TRANSFORM-1 phase 3 study: efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis.
Naveen Pemmaraju, Adam J Mead, Tim C P Somervaille et al.
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In 30 seconds
TRANSFORM-1 was a multicentre, randomised phase 3 trial comparing navitoclax plus ruxolitinib with placebo plus ruxolitinib in Janus kinase inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis. Among 252 participants, the primary endpoint—at least 35% spleen volume reduction at week 24—was achieved by 63.2% receiving navitoclax versus 31.5% receiving placebo (P< .0001). Week-24 symptom-score change did not differ significantly between groups. Navitoclax combination therapy was associated with more severe thrombocytopenia and neutropenia, while cytopenias were generally manageable and reversible with dose adjustments.
Key findings
- At week 24, spleen volume reduction of at least 35% occurred in 63.2% with navitoclax plus ruxolitinib versus 31.5% with placebo plus ruxolitinib (P< .0001).
- Mean total symptom score change at week 24 was -10.2 versus -11.6, respectively, with no significant between-group difference (P = .2852).
- Grade 3/4 thrombocytopenia occurred in 54.0% versus 19.2%, and grade 3/4 neutropenia in 40.3% versus 8.8%, with navitoclax versus placebo.
- Diarrhea of any grade was more common with navitoclax than placebo (41.9% vs 16.8%).
Why it matters
The trial found that adding navitoclax to ruxolitinib improved the likelihood of substantial spleen-volume reduction in this higher-risk, JAK inhibitor-naïve population, but did not significantly improve the measured symptom-score change at week 24. The greater frequency of cytopenias and diarrhea is relevant when weighing the observed spleen response against treatment burden and tolerability.
What to keep in mind
Follow-up was a median of 20.3 months; the abstract does not report longer-term outcomes.