Treatment Options in the 2L for HER2-Low Disease Including ADCs and Endocrine Therapy

Treatment sequencing for HER2-low breast cancer prioritizes endocrine-based approaches for up to 3 to 4 lines, depending on response patterns and disease burden, reserving ADCs for endocrine-refractory disease or specific clinical scenarios. The exception involves primary endocrine-resistant tumors, defined as those with benefit of 6 months or less from first-line therapy, where earlier introduction of chemotherapy or ADCs may be warranted even with responses lasting up to 8 months when clinical concern exists about endocrine sensitivity.

Trastuzumab deruxtecan approval for HER2-low tumors (immunohistochemistry of 1+ or 2+ nonamplified) following Destiny-Breast04 trial results provides an option after at least 1 line but no more than 2 lines of chemotherapy. The Destiny-Breast06 trial expanded this evidence to chemotherapy-naive patients and demonstrated activity in HER2-ultralow tumors (≤10% incomplete membrane staining), broadening the eligible patient population beyond traditional HER2-low definitions.

Clinical implementation considers disease progression rate, visceral involvement, prior toxicities, and patient performance status when deciding between continued endocrine approaches vs ADC therapy. Primary endocrine resistance, represented by 9% of patients in Destiny-Breast06 with less than 6-month benefit from first-line CDK4/6 inhibitor therapy, identifies a population suitable for earlier ADC intervention. The decision-making process balances the proven efficacy of endocrine combinations against the robust activity of T-DXd in HER2-expressing tumors when endocrine approaches are no longer effective.