SHR-A1811 as neoadjuvant therapy for HR-positive, HER2-low breast cancer: A single-arm, phase II clinical study.

594 Background: Human Epidermal Growth Factor Receptor ( HER2 ) -low breast cancer accounts for approximately 55% of all breast cancer cases, and it is more prevalent in hormone receptor-positive (HR+) breast cancer. Recent breakthroughs in anti-HER2 antibody-drug conjugates (ADCs) have revolutionized the therapeutic landscape for breast cancer treatment, particularly for HER2-low breast cancer. SHR-A1811 is an anti-HER2 ADC and has demonstrated acceptable tolerability and encouraging antitumor activity in HER2-low advanced breast cancer. Therefore, we conducted the phase 2 trial to investigate the efficacy and safety of SHR-A1811 as a neoadjuvant treatment in patients with HR+/HER2-low breast cancer. Methods: This is an open-label, two-stage, phase II clinical trial. In the first stage, 35 participants will be enrolled, and if at least 18 participants achieve an objective response rate (ORR), the trial will proceed to the second stage, enrolling an additional 31 subjects. Eligible patients are women aged 18-70 years; treatment-naïve; histologically confirmed invasive breast cancer stage cT2-3/N0-2M0; HR+/HER2-low, and the expression of Ki-67 exceeds 14%. Eligible patients receive SHR-A1811 as neoadjuvant therapy. SHR-A1811 is administered intravenously at a dose of 6.4 mg/kg once every three weeks for a total of eight cycles. The primary endpoint is ORR. Secondary endpoints include safety, residual cancer burden (RCB) 0-1, and pathologic complete response (pCR). Results: A total of 66 patients enrolled in this study. The median age was 49 years, with 84.8% (56/66) aged ≥ 40 years. Of all patients, 66.7% (44/66) were premenopausal, 66.7% (44/66) had node-positive disease, 86.4% (57/66) had stage II, 13.6% (9/66) had stage IIIA, and 74.2% (49/66) had HER2 expression of IHC 2+/FISH-, while 25.8% (17/66) were IHC 1+. In the modified intention-to-treat population (mITT, patients who received at least one cycle of study treatment and at least one post-baseline MRI assessment), 81.5% (53/65) of patients achieved an ORR, and two patients achieved a pathological complete response, resulting in a pCR rate of 3.1% (2/65). Additionally, the proportion of patients with RCB 0 or RCB I was 9.3% (6/65). 97% (64/66) of patients experienced at least one treatment-related adverse event (TRAE). Grade 3 or higher TRAEs occurred in 39.4% (26/66) of patients, with the most prevalent being neutropenia (27.3%, 18/66), leukopenia (16.7%, 11/66), and anemia (13.6%, 9/66). No interstitial lung disease (ILD) and treatment-related deaths were reported. Conclusions: As a neoadjuvant treatment, SHR-A1811 achieves a significant improvement in ORR and brings both pCR and RCB 0-I benefits in patients with HR+/HER2-low breast cancer. These outcomes support further exploration of SHR-A1811 in this patient population. Clinical trial information: NCT05911958 .