A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies.

Abstract

1049 Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .

Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions

“…A166 is an ADC comprised of trastuzumab linked to duostatin-5 (an auristatin derivative) as the payload. The first efficacy results from a phase I trial of 27 evaluable patients were presented in 2020 with a DCR of 59%, with partial responses observed in 7 patients (26%) at the dose levels of 3.6 mg/kg and 4.8 mg/kg [ 19 ]. This study is ongoing and updated results are awaited (NCT03602079).…”

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

“…A positive response, in terms of stable disease and partial response, was detected in almost 60% of the patients. However, these data were calculated in general, and response rates specific to each cancer type have not yet been reported [ 138 ].…”

A narrative review of human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugates in the treatment of breast cancer

“…A166 is a HER2-targeted ADC with monomethyl auristatin F (MMAF) as its payload. The phase I study yielded a disease control rate (DCR) of 59% in 27 patients, and the trial is ongoing (28). It should be noted that dry eye and vision blurring are among the most common TRAEs of those treated with A166, which differs from those of other ADCs due to its payload.…”