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

  • Clin Cancer Res. 2022 Feb 15;28(4):618-628. doi: 10.1158/1078-0432.CCR-21-2827.
Jian Zhang  #  1  2 ,  Dongmei Ji  #  1  2 ,  Li Cai  3 ,  Herui Yao  4 ,  Min Yan  5 ,  Xiaojia Wang  6 ,  Weina Shen  1  2 ,  Yiqun Du  1  2 ,  Hui Pang  3 ,  Xiuping Lai  4 ,  Huiai Zeng  5 ,  Jian Huang  6 ,  Yan Sun  1  2 ,  Xinxin Peng  7 ,  Junfang Xu  8 ,  Jing Yang  8 ,  Fei Yang  8 ,  Ting Xu  8 ,  Xichun Hu  1  2
Affiliations
  • 1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
  • 3. Department of Medical Oncology, Tumor Hospital of Harbin Medical University, Harbin, P.R. China.
  • 4. Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanghai, P.R. China.
  • 5. Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, P.R. China.
  • 6. Department of Medical Oncology, Zhejiang Cancer Hospital, Shanghai, P.R. China.
  • 7. Precision Scientific (Beijing) Co., Ltd, Beijing, P.R. China.
  • 8. Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, P.R. China.
  • # Contributed equally.
PMID: 34844975 DOI: 10.1158/1078-0432.CCR-21-2827
Abstract

Purpose: KN026 is a novel bispecific antibody that simultaneously 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 received 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 analysis 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.

Products