Navitoclax Monotherapy Mirrors Safety of Navitoclax/Ruxolitinib, But Falls Short in Efficacy in Myelofibrosis

Vinod Pullarkat, MD, MRCP

Single-agent navitoclax achieved a manageable safety profile compared with navitoclax plus ruxolitinib (Jakafi) in patients with myelofibrosis, according to results from the phase 2 REFINE trial (NCT03222609) presented at the 2022 EHA Congress.¹ However, efficacy results, specifically at 24 weeks of treatment, favored the combination over navitoclax monotherapy.

Best responses at any time were measured at a median follow-up of 7.3 months (range, 2.7-19.4) for evaluable patients in cohort 2 who received navitoclax monotherapy (n = 29). Specifically, 17% experienced a spleen volume reduction of at least 35%, and 33% of patients saw their total symptom score (TSS) reduced by at least 50% (n = 7/21). Additionally, 45% of patients experienced an anemia response (n = 10/22), and 28% saw a bone marrow fibrosis improvement of at least 1 grade (n = 5/18).

Notably, at week 24, 7% of patients in cohort 2 achieved a spleen volume reduction of at least 35% (n = 2/29), 10% saw their TSS reduced by at least 50% (n = 2/21), and 22% had a bone marrow fibrosis improvement of at least 1 grade (n = 4/18).

“Navitoclax monotherapy results in modest spleen response at week 24, with deepened spleen volume reduction and TSS [improvement] rates over time. In addition, patients had clinically relevant improvements in anemia and bone marrow fibrosis,” lead study author Vinod Pullarkat, MD, MRCP, hematologist, professor, Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, and coauthors, wrote in a poster presentation of the data.

Although JAK inhibitors are the standard of care for the treatment of patients with intermediate- and high-risk myelofibrosis, a proportion of patients do not respond to treatment or develop secondary resistance to ruxolitinib, leaving them with limited therapeutic options.

Navitoclax, an oral, small-molecule inhibitor of anti-apoptotic BCL-2 proteins, acts synergistically with JAK inhibition. REFINE is evaluating navitoclax alone and in combination with ruxolitinib. Prior results from cohort 1a, where patients received navitoclax with ruxolitinib, demonstrated that the combination produced clinically meaningful outcomes and manageable safety in patients with myelofibrosis who experienced progression or suboptimal responses to prior single-agent ruxolitinib.

Previous data from cohort 1a of REFINE showed that at week 24, 27% of patients had a spleen volume reduction of at least 35% (n = 9/34), 30% of patients had a TSS reduction of at least 50% (n = 6/20), and 21% of patients had bone marrow improvement (n = 7/34).²

Data presented at EHA focused on the efficacy and safety of navitoclax alone in cohort 2 of REFINE, which is an ongoing, open-label, multicenter study. The trial enrolled adult patients with myelofibrosis into four cohorts, based on prior experience with JAK inhibition. Patients in cohort 2 were required to have discontinued JAK inhibitor therapy. All patients were required to have an ECOG performance status of 2 or less; were ineligible or unwilling to undergo stem cell transplantation; and had no prior therapy with any BCL-2 homology 3 mimetic.

Enrolled patients in cohort 2 were administered 100 mg of oral navitoclax per day if their baseline platelet count was between 75 x 10⁹/L and 150 x 10⁹/L. Patients with platelet counts higher than 150 x 10⁹/L received 200 mg of oral navitoclax per day.

The primary end point of the trial is the rate of patients who achieve a spleen volume reduction of at least 35%, and secondary end points include rate of TSS improvement of at least 50%, anemia response, and change in grade of bone marrow fibrosis.³

Baseline characteristics for patients in cohort 2 (n = 34) included a median age of 69 years (range, 55-84). Most patients were male (59%), had secondary myelofibrosis (55%), were refractory to prior ruxolitinib (32%), had an ECOG performance status of 1 (59%), had hemoglobin levels of less than 10 g/dL (71%), had a platelet count of at least 100 x 10⁹ cells/L (79%), and had intermediate-risk disease (59%). The median duration of prior ruxolitinib exposure was 113 weeks (range, 11-496), and the median spleen volume was 2319 cm³ (range, 865-4064).

Notably, 44% of patients started navitoclax at 100 mg per day (n = 15), and 56% of patients began at 200 mg per day (n = 19), based on baseline platelet counts. At data cutoff, 44% of patients had discontinued navitoclax, including 9% due to adverse effects (AEs), 6% due to withdrawal of consent, 6% for progressive disease, 6% for relapse, 9% due to physician decision, and 9% for other reasons. Overall, 21% of patients discontinued treatment prior to or at week 24.

Pullarkat and colleagues noted that navitoclax monotherapy generated an acceptable safety profile with similar rates of AEs compared with navitoclax plus ruxolitinib in cohort 1a. The most common AEs of any grade in cohort 2 were diarrhea (47% and 76% in cohort 2 and cohort 1a, respectively), nausea (32% and 44%), anemia (32% and 32%), decreased platelet count (29% and 3%), thrombocytopenia (27% and 88%), and fatigue (21% and 65%).

The most common grade 3 or higher AEs in cohort 2 were anemia (29% and 32% in cohort 2 and cohort 1a, respectively), decreased platelet count (18% and 0%), decreased neutrophil count (15% and 6%), neutropenia (15% and 9%), and thrombocytopenia (15% and 59%).

“In contrast to observations with navitoclax plus ruxolitinib in cohort 1a, notably lower rates of thrombocytopenia were observed [in cohort 2], despite 21% of patients [presenting] with low platelet counts at baseline,” Pullarkat wrote.

The only serious AE to occur in more than one patient in cohort 2 was anemia (n = 2), and that occurred in one patient in cohort 1a.

Study authors concluded that in addition to the monotherapy regimen used in cohort 2, greater disease burden and longer time on ruxolitinib (median 113 weeks in cohort 2 vs median 91 weeks in cohort 1a) may have contributed to differential responses to navitoclax.

“These findings, in conjunction with the preclinical data and observations from cohort 1a of this study, support the synergistic activity of navitoclax and ruxolitinib,” Pullarkat concluded. “Therefore, up-front combination therapy, or the addition of a B-cell lymphoma extra-large inhibitor to ongoing JAK inhibitor [therapy] in patients with suboptimal response might be a new option.”

References

1. Pullarkat V, Cruz-Chacon A, Gangatharan S, et al. Navitoclax monotherapy in patients with myelofibrosis previously treated with JAK-2 inhibitors: safety and tolerability. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P1070.
2. Pemmaraju N, Garcia JS, Potluri J, et al. The addition of navitoclax to ruxolitinib demonstrates efficacy within different high-risk populations in patients with relapsed/refractory myelofibrosis. Blood. 2020;136(suppl 1):49-50. doi:10.1182/blood-2020-136938
3. A study evaluating tolerability and efficacy of navitoclax alone or in combination with ruxolitinib in participants with myelofibrosis (REFINE). ClinicalTrials.gov. Updated November 10, 2021. Accessed June 15, 2022. https://clinicaltrials.gov/ct2/show/NCT03222609