First-in-human phase I/IIa clinical trial of ZV0203, a novel pertuzumab-based antibody-drug conjugate (ADC), in patients (pts) with Her2 positive advanced solid tumors

BackgroundZV0203 is a pioneering pertuzumab ADC targeting Her2 positive tumors, utilizing a tubulin inhibitor as its payload connected via a stable, protease-cleavable valine-citrulline linker. In preclinical studies, ZV0203 outperformed Kadcyla and Enhertu across various CDX models, demonstrating notable antitumor efficacy without significant toxicity. GLP toxicity study revealed high tolerability for ZV0203, with an estimated therapeutic index of 35.MethodsThis open-label, multicenter, phase 1 dose-escalation trial was conducted to evaluate the dose-limiting toxicity (DLT), safety, PK, immunogenicity, and preliminary efficacy of ZV0203 in pts with Her2 positive advanced solid tumors. ZV0203 was injected intravenously from 0.3 to 3.6 mg/kg (Q3W) in a 3+3 design with accelerated titration for the starting dose. Phase 2a study further characterized the safety and preliminary tumor response at doses of 4.3 and 5.0 mg/kg among 9∼18 Her2 positive advanced pts with esophageal, colorectal or prostate cancers.ResultsAs of April 25, 2024, phase 1 study has completed with an enrollment of 15 pts with various solid tumors (breast, colorectal, gastric, and lung), of which 9 pts had received prior Her2-targeted therapies. No DLTs and interstitial lung disease were observed. The most common treatment related adverse events (TRAEs) were primarily grade 1-2, including corneal epitheliopathy, elevated liver enzymes, dry eyes, and hematological effects such as neutropenia; five pts experienced grade 3 TRAEs, which were manageable. Among 14 response evaluated pts, the disease control rate (DCR) was 71.4% and 5 pts had partial responses (PR). At efficacious doses 2.7 and 3.6 mg/kg, 3 PR and 1 SD were observed with objective response rate (ORR) of 50% and DCR of 67%; among the 2 progression disease cases, one had received prior Her2-ADC (MMAE payload) treatment and another had new lesion of Her2 negative. PK results indicated excellent linker stability. Phase 2a enrollment is under way.ConclusionsZV0203, the first in class pertuzumab ADC, was well tolerated and demonstrated promising antitumor activity in heavily pretreated Her2 positive pts. The results support continued development.Clinical trial identificationNCT05423977.Legal entity responsible for the studyHangzhou Adcoris Biopharma Co., Ltd.FundingHangzhou Adcoris Biopharma Co., Ltd.DisclosureY. Huang: Financial Interests, Personal, Full or part-time Employment: Hangzhou Adcoris Biopharma Co., Ltd. Y. Lu: Financial Interests, Personal, Full or part-time Employment: Hangzhou Adcoris Biopharma Co., Ltd. X. Wang: Financial Interests, Personal, Full or part-time Employment: Hangzhou Adcoris Biopharma Co., Ltd. F. Wang: Financial Interests, Personal, Full or part-time Employment: Hangzhou Adcoris Biopharma Co., Ltd. X. Huang: Financial Interests, Personal, Full or part-time Employment: Hangzhou Adcoris Biopharma Co., Ltd. All other authors have declared no conflicts of interest.