Navi+ Rux Efficacy in Untreated MF

Janus kinase inhibitors (JAKis) have demonstrated efficacy in alleviating symptoms and reducing spleen volume in myelofibrosis (MF) patients (pts). Despite these benefits, there remains a critical unmet need for therapies that can modify disease progression, improve overall outcomes, and extend survival. The COMFORT-1 and -2 studies established JAKi monotherapy, specifically ruxolitinib, as the standard-of-care (SOC), achieving spleen volume reductions of ≥35% at Week 24 (SVR35W24) of 42% and SVR35W48 of 29%, respectively. In the phase 2 REFINE trial, combining navitoclax with ruxolitinib (NAV + RUX) demonstrated significant antitumor activity.

Naveen Pemmaraju and his team aimed to investigate the safety and efficacy of NAV + RUX in JAK2i-naïve MF adults.

The study performed an inclusive analysis by enrolling adult pts diagnosed with intermediate-2 or high-risk MF exhibiting measurable splenomegaly and evidence of MF-related symptoms. Eligible participants had no prior treatment with JAK2 inhibitors and an ECOG Performance Score of ≤2. The randomization process assigned pts in a 1:1 ratio to receive NAV with a starting dose of 200 mg (platelet [PLT] >150 × 109/L) or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days (PLT ≤150 × 109/L), or placebo (PBO). RUX was administered at the label dose.

Stratification factors considered were intermediate-2 vs high-risk MF and PLT ≤200 × 109/L vs >200 × 109/L. The primary endpoint assessed was spleen volume reduction ≥35% at Week 24 (SVR35W24). Secondary endpoints encompassed various parameters, including the change in total symptom score at Week 24 (TSSW24) using the 7-item MFSAF v4.0 (scale 0–70), SVR35 at any time, duration of SVR35, anemia response per International Working Group criteria, reduction in marrow fibrosis, overall survival (OS), leukemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale. Exploratory endpoints covered progression-free survival (PFS).

About 252 pts with intermediate-2 or high-risk MF were enrolled in TRANSFORM-1 (NCT04472598). As of the data cutoff on April 13, 2023, after a median (range) follow-up of 14.9 months, 125 pts received NAV + RUX, and 127 received PBO + RUX. Most were male (57%), with a median age of 69 (37–87) years. TRANSFORM-1 met its primary endpoint, as 63.2% in the NAV + RUX arm achieved SVR35W24 compared to 40 pts 31.5% in the PBO + RUX arm (P<0.0001). SVR35 at any time was achieved by 96 pts (77%) with NAV + RUX versus 53 pts (42%) with PBO + RUX. Median time to SVR35 response was 12.3 (10.1–48.3) weeks for NAV + RUX versus 12.4 (11.3–72.3) weeks for PBO + RUX. Median duration of SVR35 was not reached (NR) in the NAV + RUX versus 19.4 months (95% CI 16.8, NR) in PBO + RUX. 

At Week 24, mean change in TSS from baseline was -9.7 (95% CI: -11.8, -7.6) with NAV + RUX and -11.1 (95% CI: -13.2, -9.1) with PBO + RUX (P=0.2852). Grade ≥3 adverse events (AEs) were seen in 85% with NAV + RUX and 70% with PBO + RUX, with thrombocytopenia, anemia, diarrhea, and neutropenia being common. Serious AEs occurred in 26% with NAV + RUX and 32% with PBO + RUX, including anemia (NAV + RUX: n=2; PBO + RUX: n=1), thrombocytopenia (NAV + RUX: n=2), and neutropenia (NAV + RUX: n=1). With NAV + RUX, AEs led to NAV dose reduction in 101 (81%) patients and NAV interruption in 87 (70%) patients, of which 83 (67%) and 65 (52%) were due to thrombocytopenia, respectively. Of all enrolled patients, 83 (33%) discontinued study treatment; the most common (>5% of total patients) reasons for NAV/PBO discontinuation were AEs (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). In each arm, 13 (10%) patients died; 6 with NAV + RUX and 5 with PBO + RUX died within ≤30 days post-final dose.

The study concluded that in the first randomized trial of JAKi-naïve MF pts, the NAV + RUX combination resulted in a significantly higher SVR35W24 rate, doubling that of PBO + RUX (P<0.0001). Notably, the responses proved durable, while common adverse events, such as thrombocytopenia and anemia, were effectively managed through dose modifications, without any clinically significant sequelae. Additional evaluation is ongoing.

The study is sponsored by AbbVie 

Source: https://ash.confex.com/ash/2023/webprogram/Paper173509.html

Clinical Trials: https://clinicaltrials.gov/study/NCT03222609
https://clinicaltrials.gov/study/NCT04472598

Pemmaraju N, Mead A J, Somervaille T CP, et al. (2023).” 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.” Presented at ASH 2023 (Abstract 620).