Navitoclax Combination Shows Promising Anti-Fibrosis Activity in Patients with Myelofibrosis

New data from a phase 2 trial of navitoclax in combination with ruxolitinib (AbbVie) in patients with myelofibrosis were presented at the American Association for Cancer Research annual meeting.

Navitoclax is an investigational, oral BCL-XL/BCL-2 inhibitor that is designed to activate programmed cell death in cancer cells. The safety and efficacy are currently under evaluation as part of the ongoing phase 2 and registrational phase 3 studies.

"Myelofibrosis is a cancer that originates in the bone marrow, leading to fibrosis. Currently, available therapies do not address the underlying disease biology and have not shown a consistent effect on both biomarkers of disease modification and overall survival. Disease control with reversal of bone marrow fibrosis is a key objective for improving patient outcomes," said Mohamed Zaki, MD, PhD, vice president and global head of oncology clinical development at AbbVie, in a press release. "That's why we are especially pleased about these early results of navitoclax in combination with ruxolitinib that indicate its novel mechanism of action of inducing cell death may cause reversal of bone marrow fibrosis and extend survival for patients who respond to treatment."

The results presented were from REFINE (NCT03222609), which is a phase 2 trial evaluating navitoclax in combination with ruxolitinib and includes patients with myelofibrosis who had progressed on or had a suboptimal response to at least 12 weeks of ruxolitinib monotherapy.

In the analysis of 32 patients who were evaluable for improvements in bone marrow fibrosis (BMF), 12 had a ≥1 grade improvement during any point in time during the study. Meanwhile, 26 patients were evaluable for driver gene variant allele frequency (VAF) and achieved a ≥20% reduction at week 24. Only 5 patients achieved both BMF and VAF responses.

The median overall survival (OS) for all patients was not reached, and for patients who had a ≥1 grade improvement BMF, median OS was not reached, compared with 28.5 months for patients who did not experience an improvement. All 34 patients experienced at least 1 adverse event (AE), and 44% experienced a serious AE (SAEs). The most common AEs were thrombocytopenia, diarrhea, fatigue, and nausea, and the most common SAEs were pneumonia and splenic infarction.

"Data obtained from this exploratory analysis holds promise for potential future clinical research," said Jacqueline S. Garcia, MD, Dana-Farber Cancer Institute, assistant professor of medicine at Harvard Medical School, in a press release. "What is most notable in this analysis is the overall survival among patients who demonstrate VAF and BMF responses and all patients were alive at time of analysis. Patients in this Phase 2 trial had suboptimal response to ruxolitinib at time of study entry and then had navitoclax added to ruxolitinib on the trial. VAF and BMF responses occurred despite the presence of high molecular risk mutations, which suggests the potential efficacy of combination navitoclax and ruxolitinib could be independent of underlying risk factors."

REFERENCE

AbbVie presents positive investigational navitoclax combination data in phase 2 REFINE study suggesting anti-fibrosis activity for patients with myelofibrosis. AbbVie. April 12, 2022. Accessed April 13, 2022. https://news.abbvie.com/news/press-releases/abbvie-presents-positive-investigational-navitoclax-combination-data-in-phase-2-refine-study-suggesting-anti-fibrosis-activity-for-patients-with-myelofibrosis.htm