Advanced HER2-positive Cancer Research Articles

ZW25, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

TPS3145 Background: ZW25 is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action, including activation of ADCC and inhibition of ligand-dependent and -independent cellular growth. ZW25 is well tolerated and showed single-agent antitumor activity in patients (pts) with advanced HER2-positive cancers. Previous reports suggested that tislelizumab, an investigational anti-PD-1 antibody engineered to minimize binding of FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, was generally well tolerated and had antitumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. Combining HER2-targeted agents with chemotherapy has resulted in improved survival; the highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort phase 1B/2 study is designed to evaluate ZW25 plus chemotherapy ± tislelizumab as first-line therapy in pts (n≈50) with HER2-positive metastatic breast cancer (mBC; cohort 1) or advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). In cohort 1, pts with HER2-positive (IHC3+ or ISH amplified) mBC must be treatment-naïve for metastatic disease and will receive intravenous (IV) ZW25 30 mg/kg plus docetaxel 75 mg/m2 IV once every 3 weeks (Q3W). In cohort 2, treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive ZW25 30 mg/kg plus tislelizumab 200 mg IV and chemotherapy (CAPOX regimen: capecitabine 1000 mg/m2 twice daily and oxaliplatin 130 mg/m2 IV) Q3W. A safety lead-in phase is designed for the first six pts in cohort 2, followed by dose expansion after a safety monitoring committee review. Primary endpoints are the safety/tolerability profile and objective response rate; secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: Registered, NCT number pending will provide as soon as available .

First-in-human phase I study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors.

TPS1101 Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .

A phase I and pharmacologic study of MM-111, a bispecific HER2/HER3 antibody fusion protein, in combination with multiple treatment regimens in patients with advanced HER2-positive solid tumors.

TPS3111 Background: The HER2/HER3 oncogenic heterodimer is a potent HER receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that inhibits ligand activated HER3 signaling through abrogation of ligand binding specifically in HER2 overexpressing tumors. In preclinical models of HER2+ solid tumors, MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression, and tumor growth. HER2 is a well-established target of anticancer agents such as trastuzumab and lapatinib, specifically in breast and gastric tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor activity of both trastuzumab and lapatinib and this phase I study seeks to determine if MM-111 can be safely used in combination with various standard of care HER2 targeting regimens, namely; (1) trastuzumab, cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3) trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open label, multicenter, dose-escalation study of MM-111 in an add-on design that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MM-111 in combination. Each arm is designed to run as a separate phase I study to address safety and tolerability of each combination. For eligibility, patients are required to have documented advanced HER2-positive cancer, with adequate bone marrow, hepato-renal and cardiac function. The dose escalation for each arm utilizes a standard “3 + 3” design with MM-111 dosed initially at a moderate dose of 10 mg/kg and escalated up to 20 mg/kg to identify a phase II dose in combination with each regimen. Once the maximum tolerated dose or phase II dose is identified, expansion cohorts will accrue to further evaluate these combinations. The flexibility of the design allows additional combinations arms to be added. Key exploratory analyses will include an evaluation of safety, PK, and efficacy as evidenced by best overall response and duration of response.