FIGHT-203, an Ongoing Phase 2 Study of Pemigatinib in Patients With Myeloid/Lymphoid Neoplasms (MLNs) With Fibroblast Growth Factor Receptor 1 (FGFR1) Rearrangement (MLN^FGFR1): A Focus on Centrally Reviewed Clinical and Cytogenetic Responses in Previously Treated Patients

Background: MLN^FGFR1 is a rare, aggressive hematologic malignancy. Patients (pts) may present with chronic-phase (CP) myeloid disease or blast-phase (BP) disease (myeloid, lymphoid, or mixed lineage) in the bone marrow (BM), and/or BP disease in extramedullary (EMD) sites. Diagnosis requires an 8p11 translocation resulting in FGFR1 rearrangement. Existing first-line therapies fail to induce durable clinical and cytogenetic responses in CP or deep cytogenetic responses in BP disease, leading to an unmet medical need for second-line therapies.

Pemigatinib (INCB054828) is a selective inhibitor of FGFR 1-3 approved for the treatment of adults with previously treated, advanced, or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. Efficacy and safety data for 34 pts in the ongoing FIGHT-203 study of pemigatinib in adults with MLN^FGFR1 (NCT03011372) were previously reported (Gotlib J, et al. Blood. 2021;138:385). This is an updated analysis of data from 41 pts with a focus on centrally reviewed clinical and cytogenetic responses in previously treated pts.

Methods: FIGHT-203 is a phase 2, multicenter trial enrolling pts ≥18 y of age with MLN^FGFR1. Initially, pts had to have received ≥1 prior therapy; the starting dose was pemigatinib 13.5 mg daily (2 wks on; 1 wk off). With amendments, pts without prior therapy were eligible and the starting dose was changed to 13.5 mg daily on a continuous schedule. The endpoints examined in this analysis include rates of complete response (CR), and complete cytogenetic response (CCyR) by karyotyping or fluorescence in situ hybridization (FISH). CCyR was defined as 100% reduction in 8p11 rearranged metaphases or cells, on karyotyping or FISH. A Central Review Committee (CRC) used response criteria consisting of modified MDS/MPN response criteria for CP disease in the BM, response criteria for acute leukemia, and modified Lugano criteria for EMD. Responses adjudicated by the CRC were based on local laboratory and radiologic results and central histopathology reviews; local cytogenetic and both local and central FISH results were also evaluated. Priority was given to central FISH results.

Results: As of Jun 30, 2021, 41 pts were enrolled (safety population: mean age, 58.3 [range, 23-78] y; female, 53.7%); the median relative dose intensity was 83.8% (range, 37.7-120.8). One pt did not have a FGFR1 rearrangement and was excluded from efficacy analysis. Among 40 pts with MLN^FGFR1, the most common FGFR1 fusion partner gene was ZMYM2 (13q12) (n=17, 42.5%) (Table 1).

Of the 40 pts analyzed for efficacy, 35 were previously treated and 5 were treatment-naive. For the previously treated pts, the median number of prior therapies was 1.0 (range, 1-11) and 3 pts had prior hematopoietic stem cell transplantation (HSCT); 19 (54.3%) had CP disease and 14 (40%) had BP disease. Two previously treated pts had a persistent 8p11 cytogenetic abnormality only (no morphologic evidence of disease) and were only evaluable for cytogenetic response. Of the 5 treatment-naive pts, 2 had CP disease and 3 had BP disease.

Response rates are shown in Table 2. For previously treated pts, among the 33 pts with BM and/or EMD involvement, CR rate was 75.8%. Among the 35 pts evaluable for cytogenetic response, CCyR rate was 71.4%. For the 5 treatment-naive pts, 2 of 2 pts with CP disease achieved CR and CCyR, and 1 of 3 pts with BP disease achieved CR and CCyR. Median durations of response have not been reached in all 40 pts or in the 35 previously treated pts.

At data cutoff, among 40 efficacy evaluable pts, treatment was ongoing in 19 pts (47.5%). Reasons for treatment discontinuation (n, %) included: bridging to HSCT (8, 20%), progressive disease (6, 15.0%), adverse event (3, 7.5%), physician decision (2, 5.0%), pt decision (1, 2.5%), and death (1, 2.5%).

Overall (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 in ≥10% of pts were stomatitis (17%) and anemia (15%).

Conclusion: 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. The safety profile was consistent with FGFR inhibition with no unexpected toxicities.

Verstovsek:Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy; CTI BioPharma Corp.: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; Pragmatist: Consultancy. Gotlib:Allakos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cogent Biosciences: Consultancy, Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vannucchi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphans Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Rambaldi:Celgene-BMS: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Kite-Gilead: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Roche: Honoraria; ABBVIE: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Omeros: Honoraria. Reiter:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shomali:Incyte Corporation, Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding. George:Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARUP Laboratories: Other: Associated; Cogent Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Cogent: Consultancy; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Colucci:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Oliveira:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Pemigatinib (INCB054828) is a selective and potent inhibitor of fibroblast growth factor receptor (FGFR) 1, 2 and 3. Pemigatinib is currently approved for the treatment of adults with previously treated, unresectable, locally advanced/metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. In the FIGHT-203 study, it is being investigated in adults with Myeloid Lymphoid neoplasms with an FGFR1 rearrangement and may receive approval in this indication between abstract submission and ASH presentation.