Ruxolitinib Improves ORR in Steroid-Refractory aGVHD in Early Phase III Trial Results

John Tsai, MD

John Tsai, MD

Ruxolitinib (Jakafi) demonstrated a significant improvement in overall response rate (ORR) over best available therapy at day 28 in patients with steroid-refractory acute graft-versus-host disease (aGVHD), according to topline results from the phase III REACH2 trial.¹Novartis, the company developing the JAK inhibitor, announced in a press release that this met the primary endpoint of the trial.

“As many as half of hematopoietic stem cell transplant recipients develop aGvHD,” John Tsai, MD, head of Global Drug Development and Chief Medical Officer, Novartis, said in a statement. “We are delighted that Jakavi showed such promise in this very difficult condition especially since few second-line treatment options exist. These impressive results will be part of our regulatory submissions seeking approval in Europe and other countries.”

The randomized, open-label, multicenter REACH2 trial (NCT02913261) is continuing to explore the use of ruxolitinib in comparison with the best available therapy in patients with corticosteroid-refractory aGVHD following allogeneic stem cell transplantation. Further results from the trial are expected to be presented at an upcoming medical meeting.

The trial has enrolled about 310 patients ≥12 years with grade 2 to 4 aGVHD that required the use of systemic immune suppressive therapy. Eligible patients must have required an increase in their corticosteroid dose or have failed to taper the dose to below 0.5 mg/kg/day for at least 7 days. Patients who have received more than 1 systemic treatment for steroid-refractory aGVHD, as well as those with uncontrolled infections or relapsed primary malignancies, were ineligible for the trial.

Secondary endpoints for the trial include durable ORR, duration of response, cumulative steroid dose, overall survival, event-free survival, failure-free survival, non-relapse mortality, malignancy relapse rate, incidence of chronic graft-versus-host disease, pharmacokinetics, and patient-reported outcomes.

As of the initial analysis of the REACH2 trial, no new safety signals have been observed that treatment-related adverse events reported in the trial have been consistent with the known safety profile of ruxolitinib.

Ruxolitinib was FDA approvedfor the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory aGVHD in May 2019 based on the results of the phase II REACH1 trial.

In the REACH1 trial, ruxolitinib in combination with corticosteroids induced an ORR of 57% at day 28 in patients with steroid-refractory aGVHD, including a complete response rate of 31%.2

The trial included 71 patients aged ≥12 years old who had received allogeneic hematopoietic stem cell transplantation and developed grade 2 to 4 steroid-refractory aGVHD. All of the patients had received 1 systemic treatment regimen beyond corticosteroids for aGVHD.

Among the 39 patients who responded to ruxolitinib treatment by day 28, the median duration of response had not been reached. The 3- and 6-month event-free survival probability estimates were 79.0% (95% CI, 62.3%-88.9%) and 67.0% (95% CI, 47.3%-80.7%), respectively. The median time to response was 7 days (range, 6-49).

The most commonly reported adverse events among all 71 patients were infections (55%) and edema (51%); the most common laboratory abnormalities were anemia (75%), thrombocytopenia (75%), and neutropenia (58%). Nine patients had cytomegalovirus infection, 4 had viremia, and 1 had chorioretinitis. Two patients died from sepsis and pulmonary hemorrhage) related to treatment-emergent adverse events.

Additionally, the JAK inhibitor is being explored for the treatment of patients with steroid-refractory chronic graft-versus-host disease in the ongoing phase III REACH3 trial, and results are expected to be released from the study in 2020.

References

1. Novartis announces that Jakavi® (ruxolitinib) meets primary endpoint in Phase III study of acute graft-versus-host disease [news release]. Basel: Novartis; October 16, 2019. https://bit.ly/2MiRVWE. Accessed October 16, 2019.
2. Jagasia M, Perales M-A, Schroeder MA, et al. Results from REACH1, a single-arm phase 2 study of ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 601.