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

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 HER2-positive metastatic breast cancer patients. Experimental design Female patients with HER2 positive MBC who had progressed on prior anti HER2 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 dose escalation rule followed by dose expansion. Results Sixty-three patients were enrolled. The most common treatment related adverse events 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 2 doses at 20 mg/kg Q2W or 30 mg/kg Q3W, which had objective response rates (ORRs) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% CI: 4.2 to 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.