ESMO Congress 2026

Metastatic breast cancers that are not HER2-amplified but IHC 1+ or 2+/ISH-negative used to be treated as HER2-negative; HER2-directed drugs had not held in that group. DESTINY-Breast04 changed that: 557 patients, one or two prior lines of chemotherapy, T-DXd versus physician’s-choice chemotherapy. Median PFS in the full population 9.9 vs 5.1 months (hazard ratio for progression or death 0.50), OS 23.4 vs 16.8 months (hazard ratio for death 0.64); in the hormone receptor-positive cohort, median PFS 10.1 vs 5.4 months (hazard ratio 0.51). Grade ≥3 adverse events 52.6% vs 67.4%; adjudicated drug-related ILD or pneumonitis 12.1%, including 0.8% grade 5.^[1]

DESTINY-Breast06 moved the same drug earlier: hormone receptor-positive, no prior chemotherapy for metastatic disease, after endocrine therapy, HER2-low (IHC 1+ or 2+/ISH-negative) or ultralow (IHC 0 with membrane staining). In 713 HER2-low patients, median PFS 13.2 vs 8.1 months (hazard ratio 0.62, 95% CI 0.52–0.75); OS was immature. Grade ≥3 adverse events 52.8% vs 44.4%; adjudicated ILD or pneumonitis 11.3% (three grade 5) vs 0.2%.^[2] The enrollment windows differ: 04 is after chemotherapy, 06 is after endocrine therapy and before chemotherapy.

The same molecule, trastuzumab rezetecan (SHR-A1811), already has another phase 3: HORIZON-Breast01, HER2-positive metastatic breast cancer, versus pyrotinib plus capecitabine. Interim median PFS 30.6 vs 8.3 months (hazard ratio 0.22, 95% CI 0.15–0.34). That is HER2-positive disease and a different control; those numbers do not move to HER2-low.^[3] The single-arm neoadjuvant HELEN-015 used SHR-A1811 in operable HR+/HER2-low disease (ORR 81.5%, pCR 3.1%). That is early-stage, with no chemotherapy control, and is not this metastatic phase 3.^[4]

This meeting’s HORIZON-Breast06 asks the HER2-low metastatic question: trastuzumab rezetecan versus physician’s-choice chemotherapy, ≤1 prior line of chemotherapy in the metastatic setting, prior endocrine therapy if hormone receptor-positive. Floor posts (Sara Tolaney, ScienceLink, Minhua Chu) give n=551: PFS 16.4 vs 6.8 months in the full population (HR 0.27, 95% CI 0.21–0.34); 16.6 vs 6.8 months in chemo-naive metastatic disease (HR 0.25); ORR 75.5% vs 41.2%; OS immature; grade ≥3 treatment-related adverse events 84.1% vs 67.9%; ILD 2.5%. A Spanish-language floor summary writes PFS as SLP; do not splice those numbers with TALENT’s pCR. The control is physician’s-choice chemotherapy, not T-DXd; DESTINY-Breast06 in a similar window was 13.2 vs 8.1 months, HR 0.62, and the two trials are not head-to-head. Without a head-to-head this does not already displace T-DXd in HER2-low. A salivary-gland phase 2 (PMID 42579830) is another disease; those response rates do not move here.