations on myeloid disorders in a single assay enables to fully molecularly characterize acute myeloid leukemias and other myeloid disorders. Frequencies of well-known fusions in a small community-based cohort were similar to studies performed in academic settings with subsets of gene alterations being mutually exclusive from fusions. Larger studies are needed to confirm those associations.

We demonstrated that OPA on the automated GeneXus sequencer can profile well-established biomarkers in NSCLC research samples with minimal sample input and rapid turnaround time. These improvements were developed to test the feasibility of implementing a fast and automated workflow with minimal hands-on time to help achieve the goals of precision medicine research for NSCLC. The development of a single assay capable of supporting tissue and liquid biopsy profiling will advance research into precision medicine for NSCLC.

P2, N=55, Active, not recruiting, TransThera Sciences (Nanjing), Inc. | Recruiting --> Active, not recruiting | N=80 --> 55 | Trial completion date: Sep 2023 --> May 2024 | Trial primary completion date: Sep 2023 --> May 2024

We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced anaplastic lymphoma kinase (ALK) fusion-positive DTP cell's survival...The combination of FGFR and targeted TKIs enhanced cell growth inhibition and apoptosis induction in basal FGFR1- and FGF2-high protein expressing cells with ALK-rearranged and epidermal growth factor receptor (EGFR)-mutated NSCLC, human epidermal growth factor receptor 2 (HER2)-amplified breast cancer, or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma by preventing compensatory extracellular signal-regulated kinase (ERK) reactivation. These results suggest that a targeted TKI-induced DTP state results from an oncogenic switch from activated oncogenic driver signaling to the FGFR1 pathway in basal FGFR1- and FGF2-high expressing cancers and initial dual blockade of FGFR and driver oncogenes based on FGFR1 and FGF2 expression levels at baseline is a potent treatment strategy to prevent acquired drug resistance to targeted TKIs through DTP cells regardless of types of driver oncogenes.

Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. Implications: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.

The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN.

P2, N=20, Active, not recruiting, Washington University School of Medicine | Trial completion date: Jun 2023 --> Dec 2023

We here present one of the largest European cohorts of FGFR fusions in NSCLC, predominantly occurring in sqNSCLC. The majority of pts are elderly males and former or current smokers. TP53 mutations are the most common co-occurring alterations.

All patients received radiotherapy and temozolomide as first-line therapy...TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts)... Our results confirm the activity of dabrafenib/trametinib in BRAFV600E mutant glioblastoma pts and might suggest deeper explorations in targeting ROS1 and FGFR. Further correlation among patients' outcome, molecular characteristics and TT timing are still under investigation.