Abstract P2-13-10: First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study
Authors: Zhang Jian , Ji Dongmei , Cai Li , Yao Herui , Yan Min , Wang Xiaojia , Shen Weina , Du Yiqun , Pang Hui , Lai Xiuping , Zeng Huiai , Huang Jian , Sun Yan , Peng Xinxin , Xu Junfang , Yang Jing , Yang Fei , Xu Ting , Hu Xichun 
Published: March 2022

Abstract
PURPOSE KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This firstinhuman Phase I study evaluated the safety/tolerability, pharmacokinetics (PK), preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to HER2-positive metastatic breast cancer (MBC) patients. METHODS Female patients with HER2 positive MBC who failed prior antiHER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (QW), 10 mg/kg (QW), 20 mg/kg (Q2W), or 30 mg/kg (Q3W). Dose escalation was guided by a “3+3” doseescalation rule followed by dose expansion. The primary endpoint of the study was to assess safety and ascertain the recommended phase 2 dose (RP2D). RESULTS 63 patients were enrolled with a median of 3 prior lines of systemic therapies and 2 prior lines of HER2 targeted therapies. Treatment was well tolerated with no DLTs observed. The most common treatment related adverse events (TRAEs) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). 4 patients reported Grade 3 TRAEs. Pharmacokinetic analysis indicated that KN026 exposure was dose-dependent, with a terminal elimination halflife of 146 to 282 hours after multiple doses. Results from exposure-response analysis supported the selection of the RP2Ds at 20 mg/kg Q2W or 30 mg/kg Q3W, which had corresponding objective response rates (ORRs) of 32.1% and 24.1%, disease control rates of 60.7% and 82.8%, and median progression-free survival (PFS) of 5.5 and 7.4 months, respectively. Anti-drug antibodies (ADAs) were detected in 3.2% (2/63) of patients at the end of treatment. Cell line data showed that coamplification of HER2 and CDK12 were related to the efficacy of KN026. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no coamplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). CONCLUSION KN026, a HER2 bispecific antibody, is well tolerated, with a favorable safety profile and promising anti-tumor activity in the context of its class in patients with HER2-positive breast cancer. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.
Citation Format: Jian Zhang, Dongmei Ji, Li Cai, Herui Yao, Min Yan, Xiaojia Wang, Weina Shen, Yiqun Du, Hui Pang, Xiuping Lai, Huiai Zeng, Jian Huang, Yan Sun, Xinxin Peng, Junfang Xu, Jing Yang, Fei Yang, Ting Xu, Xichun Hu. First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-10.