REACH3 Trial: Approval of Ruxolitinib in Chronic GVHD

Transcript:
Yi-Bin Chen, MD: The role of ruxolitinib in treating steroid-refractory chronic graft-vs-host disease has gone back over a few years. With its approval in myeloproliferative neoplasms and then in steroid-refractory acute graft-vs-host disease, there was available commercial access, and there’s enough in vitro evidence that it might work in chronic graft-vs-host disease as well. Some of our colleagues, as well as ourselves, had started using it anecdotally because of the lack of any approved agents in chronic graft-vs-host disease. This was met with a good amount of success, though not in an organized way. It motivated colleagues and collaborators at Incyte to conduct the REACH3 trial.

REACH3 was a large international phase 3 open-label randomized trial whose primary purpose was to evaluate the efficacy of ruxolitinib in steroid-refractory chronic graft-vs-host disease compared with the standard of care. That’s the first question: what’s the standard of care? Because we all think we know best, people across the world can never agree on 1 standard of care at that juncture. The control arm for REACH3 was something called best-available care or best-available therapy, and a list of options was provided to investigators to choose, in terms of comparing with ruxolitinib.

Eligible patients were patients 12 years or older, so it includes the older pediatric population. Patients had to have moderate or severe glucocorticoid-refractory or dependent chronic graft-vs-host disease to qualify. They were randomized between ruxolitinib at a dosage of 10 mg twice a day vs whichever best-available therapy was prespecified prior to randomization. The primary end point of this study was overall response, which means complete or partial response at week 24 of the study—about 6 months after starting therapy. The key secondary end points were a composite end point called failure-free survival and a quality-of-life measure on the modified Lee Symptom Scale.

It’s difficult to emphasize how pioneering this study was. We haven’t had many phase 3 randomized studies in the field of transplant, much less focused on steroid-refractory chronic graft-vs-host disease. If you look at the graft-vs-host decease literature in general, it’s littered with anecdotal case series and, at most, phase 2 single-arm studies that show a certain amount of efficacy. But many of these studies, when taken to the few phase 3 studies that have been done, showed no difference or improvement. That’s hampered our improvement over the last 3 or 4 decades in this field. The investigators for REACH3 should be congratulated for their achievement in putting together and conducting this trial.

The results showed that 329 patients were randomized to ruxolitinib or best-available therapy. The best-available therapy was a good representation of what we used in the past. It included photo-apheresis, ibrutinib, low-dose methotrexate, and rituximab—everything that we had used in the past for the treatment of steroid-refractory chronic graft-vs-host disease. When the results were published in the New England Journal of Medicine in 2021, the overall response at week 24, which is the primary end point, was far greater in the ruxolitinib group to the tune of 50% vs 25%. In terms of the key secondary end points, patients who received ruxolitinib had a much longer median failure-free survival. Observed in ruxolitinib was greater than 1.5 years vs less than 6 months in the control group. When looking at the modified Lee Symptom Scale, patients who received ruxolitinib had a much higher improvement in their subjective quality of life.

There were no real differences in the short follow-up for overall survival. That’s not surprising in this population of chronic graft-vs-host disease. There isn’t a significant amount of up-front mortality or quick mortality from this condition. It’s important to point out that when the patient-reported outcomes, such as the modified Lee Symptom Scale, were updated, analyzed, and presented at this year’s ASH [American Society of Hematology Annual Meeting], even if we’re looking at patients who had a response, these patients enjoyed a response in the first 6 months. Patients who received ruxolitinib had significantly higher and better changes in the modified Lee Symptom Scale. The quality of their response compared with control was much better. This was on the heels of this study. It validated many of our practices, which have shifted to using ruxolitinib in second-line therapy for chronic graft-vs-host disease and ultimately resulted in regulatory approval, which gave access to more of our patients.

Transcript edited for clarity.