Abstract LB024: Preclinical profile and first-in-human study design of KHN922, a novel dual-payload HER3-targeted ADC, for advanced solid tumors

Abstract HER3 (human epidermal growth factor receptor 3) is highly expressed in various solid tumors , where it drives tumor progression and confers therapy resistance through heterodimerization with EGFR or HER2. Although the single-payload HER3-targeted ADC patritumab deruxtecan has demonstrated promising efficacy in breast cancer and NSCLC, its progression-free survival benefit in NSCLC remains limited. To enhance efficacy and overcome resistance associated with single-payload topoisomerase I inhibitor (TOP1i)-based ADCs, we developed KHN922, a novel dual-payload antibody-drug conjugate (ADC). KHN922 consists of a humanized anti-HER3 IgG1 antibody that is conjugated, via cleavable linkers, to both exatecan (a DNA topoisomerase I inhibitor ) and triptolide (an RNA polymerase II inhibitor). This design induces downregulation of the chemoresistance marker HSP70, thereby augmenting antitumor activity. In preclinical studies, KHN922 demonstrated superior antitumor efficacy compared to patritumab deruxtecan at equivalent doses across multiple PDX models, including models resistant to EGFR TKIs in NSCLC and to trastuzumab deruxtecan (DS-8201) in gastric cancer. GLP toxicology studies in cynomolgus monkeys indicated a generally manageable profile, with hematological toxicity (neutropenia) as the dose-limiting finding at 40 mg/kg, and no observed special toxicities such as ocular toxicity or interstitial lung disease. Pharmacokinetics at 1-10 mg/kg showed approximately dose-proportional exposure increases for KHN922 analytes. Intact ADC and ADC-triptolide exhibited shorter half-life (∼20 h) than ADC-exatecan and total antibody (∼50 h). A translational framework integrating PK, tumor growth inhibition, and toxicity data supported a predicted therapeutic index in humans of 1.5 to 7.5 mg/kg administered every 3 weeks. The IND application is planned for the first half of 2026. A first-in-human, multicenter, open-label Phase I/II trial is designed to evaluate KHN922 in patients with advanced solid tumors who have failed standard therapy. The Phase I dose-escalation will employ a BOIN design (0.8 to 8.0 mg/kg, Q3W), followed by cohort backfill at the recommended dose(s). In Phase II, one to three dose levels will be expanded for optimization and to assess antitumor activity in specific cohorts, including NSCLC and HR+/HER2- breast cancer. Citation Format: Lu Qi, Rong Liao, Tian Qin, Gang Lei, Pengfei Ren, Zhengping Li, Xinzou Fan, Hao Huang, Yan Li, Yanhua Xu, Xiao Ke, Yonghao Zhao. Preclinical profile and first-in-human study design of KHN922, a novel dual-payload HER3-targeted ADC, for advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB024.