HER2-ADC trastuzumab rezetecan (SHR-A1811) in HER2-positive breast cancer with brain metastases: Update results from REIN trial.

1017 Background: HER2-directed antibody-drug conjugates (ADCs) have been demonstrated to be of intracranial activity in patients with HER2+ breast cancer (BC) with brain metastases (BM). Our prospective, non-randomized phase 2 trial (NCT05769010) aimed to assess the feasibility of SHR-A1811, a novel HER2-target ADC, with or without other anti-tumor agents in HER2-expressing BCBM. Here we report the data of SHR-A1811 combined with bevacizumab in HER2+ BCBM, and update the results of SHR-A1811 in HER2+ BCBM (preliminary ORR data of the first 25 patients in Arm 1 has been published at 2024 ASCO), presenting the efficacy and safety of SHR-A1811 alone or in combination in the treatment of HER2+ BCBM. Methods: Patients with HER2-positive or -low BC with at least one radiotherapy-naïve measurable intracranial lesion were eligible for our trial. The patients with HER2+ disease enrolled in Arm 1 received SHR-A1811 6.4 mg/kg every 3 weeks, while those in Arm 3 were assigned to SHR-A1811 4.8 mg/kg and bevacizumab 15 mg/kg every 3 weeks until disease progression, unaccepted toxicity, or no further benefit. The primary endpoint was the intracranial overall response rate (ORR-IC) per RANO-BM. Results: Between March 30, 2023, and June 3, 2024, 58 patients were enrolled in Arm 1 (n = 33) and Arm 3 (n = 25). Among these, 56 patients (96.6%) had received anti-HER2 therapy previously, and the median number of prior systemic therapies in advanced setting was 2 (range: 0-9). 54 patients received at least one efficacy assessment and the confirmed ORR-IC in Arm 1 and Arm 3 were 84.4% (27/32) and 72.7% (16/22) respectively, which were numerically identical to the overall ORR in each arm, and all patients achieved intracranial disease control. As of December 31, 2024, the median PFS of Arm 1 was 13.2 (95% CI: 10.0-15.4) months, while the median PFS of Arm 3 was not mature. 78.8% (26/33) of patients in Arm 1 and 48.0% (12/25) in Arm 3 experienced treatment-related adverse events (TRAEs) of grade 3 or 4, and the frequencies of grade 4 TRAEs were 36.4% and 4% respectively. The grade 3/4 TRAEs that occurred in more than one patient included decreased neutrophil counts (Arm 1 / Arm 3: 69.7% / 36.0%), decreased leucocyte counts (51.5% / 16.0%), decreased platelet counts (30.3% / 0%), anemia (21.2% / 8.0%), decreased lymphocyte counts (21.2% / 0%), and nausea (6.1% / 0%). Conclusions: Our findings showed that SHR-A1811 6.4 mg/kg solely or SHR-A1811 4.8 mg/kg combined with bevacizumab both can attain high intracranial remission rates, while the lower-dose combination regimen might exhibit a better safety profile. The long-term outcomes will continue to be followed up. Clinical trial information: NCT05769010 .