Background: Myeloid and lymphoid neoplasms (MLNs) with FGFR1 rearrangements are very rare but aggressive myeloproliferative malignancies, characterized by eosinophilia, lymphoid aggregates, and often myelofibrosis, and are recognized as a distinct disease group by the World Health Organization (WHO). In these neoplasms, FGFR1 rearrangements drive oncogenesis via dysregulation of downstream FGFR signaling. Allogenic hematological stem cell transplant (HSCT) is the recommended treatment for patients with FGFR1-rearranged MLNs, as these malignancies are often refractory to chemotherapy and tyrosine kinase inhibitors. Currently, no effective molecularly targeted treatments are available for these patients. Futibatinib is an oral, highly selective, irreversible inhibitor of FGFR1-4 that has shown antitumor activity against FGFR-deregulated tumors in preclinical experiments and in phase 1 studies. Recent results from a phase 2 study demonstrated the efficacy (42% objective response rate) and manageable safety of futibatinib in patients with FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In addition to cholangiocarcinoma, futibatinib treatment resulted in objective responses across tumor types harboring various FGFR aberrations in the phase 1 study. In a separate report, a patient with an FGFR1-driven myeloid neoplasm treated with futibatinib achieved complete hematologic and cytogenetic remission. Based on these data, a multicohort phase 2 study (NCT04189445) was designed to evaluate the efficacy and safety of futibatinib in patients with tumors harboring specific FGFR aberrations. Here, we describe the cohort of patients with MLNs harboring FGFR1 rearrangements.

Study Design and Methods: In this global, open-label, multicohort phase 2 study, patients (≥18 years, with Eastern Cooperative Oncology Group performance status 0-1 and adequate organ function) will be enrolled into 1 of 3 cohorts by type of tumor and/or FGFR aberration. The cohort of patients with MLNs harboring FGFR1 rearrangements (as defined by WHO criteria) will include patients who are not candidates for HSCT or other therapies or who have disease progression following HSCT. Patients with clinically significant alterations in calcium-phosphorus homeostasis, ectopic mineralization/calcification, clinically significant retinal/corneal disorder, untreated or clinically/radiologically unstable brain metastases, or prior FGFR inhibitor treatment will be excluded. Approximately 20 patients will be enrolled in this cohort (sample size considerations based on differentiating a ≤10% historical control complete response [CR] rate with a 50% target CR rate with 95% power). Patients will receive futibatinib 20 mg once daily in a continuous 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criterion is met. The primary endpoint is CR rate. Secondary endpoints include objective response rate, CR with incomplete hematological recovery (CRi) rate, complete or partial cytogenetic response rate, and safety. Additional secondary endpoints are duration of CR, CR+CRi, and response; as well as event-free (leukemia presentation only), progression-free, relapse-free, and overall survival. The study was initiated in August 2020, and patient enrollment is ongoing.

Disclosures

Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Shitara: Lilly, Ono Pharmaceutical, Dainippon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharm, Astellas Pharm, Medi Science, Eisai, Taiho Oncology: Research Funding; Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Taiho, MSD, Novartis, Abbvie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim: Consultancy; Novartis, Abbvie, Yakult: Other: Speaker fee. Rosen: Taiho Oncology: Research Funding. Rha: Taiho Oncology, Inc.: Research Funding. He: Taiho Oncology, Inc.: Research Funding. Oh: Taiho Oncology, Inc.: Research Funding; AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok: Other: Grants or contracts from any entity; AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point: Other: Participation on a data safety monitoring board or advisory board. Melisi: Taiho Oncology, Inc.: Research Funding. Iwasa: Taiho Oncology, Inc.: Honoraria, Research Funding. Jiang: Taiho Oncology, Inc.: Research Funding. Liu: Taiho Oncology, Inc.: Current Employment. Takahashi: Taiho Oncology, Inc.: Current Employment. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

Author notes

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© 2021 by The American Society of Hematology
2021
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