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Clinical Trial
. 2023 Apr 1;41(10):1864-1875.
doi: 10.1200/JCO.22.00958. Epub 2022 Dec 2.

Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study

Carrie L Kitko  1 , Mukta Arora  2 , Zachariah DeFilipp  3 , Mohammad Abu Zaid  4 , Antonio Di Stasi  5 , Vedran Radojcic  6   7 , Courtney B Betts  8 , Lisa M Coussens  8 , Michael L Meyers  7 , Hope Qamoos  7   9 , Peter Ordentlich  7 , Vinit Kumar  7   10 , Christine Quaranto  7   11 , Aaron Schmitt  7 , Yu Gu  7 , Bruce R Blazar  12 , Trent P Wang  13 , Amandeep Salhotra  14 , Iskra Pusic  15 , Madan Jagasia  16 , Stephanie J Lee  17
Affiliations
Clinical Trial

Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study

Carrie L Kitko et al. J Clin Oncol. .

Abstract

Purpose: Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development.

Patients and methods: This phase I (phI)/phase II (phII) open-label study (ClinicalTrials.gov identifier: NCT03604692) evaluated safety, tolerability, and efficacy of axatilimab in patients age ≥ 6 years with active cGVHD after ≥ 2 prior systemic therapy lines. Primary objectives in phI were to identify the optimal biologic and recommended phII dose and in phII to evaluate the overall (complete and partial) response rate (ORR) at the start of treatment cycle 7.

Results: Forty enrolled patients (17 phI; 23 phII) received at least one axatilimab dose. In phI, a dose of 3 mg/kg given once every 4 weeks met the optimal biologic dose definition. Two dose-limiting toxicities occurred at the 3 mg/kg dose given once every 2 weeks. At least one treatment-related adverse event (TRAE) was observed in 30 patients with grade ≥ 3 TRAEs in eight patients, the majority known on-target effects of CSF-1R inhibition. No cytomegalovirus reactivations occurred. With the 50% ORR at cycle 7 day 1, the phII cohort met the primary efficacy end point. Furthermore, the ORR in the first six cycles, an end point supporting regulatory approvals, was 82%. Responses were seen in all affected organs regardless of prior therapy. Fifty-eight percent of patients reported significant improvement in cGVHD-related symptoms using the Lee Symptom Scale. On-target activity of axatilimab was suggested by the decrease in skin CSF-1R-expressing macrophages.

Conclusion: Targeting profibrotic macrophages with axatilimab is a therapeutically promising novel strategy with a favorable safety profile for refractory cGVHD.

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Conflict of interest statement

Carrie L. KitkoConsulting or Advisory Role: Horizon TherapeuticsTravel, Accommodations, Expenses: Mallinckrodt Mukta AroraEmployment: AmgenStock and Other Ownership Interests: AmgenResearch Funding: Syndax (Inst), Kadmon (Inst), Pharmacyclics (Inst) Zachariah DeFilippConsulting or Advisory Role: Kadmon, Omeros, Incyte, MorphoSysResearch Funding: Incyte, REGiMMUNE, Taiho Oncology Mohammad Abu ZaidStock and Other Ownership Interests: Pieris PharmaceuticalsConsulting or Advisory Role: Syndax, Ossium HealthResearch Funding: Syndax (Inst), Pharmacyclics (Inst), Janssen (Inst), Incyte (Inst), AlloVir (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/1350343 Vedran RadojcicEmployment: Syndax Pharmaceuticals, IncStock and Other Ownership Interests: Syndax Pharmaceuticals, IncConsulting or Advisory Role: Regeneron, AllakosOpen Payments Link: https://openpaymentsdata.cms.gov/physician/114735 Courtney B. BettsOther Relationship: Akoya Biosciences Lisa M. CoussensEmployment: Oregon Health & Science University (OHSU)Honoraria: Lustgarten Foundation for Pancreatic Cancer Research, Syndax, Carisma Therapeutics, Verseau Therapeutics, Inc, Scientific Advisory Board, Zymeworks, CytomX Therapeutics, Inc, Kineta Inc, Starr Cancer Consortium, Therapeutics Working Group:, Susan G Komen Foundation, Komen Scholar, AACR: Cancer Immunology ResearchConsulting or Advisory Role: Cell Signaling Technologies, Pharmacyclics, CytomX Therapeutics, Carisma Therapeutics, Verseau Therapeutics, Zymeworks, Kineta, Inc, AbbVie, Shasqi Inc, HiberCell, Alkermes, AstraZeneca Partner of Choice Network, OHSU site leader:, Genenta Science, Susan G Komen Foundation, Komen Scholar, Syndax, PDX Pharmaceuticals, Inc, Pio Therapeutics Pty LtdResearch Funding: Syndax, Pharmacyclics, Cell Signaling Technologies, Innate Pharma, Acerta Pharma (Inst), Susan G. Komen for the Cure (Inst), ZellBio, Inc, HiberCellOther Relationship: Prospect Creek Foundation, Lustgarten Foundation for Pancreatic Cancer Research, (P30) Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology (2012-present; honorarium), (P30) Salk Institute Cancer Center (2016-2020; honorarium), Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (2016-present; honorarium), Dana Farber Cancer Center Breast SPORE (2017-present; honorarium), (P30) Dana Farber/Harvard Cancer Center (2019-present; honorarium), (P30) University of California, San Diego Moores Cancer Center (2019-present; honorarium), Cancer Research Institute (CRI; 2013-present; unpaid), The V Foundation for Cancer Research (2013-present; unpaid), Starr Cancer Consortium (2011-present, honorarium), Therapeutics Working Group (2019-present; paid), NIH/NCI-Frederick National Laboratory Advisory Committee (FNLAC; 2016-present; daily honorarium), Susan G Komen Foundation, Komen Scholar (2020-2023; honorarium), (P50) Dana Farber Cancer Center Breast SPORE, (P30) The Jackson Laboratory Cancer Center, (P01) Columbia University Medical Center, Prostate P01, (P50) MDACC GI SPORE, American Association for Cancer Research, AACR: Cancer Discovery, Cancer Cell, National Foundation for Cancer Research Michael L. MeyersEmployment: SyndaxLeadership: SyndaxStock and Other Ownership Interests: Syndax, Nuvalent, IncConsulting or Advisory Role: Syndax, Nuvalent, IncPatents, Royalties, Other Intellectual Property: Syndax, Nuvalent, Inc Peter OrdentlichEmployment: SyndaxLeadership: SyndaxStock and Other Ownership Interests: SyndaxConsulting or Advisory Role: Patrys, Twentyeight-Seven TherapeuticsPatents, Royalties, Other Intellectual Property: Issued patents and patents pending Christine QuarantoEmployment: Syndax, Aerovate TherapeuticsStock and Other Ownership Interests: Syndax Pharmaceuticals, Aerovate Therapeutics Aaron SchmittEmployment: Syndax Pharmaceuticals IncStock and Other Ownership Interests: Syndax Yu GuEmployment: Syndax, AstraZenecaStock and Other Ownership Interests: Syndax, AstraZeneca Bruce R. BlazarStock and Other Ownership Interests: BlueRock Therapeutics, Tmunity Therapeutics, Inc, Magenta TherapeuticsConsulting or Advisory Role: BlueRock Therapeutics, Magenta Therapeutics, Obsidian Therapeutics, Editas MedicineResearch Funding: BlueRock Therapeutics, Rheos Medicines, Équilibre Biopharmaceuticals Corp, Carisma TherapeuticsPatents, Royalties, Other Intellectual Property: Inducible regulatory T-cell generation for hematopoietic cell transplants (UMN Z09026), US 9,228,172, TALEN-based gene correction, Patent No. 9,393,257, Generation of natural killer cells and lymphoid tissue inducer–like (LTI-like) NK-22 cells, 9,862,928, Method for correcting a genetic sequence, 10,648,002Travel, Accommodations, Expenses: Incyte, Magenta Therapeutics, Rheos Medicines Amandeep SalhotraConsulting or Advisory Role: Kadmon, Syros Pharmaceuticals, SobiResearch Funding: Bristol Myers Squibb Iskra PusicConsulting or Advisory Role: Kadmon, Incyte, Syndax Madan JagasiaEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsConsulting or Advisory Role: Kadmon Stephanie J. LeeHonoraria: Wolters Kluwer, PERConsulting or Advisory Role: EMD Serono, Pfizer, 4SC, Mallinckrodt/Therakos, Almirall Hermal GmbH, Rain Therapeutics, Kadmon, EquilliumResearch Funding: Kadmon, Amgen, Bristol Myers Squibb, EMD Serono, Incyte, Syndax, Pfizer, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent pending for high-affinity T-cell receptors that target the Merkel polyomavirusOther Relationship: National Marrow Donor Program, Society for Investigative Dermatology (SID)No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Study schema.
FIG 2.
FIG 2.
Clinical efficacy of axatilimab. (A and B) Axatilimab treatment leads to responses in a heavily pretreated patient population. Bar graphs show (A) overall response rate at cycle 7 day 1 (primary end point of the phII study portion) in the phII patient cohort and (B) overall response rate by cycle 7 day 1 (regulatory approval end point) for both phII patients and all patients combined. (C) The swimmer lane plot bars show individual patients treated in the phII cohort and temporal relationship of their outcomes to the treatment initiation and response durability. Teal triangles indicate patients who continue on the study, orange diamonds indicate PR, red circles indicate cGVHD progression, and purple stars show adverse events leading to treatment discontinuation. (D) FFS (defined as time from first dose of axatilimab to unequivocal progression of cGVHD, addition of another systemic immunosuppression, discontinuation of axatilimab because of toxicity, relapse of underlying malignancy, or death for any reason) in patients with recurrent or refractory active cGVHD. (E) Axatilimab induces responses in all cGVHD-involved organs. Bars show cumulative response rate on the basis of observations at any point on study and highlight PR and CRs. Lung responses are based on %FEV1 if test results were available (pulmonary function testing was not mandated by the study protocol; 1 of 5 responders) and/or symptom score improvement. cGVHD, chronic graft-versus-host disease; CR, complete response; FFS, failure-free survival; NE, not evaluable; NR, not reached; PR, partial response.
FIG 3.
FIG 3.
Improvement in cGVHD symptoms with axatilimab treatment. Clinical axatilimab responses are accompanied by a reduction in cGVHD symptom burden. The waterfall plot shows the best change in cGVHD symptoms from baseline in all evaluable patients treated on study, as measured using the summary score of the Lee Symptom Scale. Bars depict individual patients and purple stars indicate patients who achieved clinical response per the NIH 2014 consensus criteria. The dashed line indicates a 7-point decrease threshold. cGVHD, chronic graft-versus-host disease; NIH, National Institutes of Health.
FIG 4.
FIG 4.
Correlative studies highlight potential response and pharmacodynamic biomarkers of axatilimab. (A) Axatilimab therapy modulates the monocyte profile in peripheral blood by reducing prevalence of nonclassical CD14+CD16++ monocytes. Cumulative data show changes in monocyte subsets in peripheral blood of patients treated with axatilimab doses of 1 mg/kg (blue circles) and 3 mg/kg (red circles) once every 2 weeks and 3 mg/kg once every 4 weeks (teal circles) during the first cycle of therapy. (B) Axatilimab reduces skin macrophage density in patients with cGVHD. Multiplex immunohistochemistry analysis of skin macrophage density documents a decrease in skin CSF-1R+ macrophage infiltration after two cycles of therapy. Representative pseudocolored images and cumulative data from analysis of four paired samples are shown. (C) Response to axatilimab is associated with a rapid decrease in key profibrotic macrophage cytokines. Plasma collected at baseline and day 1 of cycles 2 and 4 was analyzed for levels of cytokines involved in monocyte and macrophage homeostasis (TGF-β, IL-8, IL-10, TNF-α, IL-6, and IL-22), and paired samples are shown. *P = .03 (CI, 60 to 803 pg/mL). C1D1, cycle 1 day 1; C2D1, cycle 2 day 1; C3D1, cycle 3 day 1; C4D1, cycle 4 day 1; cGVHD, chronic graft-versus-host disease; CSF-1R, colony-stimulating factor 1 receptor; IL, interleukin; NR, nonresponder; TGF, transforming growth factor; TNF, tumor necrosis factor.
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