OnCo
ideasIdea

BTK degraders to pre-empt resistance in frontline CLL

If destroying BTK works when every inhibitor has failed, using it first might stop resistance from ever emerging.

BGB-16673 shows 86% response in heavily pretreated, mutation-bearing CLL; CaDAnCe-304 tests it against pirtobrutinib in relapse. Frontline degrader-based fixed-duration regimens are the logical next step.

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.
What would test it
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

Connected

10top

Pages like this

not linked directly; found by shared links

cancers

1
Chronic lymphocytic leukaemia

technologies

1
PROTACs & molecular glues (targeted protein degradation)

targets

2
BCL-2BTK (Bruton tyrosine kinase)

drugs

4
ApprovedSmall-molecule covalent BTK inhibitor (second generation)
Acalabrutinib · Calquence
Phase 3Small-molecule BTK degrader (CDAC)
BGB-16673
ApprovedSmall-molecule BCL-2 inhibitor (second generation)
Sonrotoclax · Beqalzi
ApprovedSmall-molecule BCL-2 inhibitor
Venetoclax · Venclexta

trials

1
CaDAnCe-304

bottlenecks

1
Acquired resistance to every therapy