{"entity":{"id":"gvhd-belumosudil-axatilimab-ibrutinib","kind":"technology","name":"After ruxolitinib: belumosudil, axatilimab and ibrutinib in chronic GvHD","aka":["Rezurock","Niktimvo","ROCKstar","AGAVE-201","iNTEGRATE","ROCK2 inhibitor","CSF1R blockade in GvHD"],"tldr":"Three more drugs are licensed for chronic GvHD that has not responded to earlier treatment. Their response rates look high, between half and three quarters, but they come from trials with no comparison group. Ibrutinib is the cautionary case: it looked good in a single-arm study and then did not beat prednisone alone when tested against placebo.","summary":"Belumosudil (Rezurock), an oral ROCK2 inhibitor. Approved by the FDA on 16 July 2021. The registration study, ROCKstar, was a phase 2 randomised multicentre study of belumosudil 200 mg daily (n = 66) against 200 mg twice daily (n = 66) in people with chronic GvHD who had received two to five prior lines of therapy. Randomisation was between two doses of the same drug, not against a control, so the response rate has nothing to be compared with. Best overall response was 74 per cent (95 per cent CI 62 to 84) on the daily dose and 77 per cent (95 per cent CI 65 to 87) twice daily, with responses in all subgroups and complete responses in all affected organs. Median duration of response was 54 weeks and 44 per cent remained on therapy for a year or more. Symptom reduction on the Lee Symptom Scale was reported in 59 and 62 per cent. Median follow-up was 14 months.\n\nAxatilimab (Niktimvo), an intravenous CSF1R-blocking antibody. Approved by the FDA on 14 August 2024 for chronic GvHD after failure of at least two prior lines of systemic therapy, in adults and children weighing at least 40 kg. AGAVE-201 randomised 241 patients between three doses: 0.3 mg/kg every two weeks (n = 80), 1 mg/kg every two weeks (n = 81) and 3 mg/kg every four weeks (n = 80). Again the randomisation is between doses. Overall response in the first six cycles was 74 per cent (95 per cent CI 63 to 83), 67 per cent (55 to 77) and 50 per cent (39 to 61) respectively; the FDA states 75 per cent (95 per cent CI 64 to 84) in the 79 patients treated at the recommended dosage. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60, 69 and 41 per cent. The FDA's own summary gives the number that the headline response rate hides: median duration of response, calculated from first response to progression, death or new systemic therapy, was 1.9 months (95 per cent CI 1.6 to 3.5), while in those who responded, 60 per cent (95 per cent CI 43 to 74) had no death or new systemic therapy for at least twelve months from response. Adverse events were dose-dependent laboratory abnormalities related to CSF1R blockade, and discontinuation for adverse events occurred in 6 per cent at the lowest dose against 22 and 18 per cent at the higher doses, which is why the lowest dose is the recommended one.\n\nIbrutinib (Imbruvica), an oral BTK inhibitor. Labelled for chronic GvHD after failure of one or more lines of systemic therapy, in adults and children aged one year and older. The single-arm study that led there treated 42 patients who had failed one to three prior treatments; best overall response was 67 per cent at a median follow-up of 13.9 months, 71 per cent of responders sustained response for 20 weeks or more, and median corticosteroid dose in responders fell from 0.29 to 0.12 mg/kg per day by week 49.\n\nThen ibrutinib was tested properly. iNTEGRATE was a randomised, double-blind, placebo-controlled phase 3 trial of ibrutinib 420 mg daily plus prednisone against placebo plus prednisone in 193 previously untreated patients with newly diagnosed moderate or severe chronic GvHD. Response at 48 weeks by the 2014 NIH criteria was 41 per cent with ibrutinib and 37 per cent with placebo (P = 0.54). At 33 months of follow-up, median duration of response was 19 against 10 months (P = 0.10) and median event-free survival 15 against 8 months. The primary endpoint was not met.\n\nWhat to take from this. A single-arm response rate of 67 to 77 per cent in chronic GvHD is not evidence of the same quality as a randomised difference, because untreated or differently treated chronic GvHD responds too: the placebo-plus-prednisone arm of iNTEGRATE responded 37 per cent of the time. These three drugs are licensed, they are used, and for a person whose disease has failed steroids and ruxolitinib they are reasonable options. The grade here is moderate rather than strong because none of them has shown superiority over an active or placebo comparator in chronic GvHD, and the one that was tested that way did not.\n\nOnCo does not hold a drug record for axatilimab. That is a gap, and it is named here rather than filled under the wrong prefix.","status":"approved","asOf":"2026-10-02","wikipedia":"https://en.wikipedia.org/wiki/Belumosudil","links":[{"label":"Cutler et al., Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study (Blood 2021)","url":"https://doi.org/10.1182/blood.2021012021"},{"label":"Wolff et al., Axatilimab in recurrent or refractory chronic graft-versus-host disease, AGAVE-201 (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2401537"},{"label":"FDA: FDA approves axatilimab-csfr for chronic graft-versus-host disease (14 August 2024)","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axatilimab-csfr-chronic-graft-versus-host-disease"},{"label":"Drugs@FDA: Rezurock (belumosudil), NDA 214783, original approval 16 July 2021","url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=214783"},{"label":"Miklos et al., Ibrutinib for chronic graft-versus-host disease after failure of prior therapy (Blood 2017)","url":"https://doi.org/10.1182/blood-2017-07-793786"},{"label":"Miklos et al., Ibrutinib for first-line treatment of chronic graft-versus-host disease: the randomized phase III iNTEGRATE study (JCO 2023)","url":"https://doi.org/10.1200/JCO.22.00509"}],"tags":["rejuvenation","survivorship","transplant","evidence:moderate","gvhd","treatment"],"related":["gvhd-chronic-overview","gvhd-ruxolitinib-steroid-refractory","gvhd-photopheresis","gvhd-nih-consensus-criteria"],"cancers":[],"sections":["rejuvenation","supportive-care"],"technologies":["allogeneic-hsct"],"targets":[],"drugs":["belumosudil","ibrutinib"],"companies":[],"institutions":[],"pathways":[],"terms":["gvhd","quality-of-life"],"trials":[],"people":[],"bottlenecks":["b-survivorship","b-toxicity-qol"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"principle":"Each drug hits a different phase of the three-phase model. Belumosudil inhibits ROCK2, reducing type 17 and follicular helper T cells by downregulating STAT3 and increasing regulatory T cells by upregulating STAT5, and has direct antifibrotic effects. Axatilimab blocks the colony-stimulating factor 1 receptor, depleting the monocyte-derived macrophages that drive the fibrotic phase. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T cell kinase in T cells, targeting the chronic activation phase.","strengths":["Three licensed options with different mechanisms for disease that has failed steroids and ruxolitinib","Responses reported across all affected organs, including complete responses, in ROCKstar","Belumosudil and ibrutinib are oral; axatilimab is a short intravenous infusion every two weeks","Patient-reported symptom improvement was measured, not only clinician scores"],"limitations":["No randomised comparison against an active or placebo control in chronic GvHD for any of the three","Ibrutinib failed its randomised phase 3 trial in first-line disease, 41 per cent against 37 per cent with placebo","Median duration of response for axatilimab at the licensed dose was 1.9 months by the FDA's calculation","Dose-dependent discontinuation for adverse events with axatilimab, and laboratory abnormalities from CSF1R blockade","OnCo holds no drug record for axatilimab"],"since":2021},"route":"/technologies/gvhd-belumosudil-axatilimab-ibrutinib/","neighbours":{"technology":[{"id":"rejuv-tx-what-to-ask-for","kind":"technology","name":"After a transplant or cell therapy: what to ask for","route":"/technologies/rejuv-tx-what-to-ask-for/"},{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"gvhd-chronic-overview","kind":"technology","name":"Chronic graft-versus-host disease","route":"/technologies/gvhd-chronic-overview/"},{"id":"gvhd-photopheresis","kind":"technology","name":"Extracorporeal photopheresis for graft-versus-host disease","route":"/technologies/gvhd-photopheresis/"},{"id":"gvhd-nih-consensus-criteria","kind":"technology","name":"How chronic GvHD is diagnosed and scored: the NIH consensus criteria","route":"/technologies/gvhd-nih-consensus-criteria/"},{"id":"gvhd-ruxolitinib-steroid-refractory","kind":"technology","name":"When steroids fail: ruxolitinib for steroid-refractory GvHD","route":"/technologies/gvhd-ruxolitinib-steroid-refractory/"}],"section":[{"id":"rejuvenation","kind":"section","name":"Recovery & Rejuvenation","route":"/fronts/rejuvenation/"},{"id":"supportive-care","kind":"section","name":"Supportive Care & Survivorship","route":"/fronts/supportive-care/"}],"drug":[{"id":"belumosudil","kind":"drug","name":"Belumosudil","route":"/drugs/belumosudil/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"}],"term":[{"id":"gvhd","kind":"term","name":"Graft-versus-host disease (GVHD) and graft-versus-leukaemia","route":"/terms/gvhd/"},{"id":"quality-of-life","kind":"term","name":"Quality of life","route":"/terms/quality-of-life/"}],"bottleneck":[{"id":"b-survivorship","kind":"bottleneck","name":"Survivorship and late effects are neglected","route":"/bottlenecks/b-survivorship/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}]}}