Robert Zeiser, MD of the University Medical Center, Freiburg Im Breisgau discusses the ASH abstract – 77 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.
REFERENCE:
Systemic corticosteroids are used in routine first-line cGVHD therapy; however, about 50 percent of patients (pts) are refractory or reliant (SR/D) on steroids and need additional treatment. There is no description yet of the best second-line therapy choice.
In a phase 3 trial, RUX, an oral JAK1/2 inhibitor, was superior to BAT in SR acute GVHD (aGVHD) (REACH2). The key review of the REACH3 study (NCT03112603), a phase 3, open-label, randomized study examining RUX vs BAT in pts with cGVHD SR/D, is presented here.Â
AND METHODS:
Qualified pts were around 12 years old, allogeneic hematopoietic cell transplantation was obtained, and moderate or extreme SR/D cGVHD was created. Pts were exempt from moving from aGVHD to cGVHD without tapering steroids. Pts treated with JAK aGVHD inhibitors were permitted if complete response (CR) or partial response (PR) was obtained and JAK inhibitor treatment was discontinued for approximately 8 weeks prior to day 1 of cycle 1. In addition to corticosteroids ± calcineurin inhibitors (CNI), those treated with approximately 2 prior lines of systemic therapy for cGVHD were disqualified.
Pts were randomized (1:1) to RUX 10 mg bid or investigator-selected BAT (10 options) and 6 cycles (cycle = 28 days) were handled. The Pts proceeded to obtain their corticosteroid ± CNI regimen. For infection prevention and treatment, viral prophylaxis and antibiotics were allowed as needed. Only after lack of response, intolerable toxicity, or cGVHD flare was the addition or initiation of a new BAT permitted and was deemed treatment failure. On or after cycle 7 days 1 (C7D1) in pts that did not achieve or sustain CR/PR, established toxicity to BAT, or had a cGVHD flare, crossover from BAT to RUX was permitted.
The overall response rate (ORR) at C7D1 was the primary endpoint. The proportion of pts achieving CR or PR, according to NIH consensus criteria, was described as ORR. Primary secondary endpoints in C7D1 were failure-free survival (FFS; identified as time to earliest recurrence of the underlying disease, onset of new systemic treatment for cGVHD or death) and improvement of symptoms based on change in the adjusted Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]). In the total symptom score, a mLSS responder was described as having achieved a ⇠7-point reduction from baseline. Through an overall hierarchical testing process, the main and key secondary endpoints were alpha-controlled.
RESULTATIONS:
RUX (n = 165) or BAT (n = 164) is randomised to a total of 329 pts. The baseline characteristics of the 2 arms were balanced; 61% were male, and the median age was 49 years (range, 12-76 years). Twelve pts < 18 years of age. Overall, 48% and 52% of pts, respectively, had moderate and serious cGVHD. 125 pts (38 percent) were on randomized treatment at the data cutoff (May 8, 2020) (RUX, 50 percent ; BAT, 26 percent ). RUX and BAT discontinued eighty-two (50 percent) and 122 (74 percent) pts, respectively; 61 (37 percent) had crossed over to RUX. Lack of effectiveness (15 percent RUX vs 43 percent BAT), adverse effects (AEs; 17 percent vs 5 percent), and relapse were among the reasons for discontinuation (5 percent vs 4 percent ).
The study reached its primary endpoint with the interim analysis passing the efficacy threshold (ORR, P = 0.0003). In the RUX arm vs. BAT, ORR was substantially higher at C7D1 (50 percent vs. 26 percent; odds ratio, 2.99; P < 0.0001a); the CR rate with RUX was higher (7 percent vs 3 percent ; Table).
Both primary secondary endpoints showed RUX vs BAT dominance. For RUX-treated pts, FFS was slightly longer (median FFS, not reached vs. 5.7 months; HR, 0.370 [95% CI, 0.268-0.510]; P < 0.0001; figure), and the mLSS response rate was higher (24% vs. 11%; odds ratio, 2.62; P = 0.0011). Overall, 31 RUX (19 percent) and 27 BAT (16 percent) pts died; cGVHD (RUX, n = 22 [13 percent]; BAT, n = 13 [8 percent], including 2 deaths following crossover to RUX) was the major cause of death.
In the 2 guns, AE rates up to C7D1 were comparable (RUX, 98 percent [grade ⇠3, 57 percent]; BAT, 92 percent [grade ⇠3, 58 percent]. Anemia (29 percent vs. 13 percent), hypertension (16 percent vs. 13 percent), pyrexia (16 percent vs. 9 percent), and ALT increase were the most common AEs (about 15 percent) in the RUX vs. BAT arms (15 percent vs 4 percent ). Infections of any sort occurred in 64% of RUX and 56% of BAT pts (19% vs. 18% grade 3, ranking based on Cordonnier et al 2006), and included fungal (12% vs. 6%), viral (34% vs. 29%), and bacterial (28% vs. 26%) infections.
SECTIONS:
This is the first successful RUX phase 3 randomized trial in pts with SR/D cGVHD. RUX showed superior efficacy vs. BAT, assessed by a higher ORR, longer FFS, and greater improvement in symptoms. For moderate or extreme SR/D cGVHD, RUX was successful and its safety profile is consistent with that anticipated for this drug and this population.