Kd025 For Patients With Chronic Graft-Versus-Host Disease (Cgvhd) - Long-Term Follow-Up Of A Phase 2a Study (Kd025-208)

Introduction cGVHD exhibits both autoimmune and fibrotic features across multiple organ systems. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. Methods KD025-208 enrolled 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of cGVHD patients (pts) after 1-3 prior lines of therapy. Treatment was until progression or toxicity. Primary endpoint is overall response rate (ORR) per 2014 NIH response criteria. Additional endpoints include Duration of Response (DOR), corticosteroid (CS) dose reductions, Failure Free Survival (FFS) and Lee Symptom Scale (LSS) score. Results 17, 16, and 21 pts enrolled in C1, C2, and C3. As of 8Mar19, median duration of follow up was 112, 97 and 64 weeks (wks) respectively. Median age was 52 yrs, median time from cGVHD diagnosis was 20 mos, and median prior lines of therapy was 2. Median duration of treatment was 37, 33, and 39 wks, respectively. 14 pts remained on KD025. Reasons for discontinuation: cGVHD progression (18), voluntary withdrawal (7), relapse of underlying disease (5), investigator decision (5), AE (3), and death (2). ORR [95% CI] was 65% [38, 85] in C1, 69% [41, 89] in C2, and 62% [38, 82] in C3, 65% [51, 77] across all 3 cohorts. Responses were achieved across key subgroups with ORRs of 62% (24/39) in pts with ≥2 prior lines of therapy, 70% (19/27) in pts with ≥4 organs involved and 60% (25/42) in pts with severe cGVHD, and 65% (22/34) in pts refractory to their previous line. CRs were observed in all affected organs except lung; PRs were observed in lung. Median Time to Response was 8.14 wks (IQR 8-12); 4/35 responses occurred after 24 wks. Responses were durable with a Kaplan-Meier median DOR of 34 wks across all cohorts. 57% of responders sustained a response for ≥20 wks. FFS at 6, 12 and 24 mos was 76%, 47% and 33% respectively. Overall survival was 94%, 91% and 83%. Baseline median CS dose was 0.21 mg/kg/day (prednisone eq). During treatment, median CS dose was reduced by 50%. 20% pts discontinued CS. 52% of pts reported a ≥7-point reduction in LSS with median time to improvement 9 wks. AEs were consistent with those expected in cGVHD pts receiving CS. Common AEs were URI 35%, diarrhea 31%, nausea 31%, fatigue 30%, dyspnea 28%, increased LFTs 24%, and peripheral edema 22%. 63% had a Grade ≥3 AE, the most common was dyspnea, 13%. 2% were dyspnea (7%), lung infection (6%), hypoxia (4%) and flu-like illness (4%). Three pts discontinued KD025 due to possibly related AEs (C1: diarrhea, headache; C3: fatigue). 3 pts died on study (C3: relapse of leukemia; lung infection; cardiac arrest), all considered unrelated to KD025. Conclusions Durable and clinically meaningful responses have been seen across all 3 cohorts. KD025 was well tolerated, with sustained responses and encouraging FFS in patients with advanced cGVHD.