By: Jennifer Galvet, PharmD Candidate c/o 2024
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell surface of both developmental and adult cells. Aberrant expression of FGFRs has been implicated in a wide variety of cancers and is considered an oncogenic signaling pathway.1 FGFRs are activated by the binding of fibroblast growth factors (FGFs) and subsequent receptor dimerization-induced intracellular kinase transautophosphorylation events.2 When normally regulated, the FGF and FGFR signaling pathway is involved in embryogenesis, angiogenesis, tissue homeostasis, wound repair, and the cell cycle. Aberrant activation of FGFRs can lead to the development of malignant tumors, primarily caused by gene amplification, mutation, and gene fusion.2
Myeloid and lymphoid neoplasms (MLNs) associated with the rearrangement of FGFR1 are hematologically and genetically heterogenous.3 MLNs with FGFR1 rearrangement are caused by chromosomal translocations on the FGFR1 gene, ultimately impacting cell differentiation, proliferation, and survival.4 FGFR1 gene rearrangements result in the production of multiple chimeric proteins that can self-dimerize to activate the FGFR1 tyrosine kinase and downstream signaling pathways, contributing to the pathogenesis of these neoplasms.3 MLNs with FGFR1 rearrangement may present with chronic or blast phase involvement of bone marrow with or without blast phase extramedullary disease (EMD).5 Current therapies, such as hydroxyurea, multikinase inhibitors, or multi-agent chemotherapy, often lead to partial or complete responses for short durations.5 Incyte, a global biopharmaceutical company, developed Pemazyre® (pemigatinib) as a potential new treatment for MLNs with FGFR1 rearrangement.
Pemigatinib is a small-molecule kinase inhibitor that targets FGFR1-3. Inhibition of the phosphorylation and signaling activity of these receptors results in decreased cell viability in cancer cell lines with activating FGFR amplifications or fusions while also preventing constitutive activation of FGFR signaling.6 In August 2022, the Food and Drug Administration (FDA) approved pemigatinib, the first and only targeted treatment for adults with relapsed or refractory MLNs with FGFR1 rearrangement.6 This marks the second indication for pemigatinib, which first received accelerated FDA approval in 2020 for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement.7
Overview of the FIGHT-203 Trial
FIGHT-203 is an on-going phase 2, open-label, single-arm, multicenter trial conducted throughout the United States, Canada, and Europe.8,9 The data from this trial was used by the FDA to support their approval of pemigatinib. FIGHT-203 aimed to evaluate the safety and efficacy of pemigatinib in patients with relapsed or refractory MLNs and FGFR1 rearrangement.8,9 Eligible patients had a documented lymphoid or myeloid neoplasm with 8p11 rearrangement known to cause FGFR1 activation. Included patients had to also either have relapsed after allogenic hematopoietic stem cell transplantation (allo-HSCT), relapsed after other disease modifying therapy, or not be current candidates for allo-HSCT or other disease modifying therapies.8,9 Exclusion criteria included any prior receipt of a selective FGFR inhibitor, a history of ectopic mineralization/calcification, any current corneal disorder/keratopathy, and use of any cytochrome P450 3A4 inhibitors or inducers within 14 days of the study.8,9
41 patients were enrolled in FIGHT-203. The mean age was 58.3 years (range: 23-78) with 53.7% of patients being female. All participants received 13.5 mg of pemigatinib daily on a continuous schedule.8,9 The longest duration of pemigatinib administration was 192.4 weeks with a median dosing duration of 29.3 weeks.5 The primary endpoint measured the proportion of patients who achieve a complete response (CR) based on response criteria for myeloid/lymphoid neoplasms with FGFR1 rearrangement.8,9 Secondary endpoints included the proportion of subjects who achieved a complete cytogenetic response (CCyR) and safety and tolerability assessment.8,9 Complete and partial cytogenic responses were defined as 100% or at least 50% reduction in 8p11-rearranged metaphases or cells, respectively, on karyotyping or fluorescence in situ hybridization.5,8
40 patients were analyzed for efficacy results, 35 of which had previous therapies and 5 were treatment naïve. The average number of previous therapies was 1.0 (range: 1-11).8 Efficacy analysis on the primary outcome involved a total of 38 patients, including both those that were previously treated and treatment naïve. 28 patients (73.7%) were able to achieve a CR. In patients with chronic phase disease only (n=21), 19 (90.5%) were able to achieve a CR. In patients with blast phase disease with or without EMD (n=17), 9 (52.9%) were able to achieve a CR.8 A separate efficacy analysis on the primary outcome was also done on the 33 patients who received previous therapies. In this group, 25 (75.8%) were able to achieve a CR. In patients with chronic phase disease only (n=19), 17 (89.5%) were able to achieve a CR. In patients with blast phase disease with or without EMD (n=14), 8 (57.1%) were able to achieve a CR.8
The efficacy analysis on the secondary outcome regarding the proportion of patients achieving CCyR involved 40 patients, including both those that were previously treated and treatment naïve. 28 patients (70.0%) were able to achieve a CCyR. In patients with chronic phase disease only (n=21), 18 (85.7%) were able to achieve a CCyR. In patients with blast phase disease with or without EMD (n=17), 8 (47.1%) were able to achieve a CCyR.8 A separate efficacy analysis was also done on this secondary outcome for the 35 patients who received previous therapies. In this group, 25 (71.4%) were able to achieve a CCyR. In patients with chronic phase disease only (n=19), 16 (84.2%) were able to achieve a CCyR. In patients with blast phase disease with or without EMD (n=14), 7 (50.0%) were able to achieve a CCyR.8
Regarding the safety analysis (n=41), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (73%), alopecia (56%), diarrhea (56%), stomatitis (46%), dry eye (34%), and dry mouth (34%). Grade ≥3 TEAEs were stomatitis (17%) and anemia (15%).8 By the end of the efficacy analysis of the 40 evaluable patients, only 19 (47.5%) were still undergoing treatment. Reasons for treatment discontinuation included: bridging to allo-HSCT (20%), progressive disease (15.0%), adverse events (7.5%), physician decision (5.0%), patient decision (2.5%), and death (2.5%).8
Current NCCN Guidelines for MLNs with Eosinophilia and Tyrosine Kinase Fusion Genes
In October 2022, the National Comprehensive Cancer Network (NCCN) published updated guidelines for the treatment of MLNs.10 Therapy considerations were based on whether the bone marrow/peripheral blood and/or EMD components were present, as well as whether the disease was in the chronic phase or blast phase. For chronic phase disease, preferred regimens include enrollment into a clinical trial or pemigatinib. Other recommended regimens include the use of tyrosine kinase inhibitors (TKI) with activity against FGFR1, such as midostaurin or ponatinib. For blast phase disease, preferred regimens include enrollment into a clinical trial or pemigatinib. Early referral to an allo-HSCT should also be considered if the patient is eligible. In blast phase disease with myeloid lineage, a TKI with activity against FGFR1 +/- acute myeloid leukemia induction chemotherapy is recommended, followed by allo-HSCT if eligible.10 In blast phase disease with lymphoid lineage, a TKI with activity against FGFR1 +/- acute lymphocytic leukemia induction chemotherapy is recommended, followed by allo-HSCT if eligible.10
The Future for Patients with MLNs with FGFR1 Rearrangement
Patients with relapsed or refractory MLNs with FGFR1 rearrangement being treated with pemigatinib in the FIGHT-203 study were able to achieve high rates of CR and CCyR in chronic phase disease. The high rates of CCyR in patients with blast phase disease is clinically meaningful, considering the poor response from existing treatments such as hydroxyurea, multikinase inhibitors, and intensive multi-agent chemotherapy. Pemigatinib may be the first step in researching additional pathways to address treatments for rare blood cancers.
- Dai S, Zhou Z, Chen Z, Xu G, Chen Y. Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors. Cells. 2019;8(6):614. doi: 10.3390/cells8060614.
- Yue S, Li Y, Chen X, et al. FGFR-TKI resistance in cancer: current status and perspectives. J Hematol Oncol. 2021;14(1):23. doi: 10.1186/s13045-021-01040-2.
- Liu Y, Mi X, Gadde R, et al. FGFR1 rearrangement guides diagnosis and treatment of a trilineage B, T, and myeloid mixed phenotype acute leukemia. JCO Precis Oncol. 2020;4:PO.19.00402. doi: 10.1200/PO.19.00402
- Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood. 2017;129(6):704-714. doi: 10.1182/blood-2016-10-695973
- Gotlib J, Kiladjian J, Vannucchi A, et al. A phase 2 study of pemigatinib (FIGHT-203; INCB054828) in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLNFGFR1). Blood. 2021;138(Supplement 1):385. doi: 10.1182/blood-2021-148103
- Pemazyre (pemigatinib) [package insert]. Wilmington, DE; Incyte Corporation; Revised 08/01/2022.
- FDA approves first targeted treatment for patients with cholangiocarcinoma, a cancer of bile ducts. US Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-cholangiocarcinoma-cancer-bile-ducts. Published 04/17/2020.
- Verstovsek S, Gotlib J, Vannucchi A, et al. FIGHT-203, an ongoing phase 2 study of pemigatinib in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLNFGFR1): A focus on centrally reviewed clinical and cytogenetic responses in previously treated patients. Blood. 2022;140(Supplement 1):3980-3982. doi: 10.1182/blood-2022-163099
- A study to evaluate the efficacy and safety of pemigatinib (INCB054828) in subjects with myeloid/lymphoid neoplasms with FGFR1 rearrangement – (FIGHT-203). National Institutes of Health US National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT03011372. Published 01/05/2017. Last Updated 06/28/2022.
- Gerds A, Gotlib J, Abdelmessieh P, et al. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes. National Comprehensive Cancer Network Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/mlne.pdf. Published 10/18/20