{"entity":{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","kind":"paper","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","aka":["PHOENIX trial","Younes 2019","Ibrutinib with R-CHOP in non-germinal centre diffuse large B-cell lymphoma"],"tldr":"Adding a targeted tablet to standard first-line chemotherapy failed overall, helped people under 60 substantially, and harmed people over 60 by making them unable to finish the chemotherapy.","summary":"PHOENIX is the most instructive negative trial in diffuse large B-cell lymphoma, because the reason it failed is legible. 838 patients with non-germinal-centre disease, 75.9 per cent of them of the activated B-cell subtype, were randomised to ibrutinib 560 mg daily or placebo with R-CHOP. Median age was 62.\n\nThe trial missed its primary endpoint in both the intention-to-treat population (event-free survival hazard ratio 0.934) and the activated B-cell subgroup (0.949). A preplanned analysis found a significant interaction between treatment and age. In patients under 60, ibrutinib improved event-free survival (hazard ratio 0.579), progression-free survival (0.556) and overall survival (0.330), with serious adverse events rising from 28.6 to 35.7 per cent and the proportion receiving at least six cycles of R-CHOP unchanged at 92.9 against 93.0 per cent. In patients aged 60 or over, ibrutinib worsened all three endpoints, raised serious adverse events from 38.2 to 63.4 per cent, and cut the proportion completing six cycles of R-CHOP from 88.8 to 73.7 per cent.\n\nThe mechanism of the failure is therefore not biological but practical: the added drug stopped older patients from receiving the chemotherapy that cures the disease. That is the finding behind every subsequent attempt to use a better-tolerated Bruton tyrosine kinase inhibitor in this setting, including the ARCHED trial.","asOf":"2026-10-01","links":[{"label":"Journal of Clinical Oncology 2019","url":"https://doi.org/10.1200/JCO.18.02403"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30901302/"},{"label":"Europe PMC","url":"https://europepmc.org/article/MED/30901302"}],"tags":["lymphoma-evidence"],"related":["paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","lymphoma-roadmap"],"cancers":["dlbcl","non-hodgkin-lymphoma"],"sections":["targeted-therapy","chemotherapy"],"technologies":[],"targets":["btk","cd20"],"drugs":["ibrutinib","rituximab","cyclophosphamide","doxorubicin","vincristine","prednisone"],"companies":[],"institutions":[],"pathways":["bcr-signalling"],"terms":["r-chop","cell-of-origin"],"trials":["phoenix","arched"],"people":["laurie-sehn","peter-johnson"],"bottlenecks":["b-negative-results","b-aging-comorbidity","b-biomarker-validation"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.18.02403","pmid":"30901302","authors":"Younes A, Sehn LH, Johnson P, et al.","paperType":"rct","findings":["Ibrutinib with R-CHOP did not improve event-free survival in the intention-to-treat population (hazard ratio 0.934) or in the activated B-cell population (0.949).","A preplanned analysis showed a significant interaction between treatment and age.","In patients under 60, ibrutinib improved event-free survival (hazard ratio 0.579), progression-free survival (0.556) and overall survival (0.330).","In patients aged 60 or over, ibrutinib worsened all three endpoints and raised serious adverse events from 38.2 to 63.4 per cent.","The proportion of patients receiving at least six cycles of R-CHOP fell from 88.8 to 73.7 per cent with ibrutinib in those aged 60 or over, but was unchanged in those under 60."],"whatItMeans":"A failure worth reading: the drug worked where patients could tolerate the regimen it was added to, and harmed where they could not. It is the strongest argument in lymphoma for designing first-line combinations around what an older patient can finish.","caveats":["The age subgroup result is a subgroup analysis, even though the interaction test was preplanned, and has never been confirmed by a trial restricted to younger patients.","Patients were selected by the Hans immunohistochemistry algorithm rather than by genetic subtype; LymphGen and the Schmitz classification suggest the responsive group is narrower than non-germinal-centre.","Ibrutinib is the least selective of the Bruton tyrosine kinase inhibitors, so the toxicity finding may not transfer to acalabrutinib or zanubrutinib."],"changedPractice":false,"participants":838},"route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/","neighbours":{"paper":[{"id":"paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","kind":"paper","name":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray","route":"/key-papers/paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004/"},{"id":"paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","kind":"paper","name":"Genetics and pathogenesis of diffuse large B-cell lymphoma","route":"/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/"}],"roadmap":[{"id":"lymphoma-roadmap","kind":"roadmap","name":"Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting","route":"/roadmaps/lymphoma-roadmap/"}],"cancer":[{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"}],"section":[{"id":"chemotherapy","kind":"section","name":"Chemotherapy","route":"/fronts/chemotherapy/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"cd20","kind":"target","name":"CD20","route":"/targets/cd20/"}],"drug":[{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"prednisone","kind":"drug","name":"Prednisone","route":"/drugs/prednisone/"},{"id":"rituximab","kind":"drug","name":"Rituximab","route":"/drugs/rituximab/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"}],"term":[{"id":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/"},{"id":"r-chop","kind":"term","name":"R-CHOP (lymphoma chemoimmunotherapy)","route":"/terms/r-chop/"}],"trial":[{"id":"arched","kind":"trial","name":"ARCHED","route":"/trials/arched/"},{"id":"phoenix","kind":"trial","name":"PHOENIX DDR/Anti-PD-L1","route":"/trials/phoenix/"}],"person":[{"id":"laurie-sehn","kind":"person","name":"Laurie H. Sehn","route":"/people/laurie-sehn/"},{"id":"peter-johnson","kind":"person","name":"Peter Johnson","route":"/people/peter-johnson/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-negative-results","kind":"bottleneck","name":"Failures are hidden","route":"/bottlenecks/b-negative-results/"},{"id":"b-aging-comorbidity","kind":"bottleneck","name":"Older and multimorbid patients are excluded and undertreated","route":"/bottlenecks/b-aging-comorbidity/"}],"journal":[{"id":"jco","kind":"journal","name":"Journal of Clinical Oncology","route":"/journals/jco/"}],"idea":[{"id":"lymphoma-ev-genetic-subtype-directed-first-line","kind":"idea","name":"Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain","route":"/ideas/lymphoma-ev-genetic-subtype-directed-first-line/"}]}}