Dynamics of Overall and Organ-Specific Responses to Axatilimab in Chronic Graft-Versus-Host Disease: Analysis from the Agave-201 Study
Authors: Choe Hannah , Salhotra Amandeep , Farhadfar Nosha , Kwon Mi , Thomas Britnie , Radojcic Vedran , Tian Chuan , Lou Shuyuan , Wolff Daniel , Lee Stephanie J. 
Published: December 2024

Introduction: Chronic graft-versus-host disease (cGVHD) is characterized by inflammatory and fibrotic pathology affecting multiple organs and leading to significant impairment. Axatilimab (AXA), an anti-colony-stimulating factor 1 receptor monoclonal antibody, targets monocytes and macrophages that are critical for inflammation and fibrosis in cGVHD. In the pivotal, phase 2 AGAVE-201 study (NCT04710576), AXA had robust clinical activity and was generally well tolerated in patients with cGVHD, with adverse events that were mostly low grade, reversible, and dose dependent (Wolff D, et al. Blood. 2023;142(suppl_1):1). The objective of this secondary analysis was to assess the timing/dynamics of clinical responses and modified Lee Symptom Scale (mLSS) improvements among patients with cGVHD who achieved responses in the first 6 treatment cycles with AXA in AGAVE-201.
Methods: Cumulative incidences of clinical and symptom response dynamics were assessed in patients treated with AXA in AGAVE-201 (0.3 mg/kg once every 2 wk [Q2W], 1 mg/kg Q2W, and 3 mg/kg once every 4 wk). Overall and organ-specific responses were measured using the 2014 National Institutes of Health cGVHD criteria; a ≥7-point improvement in mLSS summary score from baseline was considered clinically meaningful (Teh C, et al. Biol Bone Marrow Transplant. 2020;26(3):562-7).
Results: Baseline demographics and clinical characteristics of the 241 patients in AGAVE-201 were previously described; patients were randomized to AXA 0.3 mg/kg (n=80), 1 mg/kg (n=81), or 3 mg/kg (n=80). Median age was 53 years (range, 7-81 y). Patients had cGVHD for a median of 4.0 years (range, 0.4-17.6 y) and a median of 4 organs involved at baseline, including the skin (80.1%), eyes (75.9%), joints/fascia (67.2%), mouth (46.5%), lungs (44.8%), esophagus (25.3%), liver (16.6%), upper gastrointestinal (GI) tract (11.6%), and lower GI tract (7.5%). Patients received a median of 4 prior therapy lines (range, 2-15), including ruxolitinib (74.3%), ibrutinib (31.1%), and belumosudil (23.2%).
Within the first 6 cycles (nominally 28 d each), 153 patients (63.5%) across all doses achieved an overall response (partial response, n=151 [62.7%]; complete response, n=2 [0.8%]). Overall, 81 (52.9%) patients responded by Day (D) 56 after treatment initiation, 119 (77.8%) by D84, and 149 (97.4%) by D168; all responses were observed by D196. With 0.3 mg/kg, 59 patients (73.7%) achieved an overall response; 31 (52.5%) patients responded by D56, 49 (83.1%) by D84, and 59 (100%) by D168. Median time to overall response on study for all doses was 1.6 months (range, 0.9-8.6 mo).
Within the first 6 cycles, 114 patients (47.3%) overall and 43 (37.7%) with 0.3 mg/kg, had a ≥7-point improvement in mLSS. Among all responders by mLSS, 68 (59.6%) responded by D56, 87 (76.3%) by D84, and 109 (95.6%) by D168. Of those in the 0.3 mg/kg group, 24 (55.8%) responded by D56, 33 (76.7%) by D84, 41 (95.3%) by D168, and 43 (100%) by D224. Overall median time to a ≥7-point mLSS improvement on study for all doses was 1.4 months (range, 0.9-18.5 mo).
Median (range) times, in months, to organ-specific response on study for AXA 0.3 mg/kg and overall, respectively, were most rapid for the lower GI tract (1.2 [1.0-10.5]; 1.2 [1.0-10.5]), esophagus (1.9 [0.9-10.5]; 1.1 [0.9-10.5]), upper GI tract (1.9 [1.0-4.0]; 1.0 [0.9-6.0]), liver (1.9 [0.9-4.4]; 1.9 [0.9-6.1]), and joints/fascia (1.9 [1.0-9.5]; 1.9 [0.9-9.5]). Response times were longer for the lungs (2.0 [1.0-6.7]; 2.6 [1.0-14.8]), and mouth (2.6 [1.0-9.6]; 2.1 [1.0-9.6]), with the longest times to response observed for the eyes (2.9 [1.0-8.5]; 2.7 [1.0-9.1]) and skin (3.7 [1.0-8.3]; 3.2 [1.0-14.4]).
Conclusions: Most patients who achieved an overall clinical response or ≥7-point improvement in mLSS in the first 6 treatment cycles of AGAVE-201 did so by D84. By D56, more than half of responders had clinical responses and reported symptom improvement. Median times to organ-specific responses ranged from 1.0 to 3.7 months across organs; lower GI, upper GI, esophagus, liver, and joints/fascia were fastest to respond, whereas lung, mouth, eye, and skin responses were slower due to the highly fibrotic nature of these organ manifestations. Overall, these data highlight the potential for rapid onset of clinical activity and symptom improvement with AXA in inflammatory and fibrotic manifestations of cGVHD among a heavily pretreated population with longstanding cGVHD.