Spatial molecular analyses reveal key features associated with response to KN026 in advanced HER2-positive breast cancer

Background: KN026 is a novel bispecific HER2-targeting antibody for HER2-positive recurrent or metastatic breast Cancer that showed prolonged median PFS and lessened distinction of PFS regarding the HR subgroup in our phase II clinical trial, compared with PUFFIN study of first-line trastuzumab combined with pertuzumab therapy. A more detailed discovery of its peculiarity is needed for optimal application of KN026 treatment.

Methods: We performed whole-transcriptome Sequencing of digital spatial profiling (DSP) on 8 pre/post-treatment tumor samples. Mechanistic explorations were conducted by plasmid transfection, co-culture, CCK8 proliferation assay and flow cytometry.

Results: Compared to the tumor regions with non-objective response (OR), those with OR had high expression of CALML5, TFAP2B, and ERBB2, and relatively low expression of ESR1 in tumor cells at baseline. The expression of ESR1 had a tentative association with PI3K/Akt and Notch signaling pathways which were downstream or interactive pathways of HER2 target and also acted as interactive pathways of ER-mediated signaling. The co-expression of ERBB2 and CDK12 emerged as a distinctive signature of OR. KN026 treatment also reshaped intratumoral activated T- and B-cell subtypes in hot-tumor regions, regardless of myeloid-derived cells.

Conclusions: Both HER2 and ESR1 are determinant of KN026 efficacy in advanced HER2-positive breast Cancer, implying the potential of KN026 combined with endocrine therapy in HER2- and ER-positive breast Cancer.