The combination of navitoclax and ruxolitinib simultaneously inhibits 2 key mechanisms that promote myelofibrosis, resulting in an improvement in symptom control and positive changes in response biomarkers in patients with high-risk disease.
The combination of navitoclax and ruxolitinib (Jakafi) simultaneously inhibits 2 key mechanisms that promote myelofibrosis (MF), resulting in an improvement in symptom control and positive changes in response biomarkers in patients with high-risk disease, according to Catriona Jamieson, MD, PhD.
The dual regimen demonstrated a reduction in spleen volume and total symptom score (TSS) while improving bone marrow fibrosis, in findings from the phase 2 REFINE study (NCT03222609) presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition held virtually in December 2020. The combination also reduced the expression of driver genes and improved cytokine markers (TABLE).1
“This is a very important study. It gives us an idea of why people respond to this combination of ruxolitinib and navitoclax and certainly is encouraging news for the field in terms of being able to predict and prevent unnecessary toxicity,” said Jamieson, deputy director of the University of California, San Diego (UC San Diego) Moores Cancer Center.
Jamieson, who holds the Koman Family Presidential Endowed Chair in Cancer Research at UC San Diego, provided her insights during an OncLive® Rapid Readout program, a video series that features experts delving into key research findings presented at conferences. A hematologist who also focuses on regenerative medicine, Jamieson has participated in navitoclax research.
Improving quality of life is an important goal of therapy for patients with MF, experts say. MF, one of a group of heterogenous myeloproliferative neoplasms (MPNs), results in a heavy constitutional burden of symptoms driven by bone marrow fibrosis and extramedullary hematopoiesis, Jamieson said.
In the MPN Landmark Survey, patients reported symptoms of a severity of 6 or greater on a 10-point scale for a range of problems including fatigue, depression, headaches, sweating, unintentional weight loss, vision changes, and blood clots. MF also takes a toll on patients’ ability to work, resulting in absenteeism and early retirement.2
Ruxolitinib, a JAK1/2 inhibitor approved for patients with primary and secondary MF, is effective in improving splenomegaly and disease-related symptoms. The agent “has little impact on bone marrow fibrosis, and a number of patients are refractory or develop secondary resistance,” noted investigators, in a poster presented at the 25th European Hematology Association Annual Congress in June 2020.3
Navitoclax, a small molecule like ruxolitinib, targets members of the BCL-2 family of apoptotic receptors, including BCL-XL, which may prevent fibrosis in the bone marrow. Results from preclinical studies have shown that synergistic activity of JAK2 and BCL-2/ BCL-XL inhibitors results in cell death for JAK2-mutated cells and can help overcome resistance to JAK2-targeted therapy.3
Jamieson described the development of MF in the context of the JAK/STAT network. “This pathway is upregulated in the majority of patients with these myeloproliferative neoplasms. In some, it's based on a mutation in JAK2 that prevents the gene from being turned off; in others, a mutation in CALR can also activate JAK/STAT signaling. And in the third group, it's through the MPL mutation, which activates signaling through the thrombopoietin receptor more readily.”
Moreover, patients with MF who harbor high molecular risk (HMR) mutations at diagnosis have worse survival outcomes and are more likely to experience leukemic transformation to more aggressive disease, Jamieson said. “There is a great unmet need for therapies that are effective in myelofibrosis, regardless of disease biology or risk,” she noted.
In the ongoing REFINE study, patients include those with primary or secondary MF with splenomegaly who have had ruxolitinib failure after 12 weeks or more of continuous treatment. Participants receive navitoclax at a starting dose of 50 mg once daily along with ruxolitinib twice daily at their dose at study entry. The navitoclax dose can be increased to a maximum of 300-mg daily, provided the patient’s platelet count is greater than 100 x 109/L.3
The primary end point is the percentage of patients who achieve a spleen volume reduction (SVR) of 35% or greater from baseline through week 24. Secondary end points are the percentage of participants reaching a reduction in TSS of 50% or greater through week 24, anemia response, and change in grade of bone marrow fibrosis.
Overall, Jamieson said, the primary objectives of the study are to evaluate whether the presence of HMR mutations or the total number of mutated genes has an impact on clinical outcomes and to discover how the combination therapy affects inflammatory cytokines. Investigators are performing mutational analyses at baseline and week 24, including next-generation sequencing with a 54-gene assay of variant allele frequency (VAF) in peripheral blood samples. Cytokine levels are assessed in plasma samples.
At the ASH meeting, investigators reported data for 34 patients with MF who had received at least 1 dose of navitoclax plus ruxolitinib as of February 28, 2020. The median age of participants was 68 years (range, 42-86), ECOG performance status was 0 or 1, and median duration of prior ruxolitinib therapy was 20 months (range, 4-97). The median spleen volume was 1695 cm3 (range, 465-5047).1
In terms of mutations, 79% of participants had a JAK2 mutation and 21% had a CALR alteration. In all, 58% of patients (n = 19) had mutations in HMR genes, most frequently in ASXL1, followed by SRSF2, EZH2, U2AF1, and IDH1. Of those with HMR gene mutations, 42% (n = 8) had 2 or more aberrations (FIGURE).1
At week 24, the combination therapy resulted in an SVR reduction of 27% in 34 evaluable patients; a TSS reduction in 30% of 20 participants; and a VAF reduction of 10% or more in the driver genes of JAK2 or CALR in 46% of 26 patients. The therapy also led to bone marrow fibrosis improvements of at least 1 grade at any time in 29% of 34 patients.
Investigators observed treatment-emergent adverse events (TEAEs) in all patients, most commonly thrombocytopenia (88%), diarrhea (68%), and fatigue (62%). They reported TEAEs of grade 3 or greater severity in 85% of patients, most frequently thrombocytopenia (53%), anemia (32%), and pneumonia (12%). “Thrombocytopenia is manageable with dose modification and the pneumonia will require a little bit more investigation,” Jamieson said.
“We’re very excited about the results of this study in terms of reducing the variable allele frequency as well as bone marrow fibrosis grade,” Jamieson said. “The efficacy will really be borne out over time.”
The impact on bone marrow fibrosis was not affected by the presence of total mutations or HMR alterations. At week 24, 4 of 5 patients who reached a molecular response, defined as a reduction of 20% or greater in driver genes, demonstrated evidence of fibrosis reversal of at least 1 grade. “This is a really important finding from this study,” she said.
Additionally, investigators found a correlation between changes in spleen volume and MF-associated cytokine levels measured from baseline. Levels of 4 cytokines associated with TSS improvement were more moderate for beta-2 microglobulin, tumor necrosis factor receptor 2, tissue inhibitor of metalloproteinases 1, and vascular cell adhesion molecule 1. “It was fairly striking at week 12 and week 24,” Jamieson said. “That may be the pivotal part of this trial—defining new biomarkers of response in addition to showing nice efficacy.”
Overall, Jamieson said, the research advances understanding of MF. “This is a high-risk group of patients that desperately needs newer therapies and I think this team has gotten it right in terms of not just the combination strategy of BCL-XL inhibition in addition to JAK2 inhibition but also in terms of trying to predict who’s likely to respond.”
In July 2020, AbbVie, the company developing navitoclax, opened the randomized phase 3 TRANSFORM-1 trial (NCT04472598) in patients with primary or secondary MF who have not been previously treated with a JAK2 inhibitor. The trial, which aims to recruit 230 participants, will compare the combination of navitoclax plus ruxolitinib with placebo plus ruxolitinib. The primary end point is an SVR of 35% or greater at week 24.4
Continued ADC Development in NSCLC Necessitates Improved Knowledge of Mechanisms and Biomarker Optimization
Neoadjuvant vs Perioperative Immune Checkpoint Blockade in Resectable NSCLC: How Do We Choose?
EGFR TKI–Based Combinations May Revolutionize Frontline EGFR+ NSCLC Management
Dr Olazagasti on a Case-Based Discussion of ALK-Mutated NSCLC Treatment