AbbVie Announces Phase 2 Clinical Data of navitoclax in Myelofibrosis 2022 AACR

Recently, AbbVie presented new data from the Phase 2 REFINE (NCT03222609) trial of navitoclax in combination with ruxolitinib (a JAK1/2 inhibitor) in myelofibrosis (MF) at the 2022 American Association for Cancer Research (AACR) annual meeting
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navitoclax is an investigational first-in-class oral BCL-XL/BCL-2 inhibitor designed to activate programmed cell death (apoptosis) in cancer cells
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Currently, navitoclax is being evaluated in Phase 2 and registrational Phase 3 studies
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REFINE is an open-label, multicenter Phase 2 study evaluating the tolerability and efficacy of navitoclax in combination with ruxolitinib in patients with MF
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The trial enrolled patients with MF who had received at least 12 weeks of ruxolitinib monotherapy with disease progression or suboptimal response
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Among the first 34 patients enrolled early in the trial, the median duration of prior ruxolitinib treatment was 91 weeks (range: 19 weeks-391 weeks)
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In an exploratory analysis, 12 (38%) of 32 patients with evaluable improvement in myelofibrosis (BMF) had a grade ≥1 improvement in BMF at any time point in the study
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For reduction in driver variant allele frequency (VAF), 6 of 26 evaluable patients (23%) had a ≥20% reduction at week 24
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Five patients achieved both BMF and VAF responses
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At the time of data analysis, overall survival (OS) had not been reached for all patients after more than 2 years of follow-up
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For patients with ≥ grade 1 improvement in BMS, median OS was not reached; for patients without BMS improvement, median OS was 28.
5 months
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Similarly, for patients with a ≥20% reduction in VAF in the driver gene, median OS has not been reached; for patients with a <20% reduction in VAF, the median OS was 28.
5 months
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Regarding safety, all 34 patients (100%) experienced at least one adverse event, and 15 patients (44%) experienced serious adverse events
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The most common adverse events of any grade were thrombocytopenia (n=30, 88%), diarrhea (n=24, 71%), fatigue (n=21, 62%), and nausea (n=13, 38%)
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The most common serious adverse events were pneumonia (n=4, 12%) and splenic infarction (n=2, 6%)
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No bleeding serious adverse events occurred, and thrombocytopenia was manageable and reversible and could be achieved by reducing/interrupting navitoclax and/or ruxolitinib doses
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The REFINE study is a dose-finding study, and the target dose of navitoclax will be reduced based on the above results
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Myelofibrosis (MF) is a rare, difficult-to-treat blood cancer that causes excessive scar tissue formation (fibrosis) in the bone marrow
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Antifibrotic activity, measured by reversal of myelofibrosis (BMF) and reduction in driver variant allele frequency (VAF), have been considered potential biomarkers for disease modification in MF, but their association with survival benefit has not been investigated Extensive description
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Currently available treatments do not address the underlying disease biology of MF, nor do they show consistent effects on biomarkers of disease modification and overall survival
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Data presented at the AACR Annual Meeting showed that the estimated survival rate reached 100% for patients with a ≥ grade 1 improvement in BMF or a ≥20% reduction in VAF in a follow-up analysis of more than 2 years
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These results suggest that the mechanism of action of navitoclax-induced cell death has the potential to achieve myelofibrosis reversal and prolong survival in patients who respond to therapy
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Reference source: AbbVie Presents Positive Investigational Navitoclax Combination data in Phase 2 REFINE Study Suggesting Anti-Fibrosis Activity for Patients with Myelofibrosis