Ruxolitinib outperforms the current best available therapy for patients with steroid-refractory/dependent chronic graft-versus-host disease

The REACH3 study is the first successful randomised phase III trial in adolescent and adult patients with chronic graft-versus-host disease (cGVHD) with an inadequate response to steroids. In this trial, ruxolitinib demonstrated superior efficacy over the current best available therapy for these patients, with a significantly higher response rate and significant improvements in failure-free survival, symptoms and response.

Background

Chronic graft-versus-host disease (cGVHD) occurs in approximately 30-70% of patients who undergo an allogeneic stem cell transplantation and is a leading cause of non-relapse mortality and morbidity. The standard first-line treatment for cGVHD consists of systemic steroids, but after a while about 50% of patients will become steroid refractory or dependent. Thus far, no standard second-line treatment has been defined for cGVHD patients failing on systemic steroids and to date there have been no successful, large-scale, randomised studies in this setting. The phase III REACH3 study evaluates ruxolitinib versus best available therapy (BAT) in patients with steroid refractory/dependent (SR/D) cGVHD. For this trial, investigator-selected BAT could consist of extracorporeal photophoresis, low-dose methotrexate, mycophenolate mofetil, everolimus, sirolimus, infliximab, rituximab, pentostatin, imatinib or ibrutinib. Eligible patients had to be at least 12 years old, underwent an allogeneic hematopoietic cell transplant and developed moderate or severe SR/D cGVHD. A total of 329 patients were randomised (1:1) to ruxolitinib (10 mg, twice daily) or BAT. While on treatment, patients continued to receive their corticosteroids either with or without a calcineurin inhibitor. On or after the first day of cycle 7, patients in the BAT arm who suffered disease progression, had a mixed or unchanged response, developed toxicity to BAT or experienced a cGVHD flare could cross over to ruxolitinib.

Results

At the primary analysis, twice as much ruxolitinib-treated patients remained on treatment compared to BAT (50.3% vs. 25.6%). The most common reasons for treatment discontinuation on ruxolitinib consisted of adverse events (17,0%), and lack of efficacy (14.5%). With BAT, a lack of efficacy was the predominant reason for treatment discontinuation (42.7%). In total, 37.2% of the patients in the BAT arm crossed over to ruxolitinib. At week 24, the objective response rate was significantly higher in the ruxolitinib arm as compared to BAT at 49.7% and 25.6%, respectively (OR[95%CI]: 2.99[1.86-4.80], p<0.0001). In total, 6.7% of the patients treated with ruxolitinib and 3.0% of the patients treated with BAT obtained a complete response. Also in terms of secondary endpoints ruxolitinib outperformed BAT. First of all, the median failure-free survival (FFS), defined as time to the earliest of recurrence of underlying disease, start of new systemic treatment for cGVHD, or death, was significantly longer among ruxolitinib-treated patients compared to BAT (median not reached vs. 5.7 months; HR[95%CI]: 0.37[0.268-0.510], p<0.0001). Secondly, the modified Lee symptom score (mLSS) responder rate was higher for patients in the ruxolitinib arm (24%) compared to the BAT arm (11%, odds ratio[95%CI]: 2.62[1.42-4.82], p=0.0011). This indicates that patients treated with ruxolitinib experienced significantly greater improvements in their disease symptoms. In addition, also best overall response (76.4% vs. 60.4%; OR[95%CI]: 2.17[1.34-3.52]) and the median response duration (not reached vs. 6.24 months) were clearly in favour of ruxolitinib.

Rates of any-grade adverse events (AEs), grade ≥3 AEs, serious AEs and deaths were similar between treatment arms. In contrast, the incidence of AEs leading to dose modification (37.6% vs. 16.5%) or discontinuation (16.4% vs. 7.0%) was higher with ruxolitinib. The most common AEs (≥ 15%) in the ruxolitinib vs. BAT arms were anaemia (29% vs. 13%), thrombocytopenia (21% vs. 15%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs. 4%). Infections of any type occurred in 64% of ruxolitinib- and 56% of BAT-treated patients, and included fungal (12% vs. 6%), viral (34% vs. 29%), and bacterial (28% vs. 26%) infections. Cytomegalovirus infections or reactivations occurred in 5.5% of patients treated with ruxolitinib and in 8.2% of patients treated with BAT.

Conclusions

Compared to BAT, ruxolitinib induced a significantly higher ORR at week 24 with a significant improvement in FFS and a greater improvement in disease symptoms. Furthermore, a higher best overall response rate with a longer duration of response was observed. The safety profile of ruxolitinib was consistent with previous observations and was in line with what could be expected in patients with cGVHD. In conclusion, ruxolitinib is the first agent to demonstrate superior efficacy to BAT in a phase III trial of patients with cGVHD with an inadequate response to steroids.

Reference

Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study. Presented at ASH 2020; Abstract 77.