Addition of Tucatinib to Trastuzumab/Pertuzumab After Local Therapy for Isolated Intracranial Progression in HER2-Positive Metastatic Breast Cancer: Primary Results of the Phase II BRIDGET Trial
Mené sur 47 patients atteints d'un cancer du sein métastatique HER2+ présentant une première ou une seconde progression intracrânienne isolée traitée par radiochirurgie (durée médiane de suivi : 19,6 mois ; âge médian : 53,5 ans ; 97,9 % de femmes), cet essai de phase II évalue l'intérêt, du point de vue de la survie sans progression intracrânienne, d'ajouter du tucatinib au traitement en cours à base de trastuzumab/pertuzumab ou ado-trastuzumab emtansine
Background: Brain metastases (BrMs) are common in advanced HER2-positive (HER2+) breast cancer, often with stable extracranial disease. Current guidelines for isolated intracranial progression recommend local therapy followed by continuation of the same systemic regimen, given the absence of data supporting a change in therapy. BRIDGET tested whether adding tucatinib, a CNS-active, HER2-targeted TKI, to an ongoing HER2-targeted backbone prevents further intracranial progression after isolated CNS relapse.
Methods: BRIDGET is a single-arm, phase II trial (NCT05323955) enrolling patients with metastatic HER2+ breast cancer experiencing a first or second isolated intracranial event with stable/absent extracranial disease while on trastuzumab/pertuzumab (TP) or ado-trastuzumab emtansine (T-DM1). All new or progressive brain lesions >5mm underwent stereotactic radiosurgery before enrollment. Tucatinib 300 mg BID was added continuously to anti-HER2 antibody backbone therapy. The primary endpoint was intracranial progression-free survival (iPFS) per RANO-BM. The study was designed to distinguish a 3-month improvement in PFS to >8.0 months versus a historical control median of 5.0 months by one-sample log-rank test (one-sided
α=0.05; 90% power).
Results
:
Of 48 patients, 47 were eligible and evaluable (median age 53.5 years; 97.9% female; 93.6% on backbone TP). At a median follow-up of 19.6 months, the study met its primary endpoint: median iPFS was not reached and significantly exceeded the pre-specified historical control estimate of 5.0 months (p<0.0001). 12- and 18-month iPFS estimates were 64% (95% CI, 48
–76) and 59% (95% CI, 42–73). Extracranial progression was rare (2 patients, 4.3%), and overall survival was exceptional (46/47 patients alive). Among patients with isolated CNS relapse as their first and only metastatic event (n=25), 12-month iPFS was 62%. Grade ≥3 adverse events occurred in 32% (15/47).
Conclusions: Addition of tucatinib to ongoing HER2-targeted therapy prolonged intracranial progression-free survival after isolated CNS progression, with excellent survival, and a favorable safety profile, supporting its use as an effective strategy for HER2+ isolated or brain-only relapse.
ESMO Open , article en libre accès, 2026