HER2+ Metastatic Breast Cancer Initial Treatment and After Progression

Authored by Eric Kowalchyk, published on 2026-09-03 00:38:34.0

  1. HER2+ Unresectable/Metastatic Breast Cancer — No Prior Systemic Therapy for Advanced Disease
    • Preferred 1L → T-DXd + pertuzumab (DESTINYBreast-09)
      • Continue until disease progression or unacceptable toxicity
        • Prior T-DXd?
          • T-DXd (If no prior T-DXd)
            • Subsequent HER2-Directed Treatment Options
              • Neratinib + Capecitabine
              • Margetuximab + Chemotherapy
              • Other trastuzumab + chemotherapy combinations
              • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
              • T-DM1 (if not previously used)
              • Clinical Trial
              • HR-directed/endocrine approaches for selected HR+/HER2+ disease
          • Active/progressive CNS disease?
            • Tucatinib + Trastuzumab + Capecitabine (when appropriate based on prior therapy)
              • Subsequent HER2-Directed Treatment Options
                • Neratinib + Capecitabine
                • Margetuximab + Chemotherapy
                • Other trastuzumab + chemotherapy combinations
                • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                • T-DM1 (if not previously used)
                • Clinical Trial
                • HR-directed/endocrine approaches for selected HR+/HER2+ disease
            • Select subsequent HER2-directed therapy based on prior exposure → options below
              • Subsequent HER2-Directed Treatment Options
                • Neratinib + Capecitabine
                • Margetuximab + Chemotherapy
                • Other trastuzumab + chemotherapy combinations
                • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                • T-DM1 (if not previously used)
                • Clinical Trial
                • HR-directed/endocrine approaches for selected HR+/HER2+ disease
    • Alternative 1L: Taxane + trastuzumab + pertuzumab (THP)
      • After taxane induction and no disease progression → Assess HR status
        • HR+
          • Palbociclib + trastuzumab ± pertuzumab + endocrine therapy
            • Prior T-DXd?
              • T-DXd (If no prior T-DXd)
                • Subsequent HER2-Directed Treatment Options
                  • Neratinib + Capecitabine
                  • Margetuximab + Chemotherapy
                  • Other trastuzumab + chemotherapy combinations
                  • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                  • T-DM1 (if not previously used)
                  • Clinical Trial
                  • HR-directed/endocrine approaches for selected HR+/HER2+ disease
              • Active/progressive CNS disease?
                • Tucatinib + Trastuzumab + Capecitabine (when appropriate based on prior therapy)
                  • Subsequent HER2-Directed Treatment Options
                    • Neratinib + Capecitabine
                    • Margetuximab + Chemotherapy
                    • Other trastuzumab + chemotherapy combinations
                    • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                    • T-DM1 (if not previously used)
                    • Clinical Trial
                    • HR-directed/endocrine approaches for selected HR+/HER2+ disease
                • Select subsequent HER2-directed therapy based on prior exposure → options below
                  • Subsequent HER2-Directed Treatment Options
                    • Neratinib + Capecitabine
                    • Margetuximab + Chemotherapy
                    • Other trastuzumab + chemotherapy combinations
                    • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                    • T-DM1 (if not previously used)
                    • Clinical Trial
                    • HR-directed/endocrine approaches for selected HR+/HER2+ disease
        • HR-
          • Trastuzumab + pertuzumab maintenance
            • Prior T-DXd?
              • T-DXd (If no prior T-DXd)
                • Subsequent HER2-Directed Treatment Options
                  • Neratinib + Capecitabine
                  • Margetuximab + Chemotherapy
                  • Other trastuzumab + chemotherapy combinations
                  • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                  • T-DM1 (if not previously used)
                  • Clinical Trial
                  • HR-directed/endocrine approaches for selected HR+/HER2+ disease
              • Active/progressive CNS disease?
                • Tucatinib + Trastuzumab + Capecitabine (when appropriate based on prior therapy)
                  • Subsequent HER2-Directed Treatment Options
                    • Neratinib + Capecitabine
                    • Margetuximab + Chemotherapy
                    • Other trastuzumab + chemotherapy combinations
                    • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                    • T-DM1 (if not previously used)
                    • Clinical Trial
                    • HR-directed/endocrine approaches for selected HR+/HER2+ disease
                • Select subsequent HER2-directed therapy based on prior exposure → options below
                  • Subsequent HER2-Directed Treatment Options
                    • Neratinib + Capecitabine
                    • Margetuximab + Chemotherapy
                    • Other trastuzumab + chemotherapy combinations
                    • Tucatinib + Trastuzumab + Capecitabine (After ≥2 Prior Lines, if not previously used)
                    • T-DM1 (if not previously used)
                    • Clinical Trial
                    • HR-directed/endocrine approaches for selected HR+/HER2+ disease
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