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

作者：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^*

来源：Clinical Cancer Research, 2022, 28(4): 618-628.

DOI：10.1158/1078-0432.CCR-21-2827

• TRASTUZUMAB
• PERTUZUMAB
• EFFICACY
• SAFETY
• GENES

Purpose: KN026 is a novel bispecific antibody that simulta-neously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC). @@@ Patients and Methods: Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies receiv-ed intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a "3+3" dose escalation rule followed by dose expansion. Results: Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. @@@ Results from exposure-response anal-ysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2-8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). @@@ Conclusions: KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

• 单位
  中山大学; 复旦大学; 哈尔滨医科大学