FGFR1 rearrangement

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.

P2, N=47, Completed, Incyte Corporation | Active, not recruiting --> Completed

P2, N=47, Active, not recruiting, Incyte Corporation | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jul 2024 --> Oct 2024

P2, N=115, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

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.

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

Therefore, he underwent allogenic stem cell transplantation with a fully matched donor. A brief review of the occurrence of T-LBL in conjunction with M/Ls-Eo neoplasm was made with a special focus on molecular aspects.

No abstract available

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.

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.

Ours is the only reported case of FGFR1-rearranged neoplasms with a disease sequence of acute myeloid leukemia transforming to B-cell acute lymphoblastic leukemia and 1 of only 3 reported cases with cytogenetically cryptic FGFR1 rearrangement. Fluorescence in situ hybridization testing for FGFR1 rearrangement should be a standard investigation in leukemia of mixed or switching lineage.

No abstract available

No abstract available

These results contribute to clarifying the biological effects and molecular mechanisms mediated by the anti-FGFR TKI pemigatinib in distinct tumor settings and support its exploitation for combined therapies.

No abstract available

NGS Archer FusionPlex (RNA) confirmed the LRRFIP1::FGFR1 rearrangement. This is the second reported case of AML with LRRFIP1::FGFR1 rearrangement and the first with a complex karyotype.

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.

P2, N=47, Active, not recruiting, Incyte Corporation | Trial completion date: Jun 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jul 2024

P2, N=115, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Oct 2023 --> Jun 2024 | Trial primary completion date: Apr 2023 --> Mar 2024

Palliative drugs commonly used are AML-like chemotherapy, hypomethylating agents, hydroxyurea (HU), or PEG– IFN–α, ruxolotinib and trametinib. Atypical Chronic Myeloid Leukemia, BCR::ABL1 negative (aCML) is a rare hematological entity, with a dismal prognosis. Molecular landscape is heterogenous. Further comprensive molecular profiling may allow to find new targeted treatments in the next future.

Long term efficacy and tolerability are not yet known, and allogeneic hematopoietic stem cell transplant (alloHSCT) has been and continues to be the treatment with the highest chance of long term disease free survival in responding patients. Combinations of pemigatinib and chemotherapy, particularly for more aggressive phenotypes, warrant future investigation as does the use of pemigatinib maintenance following alloHSCT.

P2, N=82, Completed, Stemline Therapeutics, Inc. | Active, not recruiting --> Completed | N=130 --> 82 | Trial completion date: Dec 2023 --> Mar 2023 | Trial primary completion date: Dec 2023 --> Mar 2023

In addition to cholangiocarcinoma, pemigatinib showed clinical activity in gliomas, gynecologic tumors, and pancreatic cancer and safety was consistent with prior reports. We observed responses in patients with previously unreported FGFR alterations, suggesting that a broader population of patients may benefit from FGFR inhibitors. Further correlative work to predict response to therapy is needed to better identify these patients.Table.

Myeloid/lymphoid neoplasms with eosinophilia and genetic rearrangements constitute a group of deeply heterogeneous diseases with variable clinical and diagnostic characteristics and whose treatment is not clearly defined.

P2, N=130, Active, not recruiting, Stemline Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

This retrospective chart review demonstrated that, although MLNFGFR1 is rare, pts with this malignancy will present in US community practice settings. As effective targeted therapies become available, this diagnosis should be considered in pts with congruent presentations and 8p11 translocations on conventional cytogenetics and/or evidence of FGFR1 rearrangement on other molecular testing.

Pemigatinib resulted in durable clinical and cytogenetic responses in previously treated and treatment-naive pts with CP disease. Complete clinical responses and CCyRs were also seen in BP pts, but at lower rates/durability than in CP pts. Pemigatinib facilitated bridging to HSCT in both CP and BP pts.

P2, N=115, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2022 --> Oct 2023 | Trial primary completion date: Jun 2022 --> Apr 2023

P2, N=189, Recruiting, Incyte Corporation | Trial completion date: May 2025 --> Jan 2026 | Trial primary completion date: May 2025 --> Jan 2026

P2, N=20, Recruiting, The First Affiliated Hospital of Soochow University

As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization.

P2, N=189, Recruiting, Incyte Corporation | Not yet recruiting --> Recruiting

P2, N=189, Ongoing, Incyte Corporation

Two of them achieved complete remission with ponatinib or pemigatinib and were alive at 34.5 and 37 months from relapse, respectively. These data highlight the significant curative potential of allo-HCT in this aggressive disease. Maintenance with tyrosine kinase inhibitors may be a promising approach, at least in cases with detectable residual disease after transplant.

P2, N=189, Not yet recruiting, Incyte Corporation

No abstract available

The HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.