Efficacy and safety of HER2-ADC SHR-A1811 in HER2-positive breast cancer with brain metastases.

e13006 Background: A substantial proportion of patients with HER2-positive (HER2+) breast cancer would develop brain metastases. Systemic HER2-target therapy is a viable option for these patients. The new generation of HER2-directed antibody-drug conjugate (ADCs) has significantly altered the treatment landscape for breast cancer and has demonstrated promising results in patients with breast cancer brain metastases (BCBM). Therefore, we conducted a prospective, multi-arm, multi-cohort, phase 2 trial (NCT05769010) to evaluate the use of a novel HER2-target ADC SHR-A1811 in HER2-expressing BCBM. Methods: Patients with radiotherapy-naïve HER2-expressing BCBM, and not in need of immediate local treatment were enrolled, and they received SHR-A1811 as monotherapy (Arm 1 HER2+ and Arm 4 HER2-low) or in combination with pyrotinib or bevacizumab (Arm 2 and Arm 3 HER2+) until disease progression, unaccepted toxicity, or no further benefit. Here we present the interim results of Arm 1 consisted of HER2+ patients treated with SHR-A1811. Patients were required to have at least one measurable lesion as defined by RANO-BM criteria. Previous HER2-targeted treatments, chemotherapies, and endocrine therapies were allowed. The primary endpoint was the intracranial overall response rate (ORR-IC) according to RANO-BM. Key secondary endpoints included the overall response rate as per RECIST 1.1, progression-free survival, overall survival, and safety. Results: Between March 31, 2023, and November 3, 2023, 25 patients with HER2+ BCBM were enrolled in Arm 1, and they received SHR-A1811 at a dosage of 6.4mg/kg q3w. The median age of the participants was 53 years (range: 31-63), and 70% of patients had extracranial disease. All 25 participants were previously treated with HER2-targeted agents, with a median of 2 prior systemic therapies in advanced setting (range: 0-5), and 48% (12/25) had received prior BCBM-directed systemic therapies. As of January 30, 2024, all 25 patients had at least one efficacy assessment, and 21 achieved intracranial responses, with an ORR-IC of 84%. Considering the intra- and extracranial lesions together, the overall response rate was 76% (19/25). Treatment-related adverse events of grade 3 or 4 occurred in 19 patients (76%), including decreased neutrophil counts (64%), decreased leucocyte counts (48%), decreased platelet counts (28%), anemia (28%), decreased lymphocyte counts (20%), and nausea (8%). No grade 5 adverse event was reported. One patient who experienced two prior lines of BCBM-directed systemic therapies withdrew consent after 6 cycles of study agents with no progression, while the remaining patients were still undergoing treatment. Conclusions: Our interim results showed an inspiring intracranial response rate and an acceptable tolerance of the novel ADC SHR-A1811 in HER2+ BCBM. The enrollment of this study is ongoing, and the long-term outcomes will be followed up. Clinical trial information: NCT05769010 .