Ruxolitinib Hits Primary Endpoint in Phase III Acute GVHD Trial

Peter Langmuir, MD

Ruxolitinib (Jakafi) met the primary endpoint of the phase III REACH2 trial, improving the overall response rate at day 28 versus best available therapy in patients with in patients with steroid-refractory acute graft-versus-host disease (aGVHD).¹

Incyte which develops ruxolitinib with Novartis, reported in a press release that efficacy and safety data from REACH2 would be presented at an upcoming medical meeting. The company also noted that no new safety signals emerged with ruxolitinib in REACH2, with a safety profile similar to previous studies of the JAK1/JAK2 inhibitor in patients with steroid-refractory aGVHD.

“GVHD is a challenging and serious disease, and physicians around the world need access to therapies that can improve outcomes for patients,” Peter Langmuir, MD, group vice president, Targeted Therapies, Incyte, said in the press release. “This positive result of the REACH2 study is excellent news for patients as it further reinforces the potential of ruxolitinib as a treatment option that can provide meaningful results for patients with steroid-refractory acute GVHD.”

The multicenter, open-label, phase III REACH2 trial (NCT02913261) randomized patients with steroid-refractory aGVHD to ruxolitinib or investigator’s choice of best available therapy. Beyond the primary endpoint of ORR at day 28, secondary outcome measures included ORR at day 14, durable ORR at day 56, duration of response, overall survival, and event-free survival.

The FDA approved ruxolitinib (Jakafi) in May 2019 for the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory acute aGVHD, based on data from the phase II REACH1 trial. The study demonstrated that the combination of ruxolitinib with corticosteroids elicited a 57% ORR at day 28 in patients with steroid-refractory aGVHD, with a complete response (CR) rate of 31%.²

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 up to 1 systemic treatment beyond corticosteroids for aGVHD.  Of the 71 patients recruited on the trial, 49 patients were refractory to steroids alone, 12 patients had received ≥2 prior anti-GVHD therapies, and 10 patients did not otherwise meet the steroid-refractory definition by the FDA.

Ruxolitinib was administered at 5 mg twice daily, which could be increased to 10 mg twice daily if no cytopenias occurred. The primary endpoint was ORR at day 28; a key secondary endpoint was duration of response.

At the April 2, 2018, data cutoff for the primary analysis, 71 patients had received ≥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).²

Prior results showed that the ORR at day 28 was 54.9% (n = 39; 95%, CI, 42.7%-66.8%), which included a 26.8% (n = 19) CR rate, a 9.9% (n = 7) very good partial response rate, and an18.3% (n = 13)  partial response rate.³ 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 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 TEAEs.

The ongoing phase III REACH3 trial (NCT03112603) is examining ruxolitinib versus best available therapy in patients with steroid-refractory chronic GVHD after bone marrow transplantation.

Ruxolitinib is also approved by the FDA as a treatment for patients with polycythemia vera who are intolerant of or have an inadequate response to hydroxyurea, as well as for the treatment of patients with intermediate or high-risk myelofibrosis.

References

1. Incyte announces that the REACH2 pivotal trial of ruxolitinib (Jakafi®) meets primary endpoint in patients with steroid-refractory acute graft-versus-host disease. Published October 16, 2019. Accessed October 16, 2019. https://bit.ly/2MLIJZR.
2. FDA approves Jakafi (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. Incyte. Published May 24, 2019. Accessed October 16, 2019. https://bit.ly/2WiRktX.
3. 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.