December 10, 2023
By Mark L. Fuerst
A combination of navitoclax and ruxolitinib led to a clinically significant reduction in spleen size in patients with untreated myelofibrosis (MF), according to the results of a randomized, double-blind, placebo-controlled, multicenter, international Phase III trial.
In the TRANSFORM-1 trial, 79 patients (63.2%) in the navitoclax plus ruxolitinib arm achieving spleen volume reduction of ≥35% at week 24 (SVR35W24) compared with 40 patients (31.5%) in the placebo plus ruxolitinib arm, reported lead author Naveen Pemmaraju, MD, of MD Anderson Cancer Center, Houston, TX, at a press conference at the 2023 American Society of Hematology annual meeting (Abstract 620).
“The trial met its primary endpoint with twice the spleen volume reduction in the experimental arm compared to the control arm,” Pemmaraju noted.
Janus kinase inhibitors (JAKis) such as ruxolitinib provide symptom improvement and spleen volume reduction in patients with primary, post-polycythemia vera, and post-essential thrombocythemia MF. However, there remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival in MF patients.
Ruxolitinib reduces spleen enlargement and other symptoms, said Pemmaraju, but does not cure the disease, and ruxolitinib alone does not work for all patients. Previously, in the Phase II REFINE trial a combination of ruxolitinib with navitoclax, an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCL-XL, BCL-2, BCL-W) was shown to have pronounced antitumor activity in MF patients. The two-drug combination produced benefits in many patients, including reduced bone marrow scarring and decreased spleen size.
The ongoing TRANSFORM-1 trial enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2 inhibitor treatment, and ECOG Performance Score ≤2. Patients were randomized to receive navitoclax at a starting dose of 200 mg (platelet >150 × 109/L) or 100 mg escalated to 200 mg once daily if tolerated after 7 or more days (platelet ≤150 × 109/L) or placebo plus ruxolitinib at label dose, based on stratification factors of intermediate-2 vs. high-risk MF and platelets ≤200 × 109/L vs. >200 × 109/L.
The final analysis of TRANSFORM-1 included 252 patients, median age 69 years, with a median follow-up of 14.9 months. A total of 125 patients were randomized to receive navitoclax plus ruxolitinib and 127 to receive placebo plus ruxolitinib. Most patients were male (57%) and patient demographics were similar between the treatment arms.
Pemmaraju noted that SVR35 at any time was achieved by 96 patients (77%) in the navitoclax group compared with 53 patients (42%) in the placebo group, with equal median time to response. Median duration of SVR35 was not reached in the treatment arm compared with 19.4 months in the placebo arm. “Almost all of the patients in the experimental arm benefited from treatment,” Pemmaraju said.
At Week 24, the mean change in total symptom score from baseline was -9.7 with the combination compared with -11.1 with placebo, which was not a statistically significant difference.
Grade 3 or higher adverse events were experienced by 85 percent of patients with navitoclax plus ruxolitinib and 70 percent with placebo plus ruxolitinib.
The most common adverse events were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious adverse events, including anemia, thrombocytopenia, and neutropenia, were experienced by 26 percent of patients in the experimental arm and 32 percent in the control arm. With the combination, adverse events led to navitoclax dose reduction in 101 (81%) patients and navitoclax interruption in 87 (70%) patients, mostly due to thrombocytopenia.
Of all enrolled patients, 83 (33%) discontinued study treatment, most commonly due to adverse events and physician decision. In each arm, 13 (10%) patients died; 6 patients receiving the combination and 5 placebo patients died within 30 days post-final dose.
Pemmaraju concluded: “This first randomized trial in JAKi-naïve MF with navitoclax plus ruxolitinib combination led to an SVR35W24 rate that was twice as high as placebo plus ruxolitinib, with a similar symptom response despite a lower average dose of ruxolitinib. The responses were durable; adverse events of thrombocytopenia and anemia were common, but manageable with dose modification without any clinically significant sequelae.”
The preliminary data are encouraging and additional evaluations are ongoing to assess additional outcomes of overall survival and responses in subgroups, he said.
“This is one of two global randomized, double-blind, placebo-controlled clinical trials in our field to be reported that investigate the use of two targeted agents in patients with myelofibrosis who have not yet been treated with a JAK inhibitor,” Pemmaraju stated. “These results show the feasibility and tolerability of a frontline approach with this promising two-drug combination and potentially open a new era of combination therapy to modify the course of this disease.”
Mark L. Fuerst is a contributing writer.