TRANSFORM-1: High spleen volume reduction rates for navitoclax plus ruxolitinib in myelofibrosis

The combination of navitoclax plus ruxolitinib yielded improved efficacy outcomes compared with ruxolitinib alone in participants with newly diagnosed myelofibrosis, as shown by the first results of the phase 3 TRANSFORM-1 trial. Further analyses are ongoing to evaluate other outcomes including overall survival and responses in subgroups of participants.

The randomised, double-blind, placebo-controlled phase 3 TRANSFORM-1 trial (NCT04472598) enrolled 252 JAK inhibitor-naïve participants with myelofibrosis. Participants were randomised 1:1 to a combination of the BCL-XL and BCL-2 inhibitor navitoclax (100/200 mg, once daily) plus ruxolitinib (15/20 mg, twice daily), or to ruxolitinib alone. The primary outcome measure was spleen volume response (SVR), defined as a ≥35% reduction from baseline (SVR₃₅), measured by MRI or CT at week 24. Prof. Naveen Pemmaraju (MD Anderson Cancer Center, TX, USA) presented the primary results of the study [1].

At week 24, the SVR₃₅ rate was 63.2% in the combination therapy arm and 31.5% in the monotherapy arm, meeting the primary endpoint (response rate difference 31.0%; 95% CI 19.5–42.5; P<0.0001). An SVR₃₅ at any time was achieved by 76.8% and 41.7% of participants in combination and monotherapy arms, respectively. However, there was no significant difference between the 2 study arms regarding the total symptom score applied: the reduction in symptoms was close to 10 points in both groups on the EORTC QLQ-C30 physical functioning scale.

The most common grade ≥3 adverse events in the combination therapy arm were thrombocytopenia (51%), anaemia (46%), and neutropenia (38%).

In JAK inhibitor-naïve participants with myelofibrosis, navitoclax plus ruxolitinib treatment resulted in substantially higher SVR₃₅ rates at 24 weeks compared with treatment with ruxolitinib alone. “Although thrombocytopenia, anaemia, and neutropenia were common side effects, these cases were manageable with dose modifications,” clarified Prof. Pemmaraju.

1. Pemmaraju N, et al. TRANSFORM-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Abstract 620, 65^th ASH Annual Meeting, 9–12 December 2023, San Diego, CA, USA.

 

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Posted on 7 February 20247 February 2024