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 .

The Exciting New Field of HER2-Low Breast Cancer Treatment

“…It was found that the addition of fulvestrant significantly enhanced antitumor responses to the HER2 and 3 targeting agents. In this sense, as mentioned previously, the addition of the HER2/HER3 bi-specific antibody zenocutuzumab to ET showed clinical activity in ET and CDK4/6i-refractory patients, resulting in an endocrine-sensitivity rescue of 17% of them ( Table 1 ) [ 26 ].…”

“…Not only ADCs are being tested in HER2-low metastatic BC patients. Currently, the bi-specific humanized IgG1 antibody zenocutuzumab (MCLA128) is undergoing clinical development, with results from phase II trials available [ 26 , 57 ]. With the novel dock and block effect, zenocutuzumab works by docking to HER2 domain I, positioning the anti-HER3 arm fit to block the domain III of HER3, such as to prevent the binding of any activating ligand (e.g., heuregulin) [ 49 ].…”

“…In a phase I/II trial enrolling HER2-positive BC and other epithelial tumors, the zenocutuzumab recommended phase II dose was determined and shown to be remarkably safe, with very few grade 3–4 adverse events (AEs). Afterwards, this dose was tested in a phase 2, single-arm trial of endocrine-resistant, ER-positive/HER2-low BC patients, who had experienced disease progression while on a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) [ 26 , 57 ]. Fifty patients were treated with zenocutuzumab plus ET (fulvestrant or an aromatase inhibitor), and 8 sustained a clinical benefit at week 24 (clinical benefit rate of 16.7% (90% CI, 8.6–28.1)), with one patient showing a partial response followed by a long-lasting disease stabilization ( Table 1 ).…”

“…With zenocutuzumab, no treatment-related cardiotoxicities of clinical relevance were reported in both early phase trials [ 26 , 57 ]. Although the number of treated patients is smaller comparing to the trastuzumab-containing ADCs, this encouraging cardiac safety data likely reflects the improved in vitro cardiomyocyte viability with zenocutuzumab, as compared to trastuzumab [ 49 ].…”

“…In the past, trastuzumab has failed to improve the outcomes of patients with HER2-low BC, and the concept of anti-HER2 agents in this setting was put on hold [ 18 ]. Fortunately, this treatment paradigm has recently been re-challenged in light of the promising efficacy results seen with novel and more potent anti-HER2 agents in HER2-low metastatic BC [ 24 , 25 , 26 ]. It is, therefore, the objective of this article to review the previous body of data and upcoming evidence for the new wave of treatments that may revolutionize the care of HER2-low BC patients.…”