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

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.

HLX11, a Proposed Pertuzumab Biosimilar: Pharmacokinetics, Immunogenicity, and Safety Profiles Compared to Three Reference Biologic Products (US-, EU-, and CN-Approved Pertuzumab) Administered to Healthy Male Subjects

“…HLX11 and pertuzumab (US-, EU-, and CN-approved products) had similar serum drug concentrations versus time profiles. According to the bioequivalence evaluation trial of pertuzumab biosimilars, the PK profile of HLX11 obtained in this study was similar to that of other pertuzumab biosimilars reported in healthy adults [ 18 ]. A study on pertuzumab injection (a biosimilar of pertuzumab produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd) showed that under the 90% CIs, the GMRs of the primary PK parameters of AUC 0– t , C max , and AUC 0–∞ for pertuzumab and the originator of pertuzumab (produced by Roche Pharma AG) were 100.42%, 96.71%, and 101.47%, respectively, and the 90% CIs were all within 80–125%, meeting the bioequivalence standards [ 19 ].…”

Genetically engineered macrophage membrane-coated nanoparticles for enhanced tumor targeting and synergistic cancer therapy

“…Herein, PCa was used as a proof of concept to successfully demonstrate the effectiveness of our strategy. In addition to PSMA, there are many active molecules expressed on the surface of tumor cells, like epidermal growth factor receptor (EGFR), 48 human epidermal growth factor receptor 2 (HER2), 49 and Glypican-3 (GPC3). 50 Therefore, by TM-expressing the corresponding antibodies or speci c ligands on macrophages, our strategy could be further expanded for targeting other cancers, such as lung cancer, breast cancer, and hepatocellular carcinoma.…”

Targeting HER2-positive breast cancer: advances and future directions

“…KN026 is a bispecific antibody that targets two distinct epitopes on HER2 (domains II and IV) leading to dual HER2 signal blockade, presumably by causing HER2 to aggregate on the cell surface and endocytose. Results of a FIH trial of KN026 in heavily pretreated patients with HER2 + MBC showed a 28% objective response rate (ORR) and a median PFS of 6.8 months 163 . Translational research suggested that patients with co-amplification of CDK12 and HER2 had better responses to KN026 than patients without the co-amplification.…”