Ruxolitinib Effective as Second-Line Therapy for Chronic GvHD

Stephanie Lee, MD, MPH

Approximately 50% of patients with chronic graft versus host disease (GvHD) are refractory or dependent to corticosteroids. Dependent patients will often need additional treatment. The appropriate second-line therapy option has yet to be defined.

The REACH3 trial (NCT03112603) aims to determine the efficacy of ruxolitinib (Jakafi) in this patient population. The trial compares ruxolitinib versus best available therapy. The actual enrollment is 330 participants. The primary end point of the study is the efficacy of the agent versus the best available therapy. Secondary end points include rate of failure-free survival, best overall response, overall response rate, duration of response, overall survival, and cumulative incidence of non-relapse mortality.

A complete response was seen in 7% of patients in the ruxolitinib group versus 3% in the best available therapy group. Partial responses were seen in 43% of the ruxolitinib group and 23% in the best available therapy group, meeting the study’s primary end point.

In an interview with Targeted Oncology, Stephanie Lee, MD, MPH, professor and associate director of the Clinical Research Division at the Fred Hutch Cancer Research Center, reviewed the REACH3 trial in further detail along with the efficacy of ruxolitinib in the chronic graft versus host disease population.

Targeted Oncology: What is the issue with standard of care for chronic GvHD? What therapies have been explored previously in clinical trials to offer a solution?

LEE: I think standard of care for initial therapy is pretty straightforward. Most people would agree at this point in time, it's still steroids. Beyond first line therapy, though, it gets murky. Ibrutinib is currently approved for people who have had at least 1 prior line of therapy. There are a lot of people who cannot receive that drug. And so many, many different agents have been tested. I presented the results from the REACH3 trial which looked at ruxolitinib for second line therapy.

What makes ruxolitinib a good drug to use in this patient population?

This is based on a lot of other data. So, there's obviously preclinical data that suggests it might be helpful in chronic graft versus host disease. And then there's even clinical data. Ruxolitinib is approved for steroid refractory acute graft versus host disease. And we're studying chronic graft versus host disease. But some of the mechanisms may be similar. And in addition, there are other reports suggesting that it might be helpful. But those reports were not randomized clinical trials, like the one that I reported.

Can you explain the study design for REACH-3, and as there anything unique about the patient population enrolled?

I think this was a very well-designed study, which took into account the heterogeneity of practice, really around the world because this was a multinational study. So, it was for patients who had moderate to severe chronic graft versus host disease, who already had first line therapy. So, this was the second line therapy. Participants were randomized, one to one to either receive the ruxolitinib starting at a standard dose, which was 10 milligrams twice a day, versus best available therapy. And I think a lot of thought went into the study design. We know that there's many different practices around the world, within the United States. And so, this was really a nod to the idea that we really don't know what is the best second line therapy. So, there were 10 different agents that the investigators could choose from. And they pre specified which agent they would use for the best available therapy. And then they were randomized to either receive that best available therapy or ruxolitinib. Crossover was not allowed until 6 months, which is when the primary end point was, so it was a fairly clean study. And I think this is very generalizable to how we are taking care of chronic GvHD. So, I want to acknowledge that the study really did try to balance controlling and rigor and everything, and they did a good job with that, but also acknowledge the heterogeneity of practice.

Can you give some specifics on the results that you presented? 

The primary end point, which was the overall response rate, which was superior in the ruxolitinib arm compared to the best available therapy arm. Also, the key secondary end points, which was the failure free survival. That's the time until you have to start a new agent or relapse or death. And then the other key secondary end point was the patient reported outcomes. This trial was positive for all of those end points. Ruxolitinib was superior to best available therapy.

What are the implications of these data for the treatment landscape?

Well, I think a lot of people were already using ruxolitinib based on the data that we had available, I think just shows in a much more rigorous trial, that it is very effective in this indication for second line therapy. This is a registration trial, they will be putting it forth for FDA approval, and if approved, it would be the second drug that would be approved for chronic graft versus host disease.

There were other data presented at this conference by other doctors, one in particular about the use of ruxolitinib in chronic GvHD for children. Can you give a key takeaway about what the impact will be for ruxolitinib as it continues to be developed in all of these different settings?

I think that once you show effectiveness in a big adult population, of course, you're going to be looking at other populations, and children are a key population. That study and other studies are ongoing to look at it. I think, also remember that this is currently a study of second line therapy. And so, I think there'll be subsequent reports about different kinds of chronic GvHD, manifestations, and even later lines of therapy. So, now that we've shown that it can be effective in this in this indication, I think there's a lot of enthusiasm for looking at it in other different populations and contexts.

_REFERENCE:

_{Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med 2021; 385:228-238 DOI: 10.1056/NEJMoa2033122}