Navigating Third-Line Treatment Options in HER2+  Breast Cancer: ADC or TKI

Clinical Brief: Third-Line and Beyond Treatment Options

Key Themes:

• NCCN Guidelines: Current guidelines support sequencing of THP, then trastuzumab deruxtecan (T-DXd), followed by the HER2CLIMB regimen or T-DM1 in the third-line setting
• Treatment Selection Factors: Brain metastases history strongly influences third-line therapy choice, favoring tucatinib-based regimens
• HER2CLIMB Trial Population: Nearly half of patients enrolled had brain metastases, an unusually high proportion for clinical trials

Key Points for Physicians:

• T-DM1 remains an effective option but is not preferred in patients with brain metastases as it doesn’t cross the blood-brain barrier
• Tucatinib is highly specific for HER2 and generally well tolerated, with most toxicities stemming from the capecitabine component
• Different antibody-drug conjugate (ADC) sequencing is feasible when payloads have different mechanisms (topoisomerase I inhibitor vs microtubule inhibitor)

Notable Insights:

• The HER2CLIMB regimen was groundbreaking for specifically enrolling patients with brain metastases, a population typically excluded from trials
• Progression-free survival metrics for the HER2CLIMB regimen should be interpreted considering the high-risk population enrolled
• Capecitabine dosing typically requires adjustment for tolerability in real-world practice

Clinical Significance:

Third-line therapy selection in HER2+ metastatic breast cancer should consider treatment history, presence of brain metastases, and expected toxicities. The HER2CLIMB regimen is emerging as preferred for patients with central nervous system involvement due to its demonstrated efficacy in this traditionally difficult-to-treat population.