Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours

Abstract

In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody–drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard “3 + 3” design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer

“…Fifteen patients had previously received an anti-HER2 ADC other than T-DM1, including T-DXd. The ORR was 60% in these patients (9/15) [73] . A166 is another HER2-directed ADC composed of humanized HER2-targeting antibody linked to a cytotoxic drug (Duostatin-5, a microtubule inhibitor agent) via a stable cleavable linker.…”

Charting the Course in Sequencing Antibody-Drug Conjugates in Breast Cancer

“…Several novel anti-HER2 ADCs are under investigation, including A166, MM-302 and ARX788, that recently released some preliminary results from the early phase clinical trials. Allowing the exposure to previous ADCs, these trials contribute in part to shed a new light on ADC treatment sequencing [ 41 , 42 , 43 ]. Namely, A166 is a humanized anti-HER2 ADC conjugated with a novel anti-microtubule agent through a stable protease-cleavable linker, tested in pre-treated HER2-positve metastatic BC.…”

Novel HER-2 Targeted Therapies in Breast Cancer

“…Phase 1 studies revealed promising the efficacy and tolerable toxicity of A166 in HER-2-positive advanced solid tumors refractory to standard HER-2-targeted therapies [ 108 ]. There is another phase 1 trial currently ongoing in China in HER-2-overexpressing solid tumors (NCT05311397), but there are still no studies specifically in a breast cancer setting.…”