Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs.
Erika Hamilton, Thierry Petit, Barbara Pistilli, Anthony Gonçalvès, Ana Alexandra Ferreira, Florence Dalenc, Fátima Cardoso, Monica Mita, Vincent O. Dezentjé, Luís Manso, Stephanie L. Graff, François‐Clément Bidard, Philippe Aftimos, Santiago Escrivá, N. Afonso, Ernesto Wasserman, Kees Bol, Viktoriya Stalbovskaya, Anastasia Vliet, Thomas Bachelot
Abstract
3093 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 .