T-DXd Reshapes Treatment Sequencing in HER2-Positive Metastatic Breast Cancer
Trastuzumab deruxtecan is moving into earlier treatment lines for HER2-positive metastatic breast cancer, demonstrating superior efficacy over standard regimens and prompting reconsideration of long-standing treatment sequences.
The 2025 regulatory consideration of trastuzumab deruxtecan (T-DXd) plus pertuzumab signals a potential shift toward antibody-drug conjugate (ADC)-driven regimens earlier in the treatment course for HER2-positive metastatic breast cancer and may pose challenges for optimal treatment-sequencing decisions. HER2-positive breast cancer accounts for approximately 20% of breast cancers and remains a biologically aggressive subtype.
Current European Society for Medical Oncology (ESMO) guidelines continue to recommend taxane plus trastuzumab-pertuzumab as the standard first-line regimen for both hormone receptor–positive (HR+) and HR-negative (HR–) HER2+ metastatic breast cancer, followed by trastuzumab-pertuzumab maintenance. This recommendation is supported by the phase 3 CLEOPATRA trial (NCT00567190), which demonstrated significant improvements in progression-free survival (PFS; 18.5 vs 12.4 months) and overall survival (OS; 57.1 vs 40.8 months) compared with placebo plus trastuzumab and docetaxel after nearly 100 months of follow-up. The 8-year overall survival rate was approximately 37%.
The PERUSE study (NCT01572038) further confirmed that the efficacy and safety of pertuzumab plus trastuzumab were consistent across taxane backbones—docetaxel, paclitaxel, or nab-paclitaxel—with a reported median PFS of 20.7 months and a median OS of 65.3 months. For patients with HR-positive breast cancer eligible for chemotherapy-free induction therapy, the PERTAIN trial (NCT01491737) showed that adding pertuzumab to trastuzumab and an aromatase inhibitor improved PFS (median, 20.6 vs 15.8 months), but without a meaningful benefit in OS.
T-DXd has replaced ado-trastuzumab emtansine (T-DM1) as the preferred second-line therapy based on results of the DESTINY-Breast03 trial (NCT03529110), which demonstrated markedly superior PFS (28.8 vs 6.8 months) and OS (52.6 vs 42.7 months). Interstitial lung disease occurred more frequently with T-DXd (16.7% vs 3.4%). Head-to-head trial data demonstrated superior efficacy of T-DXd compared with T-DM1, and with appropriate monitoring and proactive toxicity management, these risks are manageable and should not preclude use in appropriate patients.
In DESTINY-Breast07, at a median follow-up of 31 to 33 months, first-line T-DXd monotherapy and T-DXd plus pertuzumab achieved objective response rates of 77.3% and 84.0%, respectively, with 12- and 18-month PFS rates of 82.6% and 78.2% for monotherapy and 87.5% and 78.8% for the combination. Safety was consistent with prior experience. These findings informed the phase 3 DESTINY-Breast09 trial, where T-DXd plus pertuzumab significantly improved PFS over standard taxane plus trastuzumab-pertuzumab (THP; 40.7 vs 26.9 months) in all prespecified subgroups, produced higher complete response rates (13.7%-16.5% vs 4.1%-10.7%), and achieved a median response duration approaching 3 years, with early OS trends favoring the T-DXd combination and a safety profile comparable with known profiles of each drug.
When patients have active brain metastases but are not candidates for immediate local therapy, the combination of tucatinib with capecitabine and trastuzumab can be prescribed. Tucatinib-containing regimens, such as the HER2CLIMB combination, are particularly attractive for patients with known or suspected brain metastases due to their central nervous system (CNS) activity. T-DM1 may still be appropriate for patients with poor performance status or significant comorbidities.
Maintenance strategies are also evolving. The PATINA trial (NCT02947685) demonstrated the addition of palbociclib to anti-HER2 therapy plus endocrine therapy as maintenance for HR+/HER2+ metastatic breast cancer after induction chemotherapy extended PFS (44.3 vs 29.1 months; hazard ratio [HR], 0.74). Data from HER2CLIMB-05 (NCT05132582) demonstrated that adding tucatinib to trastuzumab-pertuzumab improved PFS (24.9 vs 16.3 months; HR, 0.641), with manageable toxicity. Additional ongoing studies—including heredERA, INAVO122, and DEMETHER—aim to individualize maintenance therapy across biologically defined subgroups further.
As ADCs are increasingly used earlier in the treatment course, there is a need for carefully designed sequencing trials that account for overlapping targets, shared toxicities, cross-resistance, and real-world attrition. Sequencing strategies will be crucial to ensure that improvements in first-line efficacy lead to lasting benefits across the entire spectrum of care.