Primary results from Equator, a Phase 3 double-blind, randomized placebo-controlled study evaluating itolizumab in combination with corticosteroids as initial treatment of acute graft-versus-host disease.

Abstract Introduction: Itolizumab is a non-depleting, monoclonal antibody against CD6 that blocks its interaction with activated leukocyte cell adhesion molecule (ALCAM), thereby inhibiting T effector (Teff) cell activity and trafficking to inflamed organs. Here we present primary analysis results from EQUATOR (NCT05263999), a global, Phase 3 study of itolizumab in combination with corticosteroids (CS) to treat subjects as first line treatment for aGVHD. The primary analysis occurred when subjects completed through Day 29. Methods: EQUATOR planned to enroll 200 subjects aged ≥12 but was terminated early for financial reasons. 158 adult subjects with high-risk aGVHD, defined as Grade III-IV or Grade II with lower gastrointestinal (LGI) involvement were randomized within 72 hours of initiating CS treatment, to receive either itolizumab (1.6 mg/kg x1 followed by 0.8 mg/kg x6 doses q2 weeks[w]) or placebo (7 doses q2w). Subjects were followed for up to 1 year. Day 29 complete response (CR) was the primary endpoint; key secondary endpoints were Day 29 overall response rate (ORR) and Durable CR (DCR, defined as CR from Day 29-99). Additional secondary endpoints included duration of CR, failure-free survival (FFS), overall survival (OS), and mortality (NRM). Primary and key secondary endpoints analyses were evaluated in the intent-to-treat (ITT) population (all randomized subjects). The modified ITT (mITT) population (randomized subjects who received ≥1 dose; itolizumab [n=78], placebo [n=77]) was used for all other efficacy analyses. Results: Baseline characteristics were similar between treatment arms. The median subject age was 59 (range: 18-75); 53% were male; 75% had Grade 3-4 aGVHD, and 92% had LGI involvement. In the ITT population, Day 29 CR rates were 43.0% and 48.1% for itolizumab and placebo, respectively, a non-statistically significant difference (p=0.774, one-sided, NS). The ORR at Day 29 was 62.0% vs 54.4% for itolizumab vs placebo (p=0.404, NS). Although not statistically significant, a meaningful increase in the key secondary endpoint DCR was observed for itolizumab vs placebo (29.7% vs 16.2%, p=0.058, NS). The median duration of CR was 336.0 (84.0, NE) days for itolizumab and 72.0 (40.0, 332.0) days for placebo (Hazard ratio [HR] 0.38, p=0.017). FFS was significantly improved in subjects treated with itolizumab vs placebo (HR 0.66, p=0.043). Steroid tapering, per investigator discretion, was similar for both groups with a mean reduction in steroids by Day 99 of -1.6 mg/kg and -1.5 mg/kg for itolizumab and placebo, respectively. There were fewer deaths with itolizumab than placebo (19 vs 25), which resulted in 1-year OS rates for itolizumab and placebo of 66.7% and 49.6%, respectively (p=0.375, NS). Primary disease relapse rate was similar between both groups (6 itolizumab vs 7 placebo subjects), leading to 1-year NRM rates of 28.9% for itolizumab and 41.7% for placebo (p=0.282, NS). 152 (98%) subjects experienced at least 1 adverse event (AE), as expected in this very ill population. Treatment-related AEs were reported by 27 (34.6%) itolizumab subjects and 14 (18.2%) placebo subjects. The most common related AEs were infusion related reaction and lymphocyte count decrease, occurring more frequently in itolizumab treated subjects. Serious AEs (SAE) occurred in 45 itolizumab subjects (58%) and 47 placebo subjects (61%). The most common SAEs were infections reported by 22 (28%) itolizumab subjects and 29 (38%) placebo subjects. Conclusions: In this prematurely terminated study, the primary endpoint of Day 29 CR did not meet statistical significance. However, there were statistically significant and clinically relevant beneficial prolongation of responses for itolizumab treated subjects in the pre-specified secondary endpoints of duration of CR and FFS. Additionally, OS and NRM were numerically better in the itolizumab group. Importantly, no safety concerns were noted for itolizumab. The primary analysis highlights the beneficial risk profile of itolizumab and suggests that the improved durability of response in treated patients may offer a meaningful benefit.