{"entity":{"id":"bruin-cll-321","kind":"trial","name":"BRUIN CLL-321","aka":[],"tldr":"The randomised trial that confirmed pirtobrutinib works after other BTK inhibitors fail, leading to full approval in December 2025.","summary":"BRUIN CLL-321, trial NCT04666038 sponsored by Eli Lilly through Loxo and reported at ASH 2024 and in JCO in 2025, is the randomised trial that confirmed the non-covalent BTK inhibitor pirtobrutinib works after covalent BTK inhibitors fail in relapsed or refractory chronic lymphocytic leukaemia, leading to full approval on 3 December 2025. It randomised 238 patients to pirtobrutinib or investigator's choice of idelalisib-rituximab or bendamustine-rituximab, met its primary progression-free survival endpoint with a longer time to next treatment, while overall survival was not different because of crossover, and the label was broadened to any prior covalent BTK inhibitor. Whether pirtobrutinib belongs in the frontline, which CLL-313 and CLL-314 test, is the open question.","status":"positive","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04666038","url":"https://clinicaltrials.gov/study/NCT04666038"}],"tags":[],"related":[],"cancers":["cll","cll-relapsed"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["btk"],"drugs":["pirtobrutinib"],"companies":["eli-lilly"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":["jennifer-brown"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT04666038","phase":"3","setting":"Relapsed/refractory CLL/SLL after a covalent BTK inhibitor: pirtobrutinib vs investigator's choice (idelalisib-rituximab or bendamustine-rituximab)","sponsor":"Eli Lilly / Loxo","result":"PFS 11.2 vs 8.7 months; HR 0.58.","started":"2021-03-09","startedType":"actual","yearReported":2024,"enrolled":238,"enrolledBasis":"registry","outcomes":[{"endpoint":"Progression-free survival (median)","primary":true,"unit":"months","arms":[{"name":"Pirtobrutinib","n":119,"value":11.2},{"name":"Idelalisib-rituximab or bendamustine-rituximab","n":119,"value":8.7}],"hr":0.58,"source":"https://www.ajmc.com/view/fda-grants-full-approval-to-pirtobrutinib-for-cll-sll"}],"replication":"BRUIN phase 1/2 (n>300 CLL) showed ORR ~82% after covalent BTKi; frontline randomised trials (CLL-313, CLL-314) pending."},"route":"/trials/bruin-cll-321/","neighbours":{"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","route":"/cancers/cll-relapsed/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"}],"drug":[{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/"}],"company":[{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"}],"person":[{"id":"jennifer-brown","kind":"person","name":"Jennifer R. Brown","route":"/people/jennifer-brown/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}