Study yields 'encouraging' preliminary data for navitoclax combination in myelofibrosis
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Key takeaways:
- Navitoclax plus ruxolitinib led to improvement in spleen volume reduction in patients with untreated myelofibrosis.
- Adverse events of thrombocytopenia and anemia appeared common but manageable.
SAN DIEGO — Navitoclax added to ruxolitinib led to a significant improvement in spleen volume reduction compared with placebo among patients with untreated myelofibrosis, study results presented at ASH Annual Meeting and Exposition showed.
Findings from the phase 3 TRANSFORM-1 study suggest the combination therapy has a manageable safety profile that appeared consistent with the use of both agents in previous studies, according to researchers.
“The is the first randomized trial in JAKi-naive [myelofibrosis] with a navitoclax and ruxolitinib combination, which led to a in spleen volume reduction 35% at week 24 twice as high as placebo plus ruxolitinib, with similar symptom response despite a lower average dose of ruxolitinib,” Naveen Pemmaraju, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation.
Background and methodology
The double-blind TRANSFORM-1 study assessed the efficacy and safety of navitoclax (AbbVie) — and investigational Bcl-2 inhibitor — plus the JAK2 inhibitor ruxolitinib (Jakafi, Incyte) compared with placebo plus ruxolitinib among adults with JAK2 inhibitor-naive myelofibrosis.
Inclusion criteria included adults with intermediate- or high-risk myelofibrosis with measurable splenomegaly, evidence of myelofibrosis-related symptoms, no prior JAK2 inhibitor treatment, and an ECOG performance score less than or equal to 2.
Researchers randomly assigned patients in a 1:1 ratio to ruxolitinib plus either navitoclax or placebo.
Spleen volume reduction 35% at week 24 served as the study’s primary efficacy endpoint. Secondary endpoints included change in total symptom score at week 24, spleen volume reduction 35% at any time, duration spleen volume reduction 35%, anemia response, reduction in marrow fibrosis, OS, leukemia-free survival, reduction in PROMIS Fatigue scale and improvement in EORTC QLQ-C30 physical functioning scale.
The study included 252 patients (125 received navitoclax and ruxolitinib, 127 received placebo plus ruxolitinib; median age, 69 years; 57% male) with a median follow-up of 14.9 months (0 – 29.5 months).
Results and next steps
Researchers reported that 79 patients (63.2%) in the investigative arm achieved spleen volume reduction 35% at week 24, compared with 40 patients (31.5%) in the control arm, thus meeting the study’s primary efficacy endpoint. Additionally, researchers noted that 96 patients (77%) in the investigative arm achieved spleen volume reduction 35% at any time, whereas 53 patients (42%) did so in the control arm.
Median duration of spleen volume reduction 35% had not been reached in the investigative arm compared with 19.4 months (95% CI, 16.8 months to not yet reached) in the control arm.
Researchers observed grade 3 or higher adverse events among 85% of patients in the navitoclax arm and for 70% of patients in the placebo arm. The most common adverse events among patients receiving navitoclax included thrombocytopenia, anemia, diarrhea, and neutropenia.
Additionally, 26% of patients in the navitoclax arm and 32% of patients in the placebo arm experienced serious adverse events, including anemia, thrombocytopenia and neutropenia.
With navitoclax treatment, adverse events led to a dose reduction of the agent in 101 patients (81%) and treatment interruption in 87 patients (70%).
Among enrolled patients, 83 (33%) discontinued study treatment. The most common reason for discontinuation included adverse events (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). Thirteen patient deaths occurred in each study arm.
“Adverse events of thrombocytopenia, anemia and neutropenia were common but manageable with dose modification without any clinically significant sequelae,” Pemmaraju said. “Preliminary data are encouraging and additional evaluations are ongoing to assess additional outcomes of overall survival and responses in subgroups.”
Perspective
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Just a few years ago, it was hard to imagine conducting a combination therapy study in the front-line setting, let alone being able to sink our teeth into the week 24 data, but here we are. The combination of ruxolitnib and navitoclax more than doubled the proportion of patients who had at least a 35% reduction in spleen volume at week 24. Normally there is regression to the mean when a therapy moves from phase 2 to a phase 3 study so, in my view, it is remarkable that the response rate for the primary endpoint was the same as was observed in the preceding studies.
A secondary endpoint for symptom response was similar for the two arms, which has led to a lot of discussion. It just really confirms that ruxolitinb remains a great medication for addressing symptom burden. Also, the combination did not worsen symptoms, another important point to make. I left out the word “key” leading the term “secondary endpoint” here intentionally because it is really time that the field move beyond just symptom response and focuses on endpoints that indicate a deeper change in the disease and its course.
As anticipated, there was more myelosuppression observed for the combination than for ruxolitinb alone. However, an aggressive dose-modification plan in the protocol limited the downstream consequences, and the serious adverse event rate (any serious adverse event) was numerically higher in the ruxolitinb arm relative to the combination arm (32 vs 26%). This gives a path forward to safely administer the combination when it becomes available.
The presentation of TRANSFORM-1 as well as MANIFEST-2 at this year’s ASH Annual Meeting mark a pivotal moment for the treatment of myelofibrosis that has the potential to be on par with the introduction of JAK inhibitors over a decade ago — not only in the treatments available for patients, but also in pushing the goals of therapy further than have ever been pushed before.
Perspective
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The TRANSFORM study showed that the spleen reduction for navitoclax plus ruxolitinib was 77% versus 42% for the placebo control group, which is a very significant improvement in spleen reduction. What it didn’t demonstrate was a reduction in the total symptom score, which showed no significant difference.This result is quite similar to those attained with other combinations, such as pelabresib plus ruxolitinib, which yielded a 65% spleen reduction compared with 35% in the control group. That combination also did not achieve a remarkable reduction in total symptom score. Ruxolitinib monotherapy has demonstrated both spleen reduction and total symptom score reduction versus placebo. What does this all mean? At the moment, it’s not entirely clear. We know that for ruxolitinib, the improvement in spleen size and the total symptom score correlates with improvement in OS, which justifies the use of the drug. It’s not entirely clear what the results mean for agents that confer only spleen reduction but no treatment score reduction. Obviously, the goal for a treatment regimen is to increase OS, because that’s the gold standard. It could take years, maybe 2 to 5 years, to really know the results for navitoclax.I think agents like this are probably going to end up in large trials that are submitted to the FDA, and the FDA will have to review whether the information they have is enough to justify approval of the drug. Emerging data have shown molecular changes that suggest these drugs hit the target, that there will be an improvement in OS, but we don’t know that yet. The bottom line is that patients who have myelofibrosis are still in need of additional therapies. These combinations are interesting potential improvements that will hopefully come to the clinic soon and improve outcomes for patients with myelofibrosis.
Perspective
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Mikkael A. Sekeres, MD
Props to the myeloproliferative community for developing a total symptom score that wound up being one measure in the totality of data that the FDA uses to approve drugs to treat myelofibrosis. It’s wonderful that they're able to base part of the approval of drugs on patient-reported outcomes and quality of life.This study is fascinating to me. Although we see significant shrinkage in spleen size, we’re not seeing the symptom improvement.
i would hypothesize one reason is that with combination therapy, patients are starting to see more side effects to therapy and maybe that is compromising what we would hope to be an improvement in total symptom score. In other words, they may be getting deeper disease control, but they may be sacrificing quality of life.
i would love to say that will change with longer follow-up. However, in my own experience treating patients with myelodysplastic syndrome and running trials in MDS is that quality-of-life [analyses] get messier the longer you follow people because you don’t have as many people completing the quality-of-life instruments, and the more people drop off and have disease advancement, the worse their quality of life toward the end.
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Pemmaraju N, et al. Abstract 620. Presented at: ASH Annual Meeting and Exhibition; Dec. 5-9, 2023; San Diego.
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