{"entity":{"id":"idea-btk-degrader-frontline","kind":"idea","name":"BTK degraders to pre-empt resistance in frontline CLL","aka":[],"tldr":"If destroying BTK works when every inhibitor has failed, using it first might stop resistance from ever emerging.","summary":"The idea is to use a BTK degrader such as BGB-16673 with a BCL-2 inhibitor such as sonrotoclax as a 12-month fixed-duration frontline regimen for chronic lymphocytic leukaemia, pre-empting the acquired-resistance bottleneck. Degradation removes both kinase and scaffold functions and is not defeated by the C481, T474 or L528 mutations that arise under inhibitor pressure; BGB-16673 works in most heavily pretreated, mutation-bearing patients. The hypothesis is deeper undetectable MRD, longer treatment-free survival and fewer resistance mutations than a covalent BTK inhibitor with venetoclax. The test is a phase 2 of BGB-16673 with sonrotoclax in untreated patients, then a randomised comparison against acalabrutinib-venetoclax; CaDAnCe-304 already tests the degrader in relapse.","asOf":"2026-09-07","links":[{"label":"Montoya et al., Kinase-impaired BTK mutations are susceptible to the clinical-stage BTK and IKZF1/3 degrader NX-2127 (Science 2024)","url":"https://doi.org/10.1126/science.adi5798"}],"tags":[],"related":[],"cancers":["cll"],"sections":[],"technologies":["protac-degrader"],"targets":["btk","bcl2"],"drugs":["bgb-16673","sonrotoclax","acalabrutinib","venetoclax"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["cadance-304"],"people":[],"bottlenecks":[],"keyPapers":["paper-montoya-science","paper-acalabrutinib-cll-n-engl-j-med-2016","paper-bcl-2-cll-nat-rev-drug-discov-2017","paper-acalabrutinib-cll-j-clin-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A BTK degrader plus a BCL-2 inhibitor for 12 months produces higher uMRD and longer treatment-free survival than covalent BTKi + venetoclax, with fewer BTK resistance mutations at relapse.","rationale":"Degradation removes both kinase and scaffold functions and is not defeated by C481, T474, or L528 mutations that arise under inhibitor pressure.","test":"Phase 2 doublet (BGB-16673 + sonrotoclax) in treatment-naive CLL with uMRD at month 15 as the primary endpoint, then randomised comparison with acalabrutinib-venetoclax.","maturity":"early-clinical"},"route":"/ideas/idea-btk-degrader-frontline/","neighbours":{"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cll-treatment-naive","kind":"cancer","name":"Chronic lymphocytic leukaemia, first treatment","route":"/cancers/cll-treatment-naive/"}],"technology":[{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"}],"drug":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"bgb-16673","kind":"drug","name":"BGB-16673","route":"/drugs/bgb-16673/"},{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"trial":[{"id":"cadance-304","kind":"trial","name":"CaDAnCe-304","route":"/trials/cadance-304/"}],"paper":[{"id":"paper-acalabrutinib-cll-n-engl-j-med-2016","kind":"paper","name":"Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia","route":"/key-papers/paper-acalabrutinib-cll-n-engl-j-med-2016/"},{"id":"paper-acalabrutinib-cll-j-clin-oncol-2021","kind":"paper","name":"Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial","route":"/key-papers/paper-acalabrutinib-cll-j-clin-oncol-2021/"},{"id":"paper-bcl-2-cll-nat-rev-drug-discov-2017","kind":"paper","name":"From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors","route":"/key-papers/paper-bcl-2-cll-nat-rev-drug-discov-2017/"},{"id":"paper-montoya-science","kind":"paper","name":"Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127","route":"/key-papers/paper-montoya-science/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"}]}}