Abstract P5-02-34: Single-cell Analysis of KN026 in Combination with KN046 in Treating Patients with Advanced HER2-positive Breast Cancer

Abstract Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes (two different HER2 epitopes shared by trastuzumab and pertuzumab). KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86. Our on-going multi-centered phase II trial (NCT04521179) demonstrated that in advanced HER2-positive breast cancer (HER2+ BC) patients, who have progressed after prior anti-HER2 combinational therapies, the objective response rate (ORR) of this chemo-free therapy of KN026 in combination of KN046 was about 50.0% (SABCS 2021 poster P5-16-04). To explore the underlying mechanism of this regimen, we collected tumor specimens from patients before and after receiving this combinational treatment for single-cell analysis to provide an in-depth description of the tumor immune microenvironment and its correlation with treatment response. Methods: Paired tumor specimens before and after treatment of patients enrolled in the trial were collected for single-cell transcriptome and TCR sequencing. In addition, to reveal the immune cell characteristics of anti-HER2 resistant patients, we compared our data with previously reported single-cell analysis of treatment-naïve HER2+ BC. Results: We obtained 30 specimens from 17 patients, including 17 of pre-treatment and 13 of post-treatment. TCR expansion did not correlate with clinical efficacy. In-depth analysis of subpopulations revealed that compared to treatment-naive HER2+ BC, these enrolled prior anti-HER2-resistant patients had an additional population of T cells subpopulation characterized by CD4-low and CD8-low in their baseline tumor tissues, and the proportion of this subpopulation was significantly decreased after KN046 plus KN026 treatment in responding patients. Moreover, we found that patients with baseline CD8+ T/naïve T >1 tended to benefit more from this regimen. Conclusion: We identified a subpopulation of CD4-low and CD8-low T cells that may be associated with anti-HER2 resistance. And decreased of this subpopulation of T cells was associated with better ORR of KN046 in combination with KN026 treatment in heavily pretreated advanced HER2+ BC. Baseline CD8+ T/naïve T ratio in tumor is expected to be a predictor of ORR as well. Citation Format: Jieqiong Liu, Jianyou Liao, Zhenluan Tian, Jien Wang, Chuangui Song. Single-cell Analysis of KN026 in Combination with KN046 in Treating Patients with Advanced HER2-positive Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-34.