Phase III REACH2 Study Demonstrates Significant Improvements from Ruxolitinib Therapy

Data from the phase III REACH2 study, published in The New England Journal of Medicine, demonstrated that ruxolitinib (Jakafi) therapy led to significant improvements in efficacy outcomes in patients with steroid-refractory acute graft-versus-host disease (GVHD) compared to the best available therapy.¹

REACH2 is the first phase III study of ruxolitinib in acute GVHD to have met its primary endpoint, reinforcing the findings from the previously reported phase II REACH1 study.

“Patients with acute graft-versus-host disease face life-threatening challenges with limited treatment options, particularly for the nearly half of individuals who do not respond to initial steroid therapy,” Robert Zeiser, from the University Hospital Freiburg Department of Hematology, Oncology, and Stem Cell Transplantation, said in a press release.² "These new data from REACH2 showing superiority of ruxolitinib over current standard-of-care therapies add to a growing body of evidence on how targeting the JAK pathway can be an effective strategy in this difficult-to-treat condition.”

In this multicenter, randomized, open-label trial, researchers compared the efficacy and safety of oral ruxolitinib at a dose of 10 mg twice daily with the investigator’s choice of therapy from a list of 9 commonly used options as a control. The primary endpoint was overall response (ORR) at day 28, and the key secondary endpoint was durable ORR at day 56. 

A total of 309 patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation were included in the study, with 154 patients assigned to ruxolitinib and 155 to the control arm. 

ORR at day 28 was found to be higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; OR, 2.64; 95% CI, 1.65-4.22; P < 0.001). Further, durable ORR at day 56 was found to be higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; OR, 2.38; 95% CI, 1.43-3.94; P< 0.001).The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. 

Median failure-free survival was longer in the ruxolitinib arm, compared  with the control arm (5.0 months vs. 1.0 month; HR, 0.46; 95% CI, 0.35-0.60). Moreover, median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (HR, 0.83; 95% CI, 0.60-1.15).

The most common adverse events (AEs) observed up to day 28 were thrombocytopenia (33% in the ruxolitinib group vs 18% in the control group), anemia (30% vs 28%, respectively), and cytomegalovirus infection (26% vs 31%). Additionally, while 38% and 9%, respectively, required dose modifications, the number of patients who discontinued treatment due to AEs was low (11% vs 5%).

In an editorial, Nelson J. Chao, MD, MBA, cell therapy and hematologic malignancies specialist at the Duke Adult Blood and Marrow Transplant Clinic, indicated that though the researchers should be applauded for their findings, further research in this area is still necessary.³

“Given the effect of ruxolitinib in controlling glucocorticoid-refractory GVHD, it is interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy, but the total follow-up time was short,” Chao wrote. “Thus, as with all good research, these observations raise important questions and set the stage for further work in this area.”

In 2019, ruxolitinib was approved by the FDA for the treatment of steroid refractory acute GVHD in adult and pediatric patients 12 years and older based on positive results from the phase II REACH1 trial. The phase III REACH3 study in patients with steroid refractory chronic GVHD is ongoing and results are expected in the second half of this year. 

References:

1. Zeiser R, Bubnoff N, Butler J. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. doi:10.1056/NEJMoa1917635.

2. Incyte Announces Pivotal REACH2 Study Data Published in NEJM Highlight Superior Efficacy of Ruxolitinib (Jakafi) versus Best Available Therapy in Patients with Acute Graft-Versus-Host Disease [news release]. Wilmington, Delaware. Published April 22, 2020. investor.incyte.com/news-releases/news-release-details/incyte-announces-pivotal-reach2-study-data-published-nejm. Accessed April 24, 2020.

3. Chao N. Finally, a Successful Randomized Trial for GVHD. N Engl J Med. doi:10.1056/NEJMe2003331.