460MO Preliminary results from a phase I study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers

Abstract

ZW49 is a novel ADC comprised of a HER2-targeting bispecific antibody (directed against 2 non-overlapping HER2 epitopes) attached to a proprietary auristatin toxin with a protease-cleavable linker. The results from this ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233) are presented. DE: In a 3+3 design, patients (pts) with HER2+ cancers were dosed with ZW49 IV QW (3 weeks on, 1 off; 1-1.75 mg/kg), Q2W (1-2 mg/kg) or Q3W (2-3 mg/kg). DX: Pts with centrally confirmed HER2+ cancers and measurable disease received ZW49 at the recommended dose(s)(RD[s]) determined in DE. Primary endpoints are safety and tolerability assessments; secondary endpoints include response assessments per RECIST v1.1. As of 10 Mar 2022, 76 pts (DE [51] and DX [25]; female: 58%; median age: 59 years [range, 24-83]) have been treated with ZW49. Overall, the most common histologies were gastric (28%) and breast (22%) cancers; 70% received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range: 1-16). A RD of 2.5 mg/kg was identified for the Q3W schedule. One dose-limiting toxicity of Grade [Gr] 2 keratitis > 14 days was observed in 1 pt and resolved to Gr 1 (2.5 mg/kg Q3W DX cohort). 68 (89%) pts had treatment-related adverse events (TRAEs); majority were Gr 1 or 2 in severity. The most common TRAEs (≥ 20% pts) included keratitis (42%), alopecia (25%), and diarrhea (21%). 7 (9%) pts had Gr ≥ 3 TRAEs, including 2 Gr 4 events (infusion-related reaction [1 pt] and decreased neutrophil count [1 pt]). Serious TRAEs were reported in 3 pts, leading to 1 discontinuation (D/C); 2 other pts had D/C due to TRAE. No interstitial lung disease nor TR deaths were reported. Among 29 response-evaluable pts treated with ZW49 at 2.5 mg/kg Q3W, the confirmed objective response rate across multiple cancer types was 28% and disease control rate was 72%. ZW49 has a manageable safety profile with encouraging single-agent antitumor activity in heavily pretreated pts with HER2+ cancers. Enrollment continues at 1.75 mg/kg QW in DE and 1.5 mg/kg QW in DX.