O082 - KD025 FOR PATIENTS WITH CHRONIC GRAFT-VERSUS-HOST DISEASE (CGVHD) - LONG-TERM FOLLOW-UP OF A PHASE 2A STUDY (KD025-208) (ID 1131)
- C. Bachier
- A. Salhotra
- A. Lazaryan
- B. Zoghi
- D. Weisdorf
- J. Essell
- L. Green
- O. Schueller
- Z. Yang
- D. Eiznhamer
- S. Aggarwal
- B. Blazar
- S. Lee
- M. Jagasia
Background: 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 (C) (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 were enrolled in C1, C2, and C3. As of 30Jun19, median duration of follow up was 30, 26 and 19 months (mos) respectively. Median age was 52 yrs, median time from cGVHD diagnosis was 20 mos, and median prior lines of therapy was 2. The median duration of treatment was 9, 8, and 9 mos, respectively. 11 pts remained on KD025. Reasons for discontinuation included cGVHD progression (20), voluntary withdrawal (7), relapse of underlying disease (6), investigator decision (5), AE (3), and death (2).
ORR [95% CI] was 65% [38, 86] 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 66% (23/35) in pts with ≥2 prior lines of therapy, 70% (19/27) in pts with ≥4 organs involved, 60% (25/42) in pts with severe cGVHD, and 63% (22/35) in pts refractory to their previous line. CRs were observed in all affected organs except lung; PRs were observed in lung.
While responses were often achieved within 8 wks, 4/35 responses occurred after 24 wks.
Responses were durable with a Kaplan-Meier (K-M) median DOR of 35 wks across all cohorts. 51% of responders sustained a response for ≥20 wks. FFS at 6, 12, 18 and 24 mos was 76%, 47%, 37% and 32%, respectively.
Baseline median CS dose was 0.2 mg/kg/day (prednisone eq). During treatment, median CS dose was reduced by 50%. 19% of pts discontinued CS completely.
35% of pts reported a clinically meaningful improvement (≥7-point reduction on consecutive visits) in LSS score.
AEs were consistent with those expected in cGVHD pts receiving CS. Common AEs were URI 46%, diarrhea 33%, increased LFTs 33%, nausea 33%, fatigue 32%, dyspnea 30%, and peripheral edema 24%. 56% had a Grade ≥3 AE, the most common was dyspnea 15% and lung infection/pneumonia 15%. < 10% pts experienced Grade 3 anemia, neutropenia, or thrombocytopenia. Three pts discontinued KD025 due to possibly related AEs (C1: diarrhea, headache; C3: fatigue). No apparent increased risk of infection was observed. 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, allowing pts to remain on treatment and realize benefits of sustained therapy.
Clinical Trial Registry: NCT02841995
Disclosure: Lazaryan, Aleksandr (Kadmon); Salhotra, Amandeep (Celgene, Kadmon); Weisdorf, Daniel (Fate, Incyte, Pharmacyclics); Green, Laurie (Kadmon); Schueller, Olivier (Kadmon); Yang, Zhongming (Kadmon); Eiznhamer, David (Kadmon); Aggarwal, Sanjay K (Kadmon); Blazar, Bruce R (Abbvie, Alpine, Blue Rock, Children´s Cancer Research, Fate, Five Prime, Kid´s First, Kadmon, Leukemia/Lymphoma, Magenta, Regeneron, RXi, Tmunity); Lee, Stephanie J (Amgen, Astra Zeneca, Incyte, Kadmon, Millenium, Novartis, Pfizer, Syndax)