438P - Phase I study of ZV0203, a first in class pertuzumab ADC, in patients with HER2+ advanced solid tumors

Background

ZV0203, a first in class pertuzumab antibody-drug conjugate (ADC), targets HER2+ tumor cells with tubulin inhibitor duostatin-5 (DUO5) as its payload via a stable and protease-cleavable valine-citrulline linker. In preclinical studies, ZV0203 demonstrated superior antitumor activity compared to Kadcyla in multiple tumor cell line xenograft models with no noticeable toxicity. GLP toxicity studies indicated that ZV0203 was well tolerated with an estimated therapeutic index of 35.

Methods

This was an open-label, multicenter, phase 1, dose-escalation study in patients (pts) with HER2+ advanced solid tumors. Primary objectives were safety, tolerability and recommended phase 2 dose. Secondary objectives included pharmacokinetics (PK), immunogenicity and preliminary clinical efficacy. ZV0203 was administered intravenously Q3W on a 21-day cycle. An accelerated titration design was used for the 0.3 and 0.6 mg/kg doses, followed by a 3+3 design for 1.2, 1.8, 2.7 and 3.6 mg/kg dose levels.

Results

As of August 23, 2023, 15 pts with solid tumors (breast [11], colorectal [2], gastric [1], lung [1]) were enrolled across doses of 0.3-3.6 mg/kg with a median age of 52 years (range 35-65), of which 9 pts received prior HER2-targeted therapy (trastuzumab ± pertuzumab) and 11 pts completed 21-day DLT assessment (0.3 mg/kg and 0.6 mg/kg [1 each], 1.2 mg/kg, 1.8 mg/kg and 2.7 mg/kg [3 each]) with no DLT incidence. Treatment-related adverse events (TRAE) occurred in 11 (73.3%) pts. The most frequent TRAEs were elevated liver enzymes [6], corneal epitheliopathy [5], dry eyes [4], leukopenia, neutropenia, proteinuria and anemia [3 each], and most were grade 1-2 in severity. 2 pts experienced grade 3 TRAEs: lymphocytopenia (1.8mg/kg [1]) and blurred vision (2.7 mg/kg [1]), which were manageable during treatment. TRAEs led to 6.7% (1/15) treatment discontinuation. Among 11 pts evaluated, 2 pts achieved a best tumor response of PR; 5 pts had SD; 1 pt had Non-CR/Non-PD per RECIST v1.1. Thus, disease control rate was 73% (8/11). Interim PK results demonstrated that the PK profile of total antibody was similar to that of ZV0203 ADC, whose systematic exposure increased in a dose-dependent manner. Concentration of DUO5 remained scarce, suggesting good stability of ZV0203.

Conclusions

ZV0203 has a manageable safety profile with preliminary antitumor activity in heavily pretreated pts with HER2+ cancer. Further evaluation at higher doses is underway.

Clinical trial identification

NCT05423977.

Editorial acknowledgement

Legal entity responsible for the study

Hangzhou Adcoris Biopharma Co., Ltd.

Funding

Hangzhou Adcoris Biopharma Co., Ltd.

Disclosure

Y. Huang, Y. Lu, F. Wang, Y. Huang, X. Huang: Financial Interests, Personal, Full or part-time Employment: Adcoris Biopharma. All other authors have declared no conflicts of interest.