Trastuzumab deruxtecan plus pertuzumab as a substantial advancement in previously untreated patients with HER2-positive metastatic breast cancer.

OBJECTIVE: First-line treatment of HER2-positive metastatic breast cancer (HER2+MBC) has recently evolved with the introduction of trastuzumab deruxtecan-based regimens. We performed an indirect comparative analysis to evaluate the relative efficacy of currently available first-line treatments using reconstructed individual patient data (IPD). MATERIALS AND METHODS: A systematic PubMed search identified phase III randomized controlled trials evaluating first-line therapies for HER2+MBC with progression-free survival (PFS) reported through Kaplan-Meier curves. Reconstructed IPD were generated using the IPDfromKM method after digitization of published curves. Three trials were included: DESTINY-Breast09, EMERALD, and CLEOPATRA. Trastuzumab plus pertuzumab plus taxane (THP) was adopted as the common comparator. Treatment effects were estimated using a Cox proportional hazards model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Heterogeneity across pooled control groups and proportional hazards assumptions were also assessed. RESULTS: The combination of trastuzumab deruxtecan plus pertuzumab demonstrated the most favorable PFS profile among the evaluated regimens. Compared with pooled THP controls, this regimen significantly reduced the event risk (HR 0.49; 95% CI 0.40 to 0.60). In contrast, trastuzumab plus pertuzumab plus eribulin showed PFS outcomes substantially overlapping with THP (HR 0.96; 95% CI 0.77 to 1.20). Reconstructed HR estimates were highly consistent with those reported in the original trials, confirming the reliability of the IPDfromKM approach. CONCLUSIONS: Indirect comparisons based on reconstructed patient-level data suggest that trastuzumab deruxtecan plus pertuzumab currently represents the most effective first-line strategy for HER2+MBC in terms of PFS.