Preclinical and clinical Study of olverembatinib in patients with myeloid/lymphoid neoplasms with FGFR1 rearrangement

Abstract Introduction Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1) constitute an aggressive stem-cell derived myeloproliferative disorder driven by translocations involving the FGFR1 locus at chromosome 8p11-12. FGFR1 tyrosine kinase is constitutively activated, triggering hematopoietic malignancies spanning chronic phase (CP) of a chronic myeloid neoplasms, and blast phase (BP) of AML/ALL/MPAL, and/or extramedullary disease (EMD). Current therapeutic options for MLN-FGFR1 remain limited and carry a poor prognosis. Olverembatinib (HQP1351), a novel third-generation multi-target TKI was evaluated for antitumor activity in both preclinical and clinical settings in this study. Methods Preclinical Study Two most common FGFR1 fusions of ZNF198::FGFR1, BCR::FGFR1were transfected into Ba/F3 cells and treated with olverembatinib, ponatinib, and pemigatinib. In vivo efficacy were tested in Ba/F3 xenograft models, and olverembatinib was administered via oral gavage at 3-20 mg/kg every other day. Longitudinal monitoring included daily observation of changes in physical condition, weekly assessment of survival rates, peripheral blood immunophenotyping by flow cytometry, and bioluminescent imaging of tumor burden. Clinical Study A phase 2, open-label, multicenter study was performed to evaluate the efficacy and safety of olverembatinib in adults with newly diagnosed or relapsed MLN-FGFR1. For treatment, patients in CP received olverembatinib 40 mg on alternate days (QOD) orally, whereas those in BP received a combination with regimens for AML or ALL. Allo-HSCT was recommended for all eligible patients following at least 2 years post-transplant maintenance with olverembatinib. The primary endpoint was the complete remission (CR) rate. Key secondary endpoints included CCyR, CMR, survival and adverse events(AEs). Results Preclinical Study Olverembatinib demonstrated potent anti-proliferation activity in Ba/F3 cells transformed by ZNF198::FGFR1 and BCR::FGFR1, with IC50 at 1 and 6 nM, respectively, which is significantly lower than that of ponatinib, and comparable to that of pemigatinib. Apoptosis analysis showed that olverembatinib induced apoptosis in these cells in a dose-dependent manner. In Ba/F3 mouse models, olverembatinib given at 3-20 mg/kg (QOD) dose-dependently increased the median survival time of mice by 2-8.5 days (P < 0.05) and 1-7 days (P < 0.01) respectively. Notably, in models expressing BCR::FGFR1, olverembatinib at 20 mg/kg increased the median survival time more significantly than pemigatinib at its efficacious dose (7 vs. 3 days). Mechanistically, olverembatinib inhibited phosphorylation of FGFR1, and downstream protein STAT5, STAT3, AKT and ERK1/2, increased cleavage of caspase-3 and PARP-1, suggesting apoptosis induction. We are exploring the binding site of olverembatinib into FGFR1, which will be reported in the final report. Clinical Study - Baseline characteristics As of July 30, 2025, 17 patients were enrolled and 16 patients were evaluated for efficacy. 4 (25.0%) were in CP disease, 12 were in BP disease (including 7 CP with EMD, 3 BP without EMD, 1 BP with EMD, and an EMD only). The median age was 45 years, and 7(43.8%) patients were men. 10 patients (62.5%) had peripheral blood eosinophilia. ZMYM2 was the most commonly observed fusion partner, as detected in 11(68.8%) patients. RUNX1 mutation was detected in 8/13 (61.5%) patients. At this writing, 5 patients had bridged to allo-HSCT upon achievement of CR/CHR. -Response 14 patients (87.5%) achieved CR/CHR, among whom 1 achieved CCyR and 1 achieved CMR at 2 months' evaluation. 2 patient achieved PR. Best responses were 5 CMR, 3 CCyR, 1 PCyR, 7 CR/CHR. With a median (range) follow-up of 9.5 (2-36) months, 11 patients were still alive with no detected disease. Among the 5 patients who had received HSCT, 4 had CMR, 1 died of transplant-related infection. -Adverse Events AEs in 8 patients who were treated with olverembatinib alone, were evaluated. ≥Grade 3 AEs were reported in 5 patients. One patient reported grade 4 neutropenia, one grade 3 platelet count reduction, one grade 3 hypertension and one grade 3 cerebral infarction. Conclusions Olverembatinib was highly effective and well tolerated in patients with MLN-FGFR1 in both preclinical and clinical settings. Combined chemotherapy was preferable in patients with BP disease, and allo-HSCT remained an important strategy for extending survival.