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TRANSFORM-1 Trial of Navitoclax in Combination With Ruxolitinib for Myelofibrosis Met Primary but not Secondary Endpoint

December 7, 2023

January 2024

Lara C. Pullen, PhD

Lara C. Pullen, PhD, is a freelance medical writer in Chicago, Illinois.

The phase III results of TRANSFORM-1, the first randomized trial of navitoclax plus ruxolitinib in Janus kinase (JAK) inhibitor-naïve patients with myelofibrosis (MF), was presented at the 65th ASH Annual Meeting and Exposition.1 Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston, led the study and presented the findings.

Dr. Pemmaraju explained there is a substantial need for therapies that alter disease trajectory, improve outcomes, and enhance survival in patients with MF. Navitoclax is an oral inhibitor of BCLXL, BCL2, and BCLW, all antiapoptotic B-cell lymphoma proteins. Phase II results, published last year, demonstrated that, when added to ruxolitinib, navitoclax resulted in durable spleen volume responses and improved total symptom score (TSS), as well as improvements in hemoglobin levels and bone marrow fibrosis in patients with persistent or progressive MF.2

Dr. Pemmaraju and his colleagues built on these results in the phase III TRANSFORM-1 trial that was designed to evaluate the safety and efficacy of navitolax plus ruxolitinib when compared with placebo plus ruxolitinib in JAK inhibitor-naïve patients with MF, thereby moving from a relapse setting to a frontline setting.

The primary endpoint of the double-blind, multicenter, international trial was spleen volume reduction of at least 35% (SVR35) at week 24 (SVR35W24), as measured per International Working Group (IWG) criteria by MRI or CT scan. Secondary endpoints included a change in TSS at week 24 (TSSW24) assessed using the seven-item Myelofibrosis Symptom Assessment Form v4.0 (scale 0-70) and SVR35 at any time. Patients (n=252), the majority of whom were intermediate-2 risk, were randomized to navitolax plus ruxolitinib (n=125) or placebo plus ruxolitinib (n=127).

In his presentation, Dr. Pemmaraju reported data from 14.9 months (mean) of follow-up. To date, navitoclax plus ruxolitinib has led to SVR35W24 at a rate twice as high as placebo plus ruxolitinib (63.2% vs. 31.5%, respectively; p<0.0001). The SVR35 rate at any time was also substantially greater with navitoclax plus ruxolitinib compared to placebo plus ruxolitinib (77% vs. 42%), suggesting that the vast majority of patients in the treatment arm benefitted from treatment. Dr. Pemmaraju also reported the responses were durable. However, although TRANSFORM-1 met its primary endpoint, it did not meet its secondary endpoint of TSSW24.

The investigators conducted the trial during the COVID-19 pandemic, and the most serious adverse events (AEs) were COVID-19 pneumonia and pneumonia in three patients in each arm of the trial. Thrombocytopenia, anemia, neutropenia, and diarrhea, while common, were manageable with dose modification and did not result in any clinically significant sequelae. Despite the seemingly tolerable AEs, approximately one-third of patients from both arms discontinued treatment.

Any conflicts of interest declared by the authors can be found in the original abstract.

References

  1. Pemmaraju N, Mead AJ, Somervaille TCP, 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. Presented at the 65th American Society of Hematology Annual Meeting and Exposition; December 10, 2023; San Diego, California.
  2. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. J Clin Oncol. 2022. 20;40(15):1671-1680.

 

 

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