Key opinion leader, Yi-Bin Chen, MD, summarizes the clinical trial data supporting the recent FDA approval of ruxolitinib for the treatment of steroid-refractory acute GVHD and provides insights on a potential future role for ruxolitinib in steroid-refractory chronic GVHD.
Yi-Bin Chen, MD: I'm now going to transition to talk about ruxolitinib specifically. A lot of the progress over the last few years in graft versus host disease is due to the results we've seen from clinical trials involving ruxolitinib and the major trials the REACH1, REACH2, and REACH3 trials, respectively. These are large multicenter trials which are not so common in our field here. The company [Kadmon] and the investigators really should be applauded for carrying these out. Trials in graft versus host disease are difficult to do. Patients are sick and they're heterogeneous, but these trials, which have been now presented and published, have pushed us a step forward, and we hope more progress is on the way.
REACH1 was a phase 2 single-arm trial carried out at several centers across the United States that involved 71 patients with steroid-refractory acute graft versus host disease (aGVHD) and treated these patients with ruxolitinib. Patients were given a dose of ruxolitinib of 5 mg twice a day to start, and if after 3 days they tolerated it, the dose was increased to 10 mg twice a day. The primary end point in this trial was a 28-day overall response rate (ORR). That's the consensually agreed-upon primary end point, as it has been shown that that generally correlates with long-term outcomes of 6 months overall survival (OS) and non-relapse mortality (NRM). The overall response rate in REACH1 was 55% with 27% of patients achieving a complete remission. The best overall response rate at any time in these patients who received any doses of ruxolitinib was over 73%, and at 6 months, the overall survival was about 50% of patients. And in this high-risk population, responses were seen across all organ manifestations in general, the skin, GI [gastrointestinal] tract, and the liver. All of us who collaborated on this trial or saw the results were impressed with what we had seen. It was on the strength of this study that ruxolitinib was FDA-approved for steroid-refractory acute GVHD in patients 12 and older.
REACH2 was a great validation of the REACH1 results. REACH2 was a phase 3 international trial, and it involved 309 patients with steroid-refractory aGVHD. Patients were randomized to either ruxolitinib at 10 mg twice a day versus a control arm that was summarized as BAT, or best available therapy. The study had to do it this way. They couldn't pick one control because there is no one international standard for treating steroid-refractory aGVHD. Centers were allowed to choose among 9 commonly used options, and they were combined together to form the BAT control group. Again, the primary end point was day 28 overall response rate and this favored ruxolitinib at 62% vs 39%. When looking at the secondary end points of durable response rate at day 56, after 8 weeks on the trial, median overall survival showed a benefit as to what had been seen in REACH1 and REACH2 showed that the main adverse events were cytopenias and thrombocytopenia and possibly an increase in the reactivation of cytomegalovirus, or CMV. These results are impressive. A phase 3 study in steroid-refractory aGVHD, that was a positive result compared to a reasonable control. It should be emphasized that the durable response rate at 8 weeks, while it was 40%, which was about twice as much as the control, 40% still leaves much room for improvement here. And much more research has to be done to ultimately help these patients optimally. That's where we stand for steroid-refractory aGVHD. More agents are on the way as we do more and more trials, but the REACH1 and REACH2 trials have given us a standard. It has led to thinking, as more agents are studied, we now have a control—that is ruxolitinib—and a benchmark to better design future randomized trials. We've thought about how we are going to define graft-vs-host disease that is perhaps refractory to ruxolitinib, and is it that different than steroid-refractory aGVHD? But the approval has certainly given patients more access to an efficacious agent and certainly helped in chronic graft versus host disease (cGVHD).
The main study was REACH3, and that's been recently presented in abstract form, and we look forward to its full publication shortly. REACH3 was a phase 3 international study involving about 329 patients. The eligible patients were adults with steroid-refractory cGVHD, and patients were randomized to ruxolitinib again, to a best available therapy or BAT arm. And investigators were able to choose from a variety of options that they commonly used to treat steroid-refractory cGVHD. The primary end point here was a 6-month overall response rate. This cGVHD, so you have to give more time to observe a response and give more time for your agents to work. Again, the analysis favored patients who received ruxolitinib who had a 50% overall response rate at 6 months versus 26% in the control arm of best available therapy. It's worth pointing out that the minority of these responses under 7%, there were complete remissions which is not surprising and unfortunate for cGVHD. The secondary end points were failure free survival, which also favored the ruxolitinib arm significantly as well as a reduction in symptoms which so cGVHD we have to include now patient reported outcomes because that's hugely, hugely important for these patients who will deal with this disease chronically in the long run. On the strength of this study, we hope that ruxolitinib gains approval from regulatory agencies to treat steroid-refractory cGVHD, and we look forward to that hopefully this year in 2021. Our patients can gain more access. It certainly has brought about responses in many patients that we treat these days, that we're able to use the drug for. And we do believe it has a place in the treatment for cGVHD.
This transcript has been edited for clarity.