San Diego—In the first randomized trial conducted in patients with myelofibrosis who have not previously been treated with a JAK inhibitor, twice as many who received an investigational targeted agent (navitoclax) in addition to a JAK inhibitor had a clinically significant reduction in spleen size compared with those who received JAK inhibitor monotherapy.
In the TRANSFORM-1 study, a spleen volume reduction ≥35% (SVR35) at week 24, the primary end point, was achieved by 63.2% of patients randomized to navitoclax plus ruxolitinib at a median follow-up of almost 15 months, compared with 31.5% of patients assigned to placebo plus ruxolitinib, which was significant (P<.0001).
“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,” said lead investigator Naveen Pemmaraju, MD, who presented the findings at the 65th American Society of Hematology Annual Meeting. “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.”
The standard-of-therapy for the treatment of myeolofibrosis is a JAK inhibitor. “While these have revolutionized the care of our myelofibrosis patients, JAK inhibitors by and large have not led to a cure,” said Dr Pemmarju, professor of leukemia, MD Anderson Cancer Center, Houston, Texas, and the response rates, with the primary end point usually being spleen volume reduction of 35% at week 24 of only 29% to 42% in trials of JAK inhibitors.
Navitoclax is an orally active inhibitor of the Bcl-2 family of proteins, which are often upregulated in a wide variety of cancers and are linked to tumor drug resistance. In contrast to venetoclax, navitoclax also inhibits Bcl-XL. “It turns out that in our myeloproliferative/myelofibrosis patients, the Bcl-XL pathway appears to be a bit more important [upregulated] than Bcl-2,” he said.
The data he reported here were from the global TRANSFORM-1 study, a randomized controlled phase 3 trial that enrolled 252 patients (median age, 69 years; 57% men) with intermediate- or high-risk myelofibrosis with measurable splenomegaly and evidence of symptoms who had not been previously treated with a JAK inhibitor. Patients were randomly assigned in a double-blind fashion to treatment with either navitoclax plus ruxolitinib or placebo plus ruxolitinib. Some 83% to 87% of patients in the overall cohort at baseline were classified as intermediate-2 risk. High molecular-risk mutations were present in 43% to 48% of study participants.
In addition to the primary end point favoring navitoclax plus ruxolitinib arm at week 24, an SVR35 at any time on study improved to 76.8% in the navitoclax plus ruxolitinib arm versus 41.7% in the placebo plus ruxolitinib group, he reported, which was also significant (P<.0001).
The most common adverse events (AEs) in those receiving navitoclax were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs were experienced by 26% of patients with navitoclax plus ruxolitinib versus 32% with placebo plus ruxolitinib. Navitoclax dose reduction was required in 81% of patients due to AEs, and navitoclax interruption was required in in 70%.