Overall Survival with Momelotinib Vs Best Available Therapy in Patients with Ruxolitinib-Experienced Myelofibrosis: A Matching-Adjusted Indirect Comparison
Authors: Palandri Francesca , Kapetanakis Venediktos , Dobi Balazs , Branzanti Filippo , Ellis Catherine , Ballew Nick , Liu Tom , Phiri Kelesitse , Sen Nikitas Fulya , Biasi Melania , Zhang Shiyuan , Patnaik Dwaipayan 
Published: December 2024

Background : The JAK inhibitor ruxolitinib is the main first-line therapy for symptomatic and/or intermediate- to high-risk myelofibrosis (MF). Ruxolitinib improves symptoms and reduces splenomegaly in many patients but can cause or worsen anemia and thrombocytopenia. In the independent, real-world, retrospective RUX-MF study, 41% of patients discontinued ruxolitinib after 3 years (Palandri F, et al. Cancer. 2020). Overall survival (OS) after ruxolitinib discontinuation was generally poor, with median OS of &lt;5 months with no treatment after ruxolitinib. While treatment with best available therapy (BAT) provided some improvement, there continues to be an unmet need for more efficacious treatments that can improve long-term outcomes, including OS after ruxolitinib.

Momelotinib, a JAK1/JAK2/ACVR1 inhibitor, is approved in several regions for patients with intermediate- or high-risk MF with anemia and has demonstrated anemia benefits in addition to symptom and spleen responses in 3 phase 3 trials (SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM). This study compared OS with momelotinib vs BAT in patients with ruxolitinib-experienced MF.

Methods: A matching-adjusted indirect comparison (MAIC) was used to compare eligible patients from momelotinib phase 3 trials with 267 patients who received BAT in 26 European hematology centers in the RUX-MF study (which was recently updated to include 1055 ruxolitinib-treated patients [Palandri F, et al. EHA 2024. Poster P1041]). BAT included hydroxyurea, danazol, corticosteroids, erythropoiesis-stimulating agents, and investigational agents. In the base case model (model 1), momelotinib patients were reweighted to match the BAT population on age, sex, MF subtype, DIPSS risk, and the percentages with hemoglobin level &lt;10 g/dL, white blood cell count &gt;25×109/L, platelet count &lt;100×109/L, spleen length ≥10 cm, Total Symptom Score ≥20, and BMI &gt;25 kg/m2. OS results after ruxolitinib discontinuation were then compared between these balanced populations.

Analyses were also performed using an alternative adjustment model (model 2) with fewer matched characteristics (age, sex, BMI, diagnosis subtype, and DIPSS risk). Additionally, sensitivity analyses excluding different momelotinib trial cohorts were performed on both models to check the robustness of the results. An MAIC of OS was also conducted in an anemic subgroup (hemoglobin level &lt;10 g/dL).

Results: In the unmatched analysis, OS favored momelotinib (n=383) vs BAT (n=267), with a hazard ratio (HR [95% CI]) of 0.373 (0.297-0.469; P&lt;.001). In model 1, the momelotinib effective sample size (ESS) was 89 after adjustment, and OS favored momelotinib vs BAT with an HR (95% CI) of 0.512 (0.358-0.732; P&lt;.001). In model 2 (ESS=117), the HR (95% CI) in favor of momelotinib was 0.484 (0.347-0.675; P&lt;.001).

Consistent with the base case analysis, in a sensitivity analysis excluding the ruxolitinib-randomized patients in SIMPLIFY-1 (to remove potential survival effects of patients who were JAK inhibitor naive prior to study entry), the HR (95% CI) was 0.479 (0.292-0.786; P=.004) for model 1 (ESS=56) and 0.512 (0.330-0.797; P=.003) for model 2 (ESS=74). In a sensitivity analysis excluding the momelotinib-randomized patients in MOMENTUM (to remove potential effects of COVID-19), the HR (95% CI) was 0.551 (0.379-0.800; P=.002) for model 1 (ESS=68) and 0.521 (0.366-0.742; P&lt;.001) for model 2 (ESS=89).

Results in favor of momelotinib were also observed in the anemic subgroup. In the unmatched analysis, OS favored momelotinib (n=255) vs BAT (n=174) with an HR (95% CI) of 0.384 (0.293-0.504; P&lt;.001). HRs (95% CIs) for models 1 (ESS=98) and 2 (ESS=146) were 0.542 (0.387-0.759; P&lt;.001) and 0.487 (0.360-0.660; P&lt;.001), respectively.

HRs for all sensitivity analyses with sufficient ESS and model convergence for evaluation were consistent. While unmeasured factors may confound the MAIC analyses, key prognostic baseline characteristics were all accounted for in this study, and the consistency of findings across analyses indicates that the results were not sensitive to the specific decisions that were made to undertake this study.

Conclusion: These results suggest that momelotinib provides a greater OS benefit than BAT in patients with MF previously treated with ruxolitinib, and they complement SIMPLIFY-2 and MOMENTUM results supporting the use of momelotinib as a standard of care in patients with anemia in this setting.