First-in-Human HER2-Targeted Bispecific Antibody KN026 for HER2-Positive Metastatic Breast Cancer
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This first-in-human, phase I study of KN026, a novel HER2-targeted bispecific antibody, showed promising efficacy for the treatment of patients with HER2-positive metastatic breast cancer. The objective response rate was 28.1%, with a median progression-free survival of 6.8 months in a heavily pretreated population. Treatment was well-tolerated with mostly grade 1–2 adverse events. The most common adverse events were pyrexia, diarrhea, and transaminitis.
- The efficacy of KN026 was similar to that of trastuzumab and pertuzumab in this population. Co-amplification of CDK12 might be a promising biomarker in predicting the response to KN026.
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Reshma L. Mahtani DO
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
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.
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Additional Info
Disclosure statements are available on the authors' profiles:
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 Jan 04;[EPub Ahead of Print], J Zhang, D Ji, L Cai, H Yao, M Yan, X Wang, W Shen, Y Du, H Pang, X Lai, H Zeng, J Huang, Y Sun, X Peng, J Xu, J Yang, F Yang, T Xu, X HuFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.