FDA Extends Review Period for Ruxolitinib in GVHD

Steven Stein, MD

The FDA has added 3 months to the review period for a supplemental new drug application (sNDA) for ruxolitinib (Jakafi) for the treatment of patients with acute graft-versus-host disease (aGVHD) who have had an inadequate response to corticosteroids, making the new action date May 24, 2019.

The extension will allow ample time for the FDA to review additional data the agency requested from Incyte, the manufacturer of the JAK1/JAK2 inhibitor ruxolitinib. The sNDA, which previously received a priority review, is based on results from the pivotal phase II REACH1 trial, in which ruxolitinib combined with corticosteroids induced an overall response rate (ORR) of 55% at day 28 in patients with steroid-refractory aGVHD, meeting the primary endpoint of the study. Additionally, 52 patients had a response at any time point in the study, translating to a best overall response rate (ORR) of 73%.

“We remain confident in the data supporting our sNDA submission and look forward to continued dialogue with the FDA throughout the review process,” Steven Stein, MD, chief medical officer, Incyte, said in a statement. “We are committed to bringing ruxolitinib forward as a treatment option for patients with acute GVHD.”

The open-label, single-cohort, multicenter phase II REACH1 study accrued patients aged ≥12 years old who had received allogeneic hematopoietic stem cell transplantation and developed grade 2 to 4 steroid-refractory aGVHD. Patients had received at most 1 systemic treatment beyond corticosteroids for aGVHD.

Patients were treated with 5 mg of ruxolitinib twice daily, which could be increased to 10 mg twice daily if no cytopenias occurred. ORR at day 28 was the primary endpoint, with duration of response as the key secondary endpoint.

At the April 2, 2018, data cutoff for the primary analysis, 71 patients had received at least 1 dose of ruxolitinib. There was nearly an even number of male and female patients, and the mean age was 52.9 years (range, 18-73). At 28.2% each, acute myeloid leukemia and myelodysplastic syndrome were the most common primary malignancies.

Overall, 80.3% of patients received peripheral blood stem cells, 18.3% received bone marrow, and 1.4% received cord blood as the stem cell source. At baseline 32.4%, 47.9%, and 19.7% of patients had grade II, III, and IV aGVHD, respectively. Half (50.7%) of patients had ≥2 organs involved. At the data cutoff, treatment was ongoing in 23.9% of patients (n = 17).

The ORR at day 28 was 54.9% (n = 39; 95%, CI, 42.7%-66.8%), including a complete response (CR) rate of 26.8% (n = 19), a very good partial response rate of 9.9% (n = 7), and a partial response rate of 18.3% (n = 13). Responses were observed regardless of grade or steroid-refractory criteria. The ORRs were 82.6% (19/23), 41.2% (14/34), and 42.9% (6/14), among patients with grade 2, 3, and 4 aGVHD, respectively.

Among the 39 patients who responded 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 7.0 days (range, 6-49).

The most frequently observed grade 3/4 treatment-emergent adverse events (TEAEs) were anemia (46.5%), decreased platelet count (38.1%), decreased neutrophil count (31.0%), hypokalemia (18.3%), and peripheral edema (11.3%). Nine patients had cytomegalovirus infection, 4 had viremia, and 1 had chorioretinitis. There were 2 patient deaths (sepsis, pulmonary hemorrhage) related to TEAEs.

The FDA granted a breakthrough therapy designation to ruxolitinib in June 2016 for the treatment of patients with aGVHD. Ruxolitinib is currently approved by the FDA as a treatment for patients with polycythemia vera who are intolerant of or have an inadequate response to hydroxyurea. The JAK1/JAK2 inhibitor also has an FDA-approved indication for the treatment of patients with intermediate or high-risk myelofibrosis.

The ongoing REACH program also includes the phase III REACH2 trial (NCT02913261), comparing ruxolitinib versus best available therapy in patients with corticosteroid-refractory aGVHD after ASCT, as well as the phase III REACH3 trial (NCT03112603) examining ruxolitinib versus best available therapy in patients with corticosteroid-refractory chronic GVHD after bone marrow transplantation.

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.