REACH3 Meets Primary End Point in Chronic Steroid-Refractory or Dependent GVHD

Ruxolitinib (Jakafi) demonstrated a superior overall response rate (ORR) versus best available treatment (BAT) at week 24 in patients with steroid-refractory or steroid-dependent chronic graft-versus-host-disease (GVHD), according to topline results from the phase 3 REACH3 study.¹

Treatment with ruxolitinib also led to an improvement in failure-free survival and patient-reported outcomes, 2 key secondary end points of REACH3. Detailed data from the study will be presented at an upcoming major medical congress.

“These positive topline results of the pivotal phase 3 trial in chronic GVHD show that treatment with Jakafi results in superior overall response and failure-free survival compared to alternative treatment options and will help to inform treatment decisions among patients refractory to steroids following bone marrow transplantation,” said David Feltquate, MD, PhD, head of the Hematology Development Unit, Novartis, in a statement.

The positive results from REACH3 build upon prior positive data observed with ruxolitinib in the phase 3 REACH2 trial. Results published in the New England Journal of Medicine showed an ORR of 62% with ruxolitinib versus 39% with BAT at day 28 (odds ratio [OR] 2.64, 95% CI, 1.65-4.22; P <.001). Additionally, complete responses were observed in 34% of patients in the ruxolitinib arm compared with 19% in the BAT arm.²

Responses in REACH2 were durable and ruxolitinib had a durable overall response at day 56 that was significantly higher than that observed with BAT; specifically, the durable overall responses rates were 40% and 22%, respectively (OR, 2.38; 95% CI, 1.43-3.94; P <.001). Loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control arm.

Failure-free survival, another end point in REACH2 that is also being explored in REACH3, was significantly extended in the ruxolitinib arm at 5.0 months compared with 1.0 months in the BAT arm (HR, 0.46; 95% CI, 0.35-0.60). There was a 13% cumulative incidence of relapse observed with ruxolitinib at 18 months versus 19% with BAT. The cumulative incidence of non-relapse-related death at 18 months was 49% in the ruxolitinib arm versus 51% in the BAT arm.

The efficacy end point of REACH2, overall survival, was also superior in the ruxolitinib arm compared with the BAT arm at 11.1 months versus 6.5 months, respectively (HR, 0.83; 95% CI, 0.60-1.15).

Ruxolitinib demonstrated tolerable safety in REACH2, with a consistent profile to previously reported data. Seventy-two percent of the ruxolitinib population discontinued treatment compared with 85% of the BAT population. Lack of efficacy was the most common reason for treatment discontinuation, which occurred in 21% of patients who received ruxolitinib and 44% of patients who received the control drug.

The most common any-grade adverse events in the study up to day 28 in the ruxolitinib arm versus the BAT arm were thrombocytopenia (33% vs 18%, respectively), anemia (30% vs 28%), and cytomegalovirus infection (26% vs 21%). The most common grade 3 AEs in the ruxolitinib arm versus the control arm were thrombocytopenia (27% vs 15%), anemia (22% vs 19%), platelet count decrease (14% vs 13%), and neutropenia (13% vs 9%). Twenty-two percent of the patients who received ruxolitinib experienced a grade 3 infection compared with 19% of the BAT group. Patients in both arms also experienced serious AEs, which occurred in 38% of the ruxolitinib arm versus 34% of the control arm. Serious AEs led to treatment discontinuation in 11% of patients in the ruxolitinib arm versus 5% of the BAT arm.

In REACH2, 309 patients were randomized 1:1 and received a 10 mg dose of ruxolitinib twice daily or BAT. The options for BAT included antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, mTOR inhibition with everolimus (Afinitor) or sirolimus (Rapamune), etanercept, or infliximab. Patients with loss of response to BAT were permitted to cross over to the ruxolitinib treatment arm at day 28. A group of patients in the study also received supportive therapy of either growth factors, anti-infective medication, transfusion support, or other standard supportive care measures.

REACH3 follows a similar study design to REACH2. The randomized, open-label, global, multicenter trial will enroll 331 patients who will receive either the protocol defined starting dose of ruxolitinib twice daily or BAT.¹

To be eligible to enroll in REACH3, patients are required to have undergone a prior allogeneic stem cell transplantation, have evidence of myeloid and platelet engraftment, and a clinical diagnosis of chronic GVHD prior to randomization that is in accordance with the National Institutes of Health Consensus Criteria.

“We look forward to sharing further details of the data, which complement the previous findings for Jakafi in the acute form of the disease, and plan to initiate regulatory filings for steroid-refractory GvHD in Europe and other ex-US countries,” Feltquate added.

_References:

_{Novartis announces phase III study of Jakavi® in chronic graft-versus-host disease met primary and key secondary endpoints. News release. Novartis. July 23, 2020. Accessed July 23, 2020. https://bit.ly/2ZSMdBt}

_{Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635}