ESMO Congress 2026

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor, belonging to the same TKI family as lapatinib, neratinib, and pyrotinib, which have established roles in HER2-positive breast cancer; central nervous system involvement is precisely the setting where this drug class is highly anticipated, as treatment options were previously limited and the prognosis poor ^[4]. Its core evidence comes from the randomized, double-blind, placebo-controlled HER2CLIMB trial: in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, adding tucatinib to trastuzumab plus capecitabine increased the 1-year progression-free survival rate from 12.3% to 33.1% (HR 0.54) ^[1]; in exploratory analyses of 291 patients with brain metastases, the risk of intracranial progression or death was reduced by 68% versus the control arm (HR 0.32) ^[2]; the subsequent final overall survival analysis followed patients to a median of 29.6 months ^[6].

At ESMO26, Sarah Sammons presented the single-arm phase II BRIDGET trial: for patients with advanced HER2-positive breast cancer who developed isolated intracranial progression while on systemic therapy and received local SRS, tucatinib was added on top of the ongoing HP (trastuzumab/pertuzumab) or T-DM1 backbone. Among 47 evaluable patients, the primary endpoint was intracranial PFS (iPFS) assessed by RANO-BM. Median iPFS was not reached; p<0.0001 versus a historical median of 5 mo; iPFS was 91% at 6 mo, 64% at 12 mo, and 59% at 18 mo; grade ≥3 AEs occurred in 15%, and extracranial progression was only 4.3%. The trial met its primary endpoint, with more than half of patients free of intracranial progression at 18 months.

Compared with the wholesale switch to tucatinib plus trastuzumab and capecitabine after multiple lines of therapy established by HER2CLIMB ^[1], BRIDGET answers a more specific question: when only the brain progresses while extracranial disease remains controlled, can local radiotherapy plus tucatinib reinforce CNS control while preserving an otherwise effective systemic regimen? The 59% iPFS at 18 months and the mere 4.3% extracranial progression suggest that this site-specific strategy maintained systemic efficacy while keeping the original backbone, corroborating the intracranial activity already demonstrated for tucatinib ^[2] and reflecting the value of TKIs in the CNS setting ^[4].

That said, BRIDGET is a single-arm design with only 47 patients, benchmarked against a historical median of 5 mo; median iPFS remains immature, and outcomes such as overall survival are undisclosed, so this strategy still awaits validation in randomized trials.