Abstract B130: Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers
Authors: Oh Do-Youn , Bedard Philippe L , Lee Keun-Wook , Han Hyo Sook , Kang Yoon-Koo , Miller Wilson H , Rha Sun Young , Kim Jwa Hoon , Dotan Efrat , Liao Chih-Yi , Tolcher Anthony , Spira Alexander , Hamilton Erika , Karapetis Christos , Boyken Lisa , Chen Charles , Woolery Joseph , Jhaveri Komal 
Published: December 2023

Abstract
Background ZW49 is a novel, humanized, antibody-drug conjugate comprised of a bispecific antibody directed against 2 non-overlapping HER2 epitopes and attached to a proprietary auristatin toxin with a protease-cleavable linker. Here we present data supporting the selection of the ZW49 RD in an ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233).1
Methods The 3+3 DE phase evaluated safety and tolerability of ZW49 IV (1-1.75 mg/kg QW; 1-2 mg/kg Q2W; and 2-3 mg/kg Q3W) in pts with HER2+ cancers. The DX phase further evaluated safety and antitumor activity of ZW49 IV (1.25 and 1.5 mg/kg QW; 2.5 mg/kg Q3W) in pts with centrally confirmed HER2+ (IHC 3+ or IHC 2+/FISH+) cancers. Primary endpoints are safety, tolerability, and maximum tolerated dose/RD. Secondary endpoints are pharmacokinetics (PK) parameters and response per RECIST1.1. Analyses of data for 66 pts treated with ZW49 at select cohorts/regimens in DE and DX are herein presented.
Results As of 19 Dec 2022, 66 pts (n = 18, 1.25 mg/kg QW; n = 18, 1.5 mg/kg QW; and n = 30, 2.5 mg/kg Q3W; male, 52%; median age, 60.5 years [range, 32 – 83]) were treated with ZW49 in the selected population. The most common cancer types were gastric (35%) and breast (15%); 67% of pts had received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range, 1 – 13). The overall incidence of treatment-related adverse events (TRAEs) was 91% (100% [18/18 pts] in 1.5 mg/kg QW, 93% [28/30 pts] in 2.5 mg/kg Q3W, and 78% [14/18 pts] in 1.25 mg/kg QW regimens). Overall, the most common (≥ 20%) TRAEs were keratitis (44%), alopecia (26%), and diarrhea (24%); the majority were Grade (Gr) 1 or 2 in severity; Gr 3 or 4 TRAEs occurred in 14 (21%) pts. Serious TRAEs occurred in 4 (6%) pts. Eight pts discontinued (D/C) due to TRAEs, including 1 pt D/C due to a serious TRAE (Gr 4 infusion-related reaction [IRR]; 2.5 mg/kg Q3W). No interstitial lung disease or TR-deaths were reported. Seven dose-limiting toxicities (DLTs) occurred, including 4 DLTs in 1.5 mg/kg QW (3 Gr 2 keratitis events and 1 Gr 3 diarrhea), 2 DLTs in 1.25 mg/kg QW (Gr 3 blurred vision and Gr 3 IRR), and 1 DLT in 2.5 mg/kg Q3W (Gr 2 keratitis) regimens. The 1.5 mg/kg QW regimen was closed due to the frequency of DLTs and dose modifications observed. The safety profile was comparable between the 1.25 mg/kg QW and 2.5 mg/kg Q3W regimens. Preliminary PK analyses indicated that the half-life was similar across these dose/regimens. The confirmed objective response rate and disease control rate in HER2+ response-evaluable pts were 6% (1/17 pt) and 53% (9/17 pts) in 1.25 mg/kg QW regimen; and 31% (9/29 pts) and 72% (21/29 pts) in 2.5 mg/kg Q3W regimen, respectively. Based on these results, 2.5 mg/kg Q3W regimen was chosen as the RD.
Conclusions ZW49 2.5 mg/kg Q3W IV was well tolerated, showed encouraging antitumor activity in heavily pretreated pts with advanced HER2+ cancers, and has been identified as the RD for further clinical development.
References 1 Jhaveri K, et al.; ESMO; Sep 09 -13 2022
Citation Format: Do-Youn Oh, Philippe L Bedard, Keun-Wook Lee, Hyo Sook Han, Yoon-Koo Kang, Wilson H Miller, Sun Young Rha, Jwa Hoon Kim, Efrat Dotan, Chih-Yi Liao, Anthony Tolcher, Alexander Spira, Erika Hamilton, Christos Karapetis, Lisa Boyken, Charles Chen, Joseph Woolery, Komal Jhaveri. Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B130.