KEY TAKEAWAYS
- The TRANSFORM-1 phase 3 trial aimed to investigate the long-term efficacy and safety of NAV in combination with RUX vs. RUX + placebo in JAKi-naïve adults with MF.
- The primary endpoint was to determine SVR.
- Researchers noticed NAV+RUX significantly improved outcomes with fewer serious AEs.
Janus kinase inhibitors (JAKis) are effective in spleen volume reduction (SVR) and alleviating symptoms in patients (pts) with myelofibrosis (MF), a type of leukemia. However, they have a limited effect on the underlying disease biology, highlighting the need for new treatment options. Navitoclax (NAV) is an orally administered inhibitor targeting anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-XL, BCL-2, and BCL-W. When combined with JAKi ruxolitinib (RUX), NAV has demonstrated significant efficacy, including reducing variant allele frequency (VAF) and enhancing the depth of response in pts with MF.
Naveen Pemmaraju and the team aimed to assess the long-term efficacy and safety of NAV+RUX compared with placebo (PBO)+RUX in JAKi-naïve adults with MF.
They conducted a comprehensive analysis in TRANSFORM-1, enrolling adults with intermediate-2 (INT-2) or high-risk JAKi-naïve myelofibrosis per DIPSS+ criteria, with measurable splenomegaly, and an ECOG Performance Score ≤2. Patients received placebo PBO or NAV at the 200 mg/day starting dose (if platelet [PLT] >150 × 109/L) or 100 mg escalated to 200 mg/day (if PLT ≤150 × 109/L), in combination with RUX at the label dose. The primary endpoint was ≥35% (SVR35) at week 24 (SVR35W24).
Key secondary endpoints included mean change in total symptom score (TSS) at week 24, SVR35 at any time during study treatment, anemia response per IWG criteria, and patient-reported outcomes (PROs) for fatigue (PROMIS Fatigue SF 7a) and physical functioning (EORTC QLQ-C30). Exploratory endpoints assessed responses in pts with high molecular risk (HMR) mutations within ASXL1, SRSF2, EZH2,IDH1/2, and U2AF1 p.Q157 and change from baseline in driver gene (JAK2, CALR, MPL) VAF. Additionally, the proportion of pts achieving a meaningful change in TSS (≥-10 points) at any time was evaluated.
About 252 pts on September 28, 2023, were enrolled with a median follow-up of 20.3 months (range 0.0–35.3); pts were randomized 1:1 to receive NAV+RUX (n = 125) or PBO+RUX (n = 127). Demographics were comparable between groups, with over 80% of pts categorized as INT-2 risk and nearly 50% harboring HMR mutations. The primary endpoint was achieved: 63% (n = 79) in the NAV+RUX arm achieved SVR35W24 compared to 32% (n = 40) in the PBO+RUX arm (P<0.0001).
A similar trend was observed across subgroups for SVR35 at any time during the study. SVR35 was achieved at any time by 77% (n = 96) with NAV+RUX versus 43% (n = 55) with PBO+RUX.
In pts with HMR mutations, SVR35W24 rates were 59% (35/59) with NAV+RUX and 41% (22/54) with PBO+RUX. Hemoglobin response rates were 34% (n = 43) versus 28% (n = 35), and VAF reduction (≥20% at any time) was observed in 57% (67/118) versus 42% (51/121) in the NAV+RUX and PBO+RUX arms, respectively. The mean change in TSS from baseline at Week 24 and the TSS change of ≥-10 points did not differ significantly between arms.
Fatigue and physical functioning changes were numerically comparable between groups at Week 24. Common adverse events (AEs) (>30% of pts receiving NAV+RUX) included thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs occurred in 28% of pts with NAV+RUX and 38% with PBO+RUX.
The study concluded that NAV+RUX achieved a 2-fold improvement in SVR35W24 compared to PBO+RUX in JAKi-naïve pts with MF, despite adverse prognostic factors. Favorable SVR35 outcomes persisted across subgroups throughout the study period. NAV+RUX also demonstrated higher rates of hemoglobin response and VAF reduction, with similar impacts on PRO endpoints for symptom and physical functioning. Importantly, the NAV+RUX arm exhibited a lower incidence of serious AEs, and no new safety concerns were identified.
The trial was sponsored by AbbVie.
Clinical Trial: https://clinicaltrials.gov/study/NCT04472598
Pemmaraju N, Mead A, Somervaille T.C.P., et al. (2024). “EFFICACY AND SAFETY OF NAVITOCLAX IN COMBINATION WITHRUXOLITINIB VERSUS RUXOLITINIB PLUS PLACEBO IN PATIENTS WITH UNTREATED MYELOFIBROSIS IN THE PHASE 3 RANDOMIZED, DOUBLE-BLINDTRANSFORM-1 STUDY.” Presented at EHA 2024. (S222)
