Hangzhou Adcoris Biophama Co. Ltd (Adcoris) presented preliminary phase 1 clinical study results for ZV0203 (ADC2122) as a poster at the 2023 ESMO (European Society for Medical Oncology) Congress (Oct. 20-24, Madrid, Spain) that attracted over 33000 attendees of oncologists, medical experts and drug research and development scientists from all over the world.
At the congress, many medical advances in clinical oncology, including novel therapeutics, diagnostic methods and combination therapy were presented, of which ADC took the spotlight for multiple breakthroughs. For the first time, Adcoris released preliminary phase 1 clinical data as a poster exhibition for ZV0203 (ADC2122), a first-in-class (FIC) pertuzumab ADC that was developed in-house with HER2 tumor associated antigen as its target and tubulin inhibitor duostatin-5 (DUO5) as its payload via a stable and protease-cleavable valine-citrulline linker. A multicenter phase 1 clinical study, led by Professor Jin Li from Shanghai East Hospital, has been completed in 6 dose enrollments, including 0.3, 0.6, 1.2, 1.8, 2.7 and 3.6 mg/kg, and demonstrated to be safe, tolerable and efficacious. During the exhibition, many conference attendees from all over the world stopped by and had a variety of warm exchanges and discussions in a wide range of interest with the presenter.
ZV0203 Poster Display
ZV0203 (ADC2122) is the world's first pertuzumab ADC entering clinical study. Its structure contains a biosimilar of pertuzumab that is site-specifically conjugated to a highly active tubulin inhibitor DUO5 through a valine-citrulline dipeptide linker with a DAR value of 2. Pertuzumab antibody targets domain II of the HER2 receptor and blocks the homodimerization of HER2 and HER2 as well as the heterodimerization of of HER2 and EGFR, HER2 and HER3, and HER2 and HER4. Whereas, trastuzumab mainly blocks HER2 and HER2 homodimerization. Preliminary phase 1 results from safety, tolerability and preliminary efficacy evaluations indicated there were no DLT (dose-limiting toxicity) events, no SAE (serious adverse events), and no SUSAR (suspicious and unexpected serious adverse reactions). In addition, doses above 1.2 mg/kg showed significant anti-tumor effects. ZV0203 is currently in planning for clinical Ib/IIa dose expansion study.
More information about ZV0203（ADC2122）
1、Background
HER2 is a clinically proven target with significant therapeutic effect and highly expressed in a variety of solid tumors, such as breast cancer, gastric cancer and urothelial carcinoma. Three ADC products targeting HER2, T-DM1, T-Dxd and RC-48, have been approved in USA (2) and China (3) for the treatment of breast cancer (high expression), breast cancer (high, medium and low expression of HER2) and gastric cancer (high expression), respectively. However, these ADC products are all based on trastuzumab coupled to different linkers and payloads. Pertuzumab not only inhibits homodimerization but also heterodimerization. In addition, pertuzumab has high affinity for HER2 and good internalization rate after binding and their affinity decreases as the increase of pH. As a result, HER2 is recycled onto the cell membrane without causing drug resistance. Therefore, pertuzumab may have better pharmacological attribute as an Ab of ADC.
2、Molecular Structure of ZV0203
3、Clinical Study Design
This multicenter, open-label, first-of-its-kind human phase I trial enrolled subjects with HER2-expressing solid tumors. The primary endpoints include safety and tolerability, recommended Phase II dose (RP2D), and secondary endpoints include pharmacokinetics (PK), immunogenicity, and initial efficacy.
4、Safety
1. The most common adverse events were corneal epitheliopathy (7), dry eye (6), elevated liver enzymes (6), anemia (4), keratitis, leukopenia and neutropenia (3 cases each), most of which were grade 1/2.
2. 3 subjects had grade 3 adverse events: lymphocytopenia (1), blurred vision (2), and keratitis (1), which were manageable during treatment;
3. No grade 4 or 5 adverse events were observed.
5、Efficacy
1. Low doses showed good efficacy: partial responses (PR) were observed in both 1.2mg/kg and 1.8mg/kg groups.
2. The antitumor effects of high doses were superior: 2 cases of PR in 2.7mg/kg group and 1 case of PR and 1 case (-15%) SD in 3.6mg/kg group; The subjects currently remain to be in the treatment group, and the tumors continue to shrink.
3. PR and ORR (objective response rate) were 100% in both subjects with colorectal cancer after previous multiline therapy.
6、Conclusions:
ZV0203 (ADC2122), the world’s FIC pertuzumab ADC approved for clinical trial, has a good safety, tolerability, and antitumor activity at and above moderate dose levels in patients with HER2+ tumors.