Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i).

Abstract

1037 Background: MCLA-128 (zenocutuzumab) is an ADCC-enhanced humanized bispecific antibody targeting HER2 and HER3 and potently blocking HER3-ligand induced receptor dimerization. Upregulation of Her2:Her 3 pathway is a means of resistance to ET in HR+ breast cancer, indicating a potential role for MCLA-128. In preclinical studies, the combination of MCLA-128 with ET in breast cancer xenografts outperformed single drug treatments. The current study explores the use of MCLA-128 to rescue pts with ET-resistant MBC who have progressed on a CDK4/6i. Methods: This phase II, open-label trial planned for up to 40 evaluable women with HR+, HER2 low (IHC 1+/IHC 2+ with negative FISH) MBC, who had progressed on a CDK4/6i and up to 3 lines of ET, who had received ≤ 2 chemotherapy regimens in the metastatic setting. Pts received MCLA-128 (750 mg, 2h IV, flat dose) q3w combined with last ET on which the pt had previously progressed immediately prior to study entry. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK, are evaluated. Data cut off was 14Nov2019. Results: 48 pts were treated, all of whom had progressed on a CDK4/6i. Pts had received a median 2 prior ET lines (range 1-5) and 1 line (range 1-3) of chemotherapy. Pts had a median number of 3 metastatic sites (range 1-6) and 42 (88%) had visceral involvement. Among 42 pts evaluable for efficacy, DCR was 45% (90% CI 32-59) with 2 pts having unconfirmed PR and 19 pts SD as BOR. Common related AEs (all grades; G3-4) were asthenia/fatigue (27%; 2%), diarrhea (25%; 0), nausea (21%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough level of MCLA-128 was 15.5 µg/mL, and mean terminal half-live was 102 h (n = 19-21). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The addition of MCLA-128 to the last line of ET showed clinical activity after ET+CDK4/6i failure and a favorable safety profile. Clinical trial information: NCT03321981 .