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1 Safety and Efficacy of Axatilimab at 3 Different Doses in Patients with Chronic Graft-Versus-Host Disease (AGAVE-201)

Program: General Sessions
Session: Plenary Scientific Session
Hematology Disease Topics & Pathways:
Research, Biological therapies, clinical trials, Clinical Research, GVHD, Diseases, Immune Disorders, patient-reported outcomes, Therapies, Monoclonal Antibody Therapy
Sunday, December 10, 2023, 2:00 PM-4:00 PM

Daniel Wolff1*, Corey Cutler2,3, Stephanie J. Lee4, Iskra Pusic5, Henrique Bittencourt6, Jennifer White, MD, MSc, FRCPC7*, Mehdi Hamadani, MD8, Sally Arai, MD9, Amandeep Salhotra, MD10, Jose A. Pérez-Simón11, Amin Alousi12*, Hannah Choe, MD13, Mi Kwon14, Arancha Bermúdez15*, Inho Kim16*, Gerard Socié17, Vedran Radojcic18, Timothy O'Toole19*, Chuan Tian20*, Peter Ordentlich19*, Zachariah DeFilipp21 and Carrie L. Kitko, MD22

1University Hospital Regensburg, Regensburg, Germany
2Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Fred Hutchinson Cancer Center, Seattle, WA
5Division of Oncology, Washington University School of Medicine, Saint Louis, MO
6CHU Sainte-Justine, Montreal, Canada
7The University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada
8Division of Hematology and Oncology, The Medical College of Wisconsin Inc, Milwaukee, WI
9Stanford Health Care, Stanford, CA
10Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
11Department of Hematology, Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBIS), CSIC, University of Sevilla, Sevilla, Spain
12Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
13The James Cancer Hospital Solove Research Institute and The Ohio State University Wexner Medical Center, Columbus, OH
14Hospital General Universitario Gregorio Marañón, Madrid, Spain
15Department of Hematology, Hospital Universitario Marqués de Valdecilla, Cantabria, Spain
16Seoul National University Hospital College of Internal Medicine, Seoul, Korea, Republic of (South)
17Hopital St. Louis, Department of Hematology - BMT, Paris, France
18Syndax Pharmaceuticals, Inc., Waltham, MA
19Syndax Pharmaceuticals, Inc, Waltham, MA
20Incyte, Wilmington, DE
21Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA
22Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt University, Nashville, TN

Background: Chronic graft-versus-host disease (cGVHD) is an immune-mediated complication of allogeneic hematopoietic cell transplant (alloHCT) that affects multiple organs with inflammatory and fibrotic pathology, leading to significant patient burden and mortality. Colony-stimulating factor 1 receptor (CSF-1R)–dependent monocytes and macrophages play a key role in cGVHD inflammation and fibrosis. Axatilimab (SNDX-6352) is an investigational, high-affinity anti–CSF-1R monoclonal antibody that targets monocytes and macrophages. We previously demonstrated the biological and clinical activity of axatilimab with organ-specific responses and symptom improvement in a phase 1/2 study (NCT03604692) in patients with cGVHD.
Methods: This pivotal phase 2, open-label, randomized, multicenter study evaluated axatilimab at 3 different doses in alloHCT patients with recurrent or refractory cGVHD (AGAVE-201; NCT04710576). Eligible patients were randomized 1:1:1 to receive intravenous (IV) axatilimab at 0.3 mg/kg every 2 weeks (Q2W), 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Randomization was stratified by severity of cGVHD and prior use of ibrutinib, ruxolitinib, or belumosudil. Concomitant use of corticosteroids, calcineurin inhibitors, or mammalian target of rapamycin inhibitors (sirolimus or everolimus) was allowed. Axatilimab treatment could be continued as long as there was clinical benefit as assessed by the investigator. The primary efficacy endpoint was overall response rate (ORR) in the first 6 cycles (24 weeks) as defined by the NIH 2014 consensus criteria; the efficacy boundary of the ORR is based on the lower bound of the 95% CI exceeding 30%. The key secondary endpoint was the proportion of patients reporting a clinically significant reduction of symptoms, as measured by the modified Lee Symptom Scale (mLSS) score with a threshold of ≥7 points. Safety endpoints included frequency and severity of treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs).
Results: A total of 241 patients were enrolled across 121 study sites and 239 (99.2%) patients were treated with axatilimab at the data cutoff of 7 April 2023. Patients were heavily pretreated with a median of 4 prior lines of therapy, including ruxolitinib (74%), belumosudil (23%), and ibrutinib (31%). Demographics and disease characteristics were balanced among the 3 dose cohorts (Table 1). ORR (95% CI) was 74% (63, 83) with 0.3 mg/kg Q2W, 67% (55, 77) with 1 mg/kg Q2W, and 50% (39, 61) with 3 mg/kg Q4W (Table 1). Median duration of response (DOR) has not been reached in any of the cohorts, with 60%, 60% and 53% of patients maintaining response at 12 months in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. Clinical benefit, as measured by reduction in mLSS score, was reported in 55%, 54%, and 36% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W cohorts, respectively, in the first 6 cycles. Drug discontinuation owing to TEAEs occurred in 6% of patients with 0.3 mg/kg Q2W, 22% with 1 mg/kg Q2W, and 18% with 3 mg/kg Q4W. The most common TEAEs are summarized in Table 2. Fatal TEAEs occurred in 1.3%, 8.6%, and 7.6% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. The frequency of TRAEs and grade ≥ 3 TRAEs were dose dependent, consistent with CSF-1R inhibition-mediated macrophage clearance. Most infections were mild, with 3 reported cytomegalovirus infections, including reactivations, in the higher dose cohorts.
Conclusions: The AGAVE-201 pivotal trial met its primary endpoint for all doses studied. Axatilimab treatment of refractory cGVHD in heavily pretreated patients resulted in robust clinical activity and durable responses in all 3 dose cohorts, with the highest ORR and least toxicity at the 0.3 mg/kg Q2W dose. Adverse events consisted primarily of transient laboratory abnormalities and other on‑target effects known to be associated with CSF-1R block.

Disclosures: Wolff: Novartis: Honoraria, Research Funding; Mallickrodt: Honoraria; Incyte: Honoraria; Sanofi: Honoraria; Behring: Honoraria; Takeda: Honoraria; Gilead: Honoraria. Cutler: Cimeio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Oxford Immune Algorithmics: Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy; Astellas: Consultancy; InhibRx: Consultancy; Pluristem Therapeutics: Other: DSMB; Allovir: Other: Data Safety Monitoring Board (DSMB). Lee: Amgen, AstraZeneca, Incyte, Kadmon, Pfizer, Syndax: Research Funding; Novartis: Other: Steering Committee member; Janssen: Other: Study medication provider; Equillium, Kadmon, Mallinckrodt: Consultancy. Pusic: Incyte: Honoraria; Syndax: Honoraria. White: Novartis: Honoraria. Hamadani: SeaGen: Consultancy; Astra Zeneca: Speakers Bureau; Novartis: Consultancy; MorphoSys: Consultancy; Legend Biotech: Consultancy; Kadmon: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Gamida Cell: Consultancy; BeiGene: Speakers Bureau; Kite, a Gilead Company: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Caribou: Consultancy; Bristol Myers Squibb: Consultancy; Genmab: Consultancy; CRISPR: Consultancy; Omeros: Consultancy; Abbvie: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Myeloid Therapeutics: Honoraria; BeiGene: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; Astellas: Research Funding; Spectrum Pharmaceuticals: Research Funding; Takeda: Research Funding; Genentech: Honoraria. Salhotra: Gilead: Research Funding; Kura Oncology: Research Funding; OrcaBio: Research Funding; Jazz Pharma: Research Funding; Rigel Pharma: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Speakers Bureau; BMS: Research Funding. Choe: Opna: Other: Receipt of equipment, materials, drugs to institution, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs to institution; MJH Life Sciences: Honoraria; Actinium Pharmaceuticals: Other: Support for attending meetings and/or travel; NIH National Cancer Institute: Research Funding. Kwon: Kite-Gilead: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Speakers Bureau. Bermúdez: Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfitzer: Consultancy, Speakers Bureau. Radojcic: Syndax: Current Employment, Current equity holder in publicly-traded company. O'Toole: Syndax: Current Employment, Current equity holder in publicly-traded company. Tian: Incyte: Current Employment, Current holder of stock options in a privately-held company. Ordentlich: Syndax: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Patents assigned to Syndax Pharmaceuticals. DeFilipp: Incyte: Consultancy, Honoraria, Research Funding; Regimmune: Research Funding; Taiho Oncology: Research Funding; Sanofi: Consultancy; MorphoSys: Consultancy, Honoraria; Inhibrx: Consultancy; PharmaBiome AG: Consultancy; Ono Pharmaceuticals: Consultancy. Kitko: Horizon: Membership on an entity's Board of Directors or advisory committees.

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