Background: MCLA-128 (zenocutuzumab ), a HER3 pathway inhibitor, is a humanized bispecific full-length IgG1 antibody targeting both HER2 and HER3 with enhanced ADCC activity. The unique Dock & Block mechanism inhibits HER3 from interacting with its ligands and targets HER2 at a different epitope than trastuzumab, blocking HER2/HER3 dimerization and downstream PI3K/AKT/mTOR signaling. In MBC, HER3 overexpression and/or HER3 ligand upregulation are important drivers leading to trastuzumab resistance, indicating a role for MCLA-128. Preclinical activity was seen in HER2+ breast models when MCLA-128 was combined with trastuzumab. Furthermore, single agent MCLA-128 showed consistent antitumor activity in heavily pretreated HER2+ MBC pts. A phase 2, open-label study explored the MCLA-128/trastuzumab plus vinorelbine triplet in an MBC population. Methods: This open-label trial planned for up to 40 evaluable women with HER2+/amplified MBC progressing on up to 5 anti-HER2 lines including trastuzumab, pertuzumab and an anti-HER2 ADC. Pts received MCLA-128 (750 mg, 2h IV), trastuzumab (8 mg/kg loading, then 6 mg/kg) and vinorelbine (25 mg/m², D1 and 8), q3w. A safety run-in of MCLA-128 + trastuzumab ± chemotherapy was performed. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK are evaluated. Data cutoff was 14Nov2019. Results: 28 pts with a median 3 lines (range 2-5) of anti-HER2 therapy (metastatic setting) and 3 (range 1-6) metastatic sites, received a median of 5 (range 1-17) MCLA-128 cycles. Among 26 pts evaluable for efficacy, 20 patients had CR/PR/SD as BOR; DCR was 77% (90%CI: 60-89) with 1 confirmed CR and 4 PRs (2 unconfirmed). Common related AEs (all grades; G3-4) were neutropenia/neutrophil count decrease (61%; 46%), diarrhea (61%; 4%), asthenia/fatigue (46%; 0), nausea (29%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough levels of MCLA-128 was 19.1 µg/mL, and mean terminal half-life was 112 h (n = 8-11). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The triplet MCLA-128-based combination is active in heavily pretreated pts with HER2+/amplified MBC. The regimen is safe and well tolerated with a manageable AE profile mostly related to the chemotherapy component. Clinical trial information: NCT03321981.