On December 10, 2022 AbbVie (NYSE: ABBV) reported new data from Cohort 3 of its Phase 2 REFINE study of investigational navitoclax in combination with ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (MF) (Press release, AbbVie, DEC 10, 2022, View Source [SID1234625007]). The exploratory analysis suggests the combination of navitoclax and ruxolitinib led to reductions in bone marrow fibrosis (BMF) and variant allele frequency (VAF) for common genetic mutations found in individuals with myelofibrosis that may indicate potential disease modification.1 The findings were shared in an oral presentation (abstract #237) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper).

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"While the current standard of care for patients with myelofibrosis can improve disease symptoms, impact on underlying disease biology is limited. It is our hope that patients have an option that goes beyond symptom control," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development, AbbVie. "Consistent with previous evidence, these results suggest navitoclax combination may have disease modifying potential, both as an anti-fibrosis agent and by reducing variant allele frequency of driver mutations."

REFINE (NCT03222609) is a Phase 2 non-randomized open-label multi-cohort study evaluating the safety and efficacy of navitoclax alone or in combination with ruxolitinib in MF.2

These data build on AbbVie’s history of transforming standards of care in blood cancers, including recent presentations of investigational navitoclax data from the REFINE study earlier this year at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress.

The findings presented at ASH (Free ASH Whitepaper) were based on an exploratory analysis of 32 JAK inhibitor-naïve patients with MF from Cohort 3 of the Phase 2 REFINE study. The primary endpoint was spleen volume reduction of ≥35 percent (SVR35) from baseline at week 24.1 Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, MPL or Triple-negative), respectively.1

In this exploratory analysis, SVR35 at week 24 was observed in higher-risk groups, improving over time. The four poor prognosis subgroups were: Type (primary or secondary) of MF (primary MF, 59 percent [n = 10/17]; age (≥75 years, 50 percent [n = 4/8]); prognostic risk score, as measured by Dynamic International Prognostic Scoring System or DIPSS (intermediate-2, 63 percent [n = 12/19]; high, 33 percent [n = 1/3]); and presence of high molecular risk (HMR) mutations (47 percent [n = 9/19].1

In Cohort 3, BMF grade improvement was evaluable in 81 percent (26/32) of patients.1 Of these study participants, 35 percent (9/26) achieved ≥ 1 grade improvement at any time during treatment with a median time-to-improvement of 12.3 weeks.1 Complete resolution of BMF was observed in 22 percent (2/9) of patients.1

Reduction in driver gene mutation VAF > 20% from baseline at week 12 or 24 was observed in 50 percent (14/28) of patients, while 18 percent (5/28) of patients achieved > 50% VAF reduction from baseline. There were no differences in > 20% VAF reductions from baseline to week 12 or 24 between those with or without HMR mutations (47 percent [7/15] versus 54 percent [7/13], respectively).

Preliminary safety analysis identified no new safety signals. Twenty-five (78 percent) patients reported one or more adverse events (AE). The most common grade ≥3 AEs were thrombocytopenia (47 percent), anemia (34 percent), and neutropenia (25 percent). 9.4 percent of patients discontinued therapy due to an AE.3

"These results are promising for patients who need a treatment option that goes beyond just symptom control," said Francesco Passamonti, full professor of hematology, University of Insubria and chief, hematology, Varese Hospital, Italy. "The suggestion of disease modification in this analysis from combination therapy with navitoclax is encouraging, particularly when combined with clinical efficacy in terms of SVR35 rates in the higher risk groups that improved over time."

About Navitoclax
Navitoclax is an investigational, oral BCL-XL/BCL-2 inhibitor. Navitoclax is not approved by any health authority worldwide at this time. Its safety and efficacy are under evaluation as part of ongoing Phase 2 and registrational Phase 3 studies.

AbbVie has an extensive late-stage clinical trial program for investigational navitoclax that is currently enrolling. Please visit us here for more information about enrolling in a clinical trial.

About the REFINE Study
REFINE is a multi-cohort, Phase 2, randomized, open-label, multicenter study evaluating the tolerability and efficacy of navitoclax alone or when added to ruxolitinib in patients with myelofibrosis (MF).2 The primary outcome measure is the percentage of patients who achieve spleen volume reduction of greater than or equal to 35 percent (SVR35) from baseline to week 24.2 Secondary outcomes measures include percentage of participants achieving 50 percent reduction in total symptom score from baseline to week 24; anemia response every 12 weeks up to approximately 96 weeks, measured according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria; and change in grade of bone marrow fibrosis assessed according to the European Consensus Grading System.2

Data presented at ASH (Free ASH Whitepaper) 2022 include safety and efficacy results from Cohort 3 of REFINE (n=32). Patients in Cohort 3 had primary or secondary MF with splenomegaly (DIPSS ≥ intermediate-1) and had not received JAK-2 therapy or bromodomain and extra terminal motif (BET) inhibitors prior to enrollment. The primary endpoint of SVR35 was assessed by MRI conducted by central review. Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF obtained from BM biopsies by local evaluation and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, or MPL), respectively. Studied HMR mutations included ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 p.Q157. Driver gene VAF and HMR mutations were determined in whole blood with a 50-gene focus myeloid next-generation sequencing panel. The findings presented at ASH (Free ASH Whitepaper) 2022 are representative of data from Cohort 3 of the REFINE study as of February 7, 2022.

More information about the REFINE study can be found at View Source (NCT03222609).

About Myelofibrosis
Myelofibrosis (MF) is a rare, difficult-to-treat blood cancer that results in excessive scar tissue formation (fibrosis) in the bone marrow. Patients living with MF experience symptoms such as an enlarged spleen, fatigue, weakness, and severe anemia which are often debilitating and greatly impact quality of life. MF also carries a risk of transformation to more aggressive disease such as acute myeloid leukemia.