Neoadjuvant SHR-A1811 shows promise in treatment of HER2-positive breast cancer

The third-generation human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugate (ADC) SHR-A1811 has passed its phase II trial, demonstrating safety and efficacy in the neoadjuvant setting for patients with HER2-positive breast cancer.

“This trial is the first to demonstrate the efficacy and safety of third-generation HER2-directed ADCs and ADCs combined with tyrosine kinase inhibitors (TKIs) in the neoadjuvant treatment of HER2-positive breast cancer,” the researchers said.

Between 27 December 2022 and 11 February 2024, 265 patients aged ≥18 years with stage II-III HER2-positive breast cancer were randomized to receive neoadjuvant treatment either with SHR-A1811 monotherapy (n=87), SHR-A1811 with pyrotinib (n=88), or nab-paclitaxel combined with carboplatin, trastuzumab, and pertuzumab (PCbHP; n=90) for 24 weeks.

Safety analysis was carried out in patients receiving at least one dose of the study medication.

The baseline characteristics did not significantly differ across treatment groups. Of the patients, about 45 percent were hormone receptor (HR)-positive, and 70 percent had stage III disease. [Ann Oncol 2025;36:651-659]

Primary endpoint

The rate of pathological complete response (pCR), the primary endpoint, was 63.2 percent for SHR-A1811 monotherapy (50 percent for HR-positive and 74.5 percent for HR-negative), 62.5 percent for SHR-A1811 plus pyrotinib (44.7 percent for HR-positive and 76 percent for HR negative), and 64.4 percent for PCbHP (54.1 percent for HR-positive and 71.7 percent for HR-negative).

No significant between-group differences were noted.

Regarding safety, 44.8 percent of patients on SHR-A1811 monotherapy, 71.6 percent of those on SHR-A1811 plus pyrotinib, and 38.8 percent of those on PCbHP developed grade ≥3 treatment-related adverse events. One patient had grade 2 interstitial lung disease in SHR-A1811, and 9.1 percent had grade 3 diarrhoea in SHR-A1811 plus pyrotinib. Treatment-related deaths were not recorded.

“Neoadjuvant SHR-A1811 showed robust activity and a favourable safety profile as monotherapy with a pCR rate of up to 63.2 percent, presenting a potential alternative to the conventional four-drug combination regimen,” the researchers said.

“Future trials may explore whether SHR-A1811 can serve as a backbone and be combined with other target drugs in the neoadjuvant setting,” they added.

Limitations

This study, however, was limited by its single-centre design, and only 265 patients were included after the enrolment was terminated based on the Bayesian analysis of the pCR rates of the first 60 patients in each group, which showed neither superiority nor inferiority.

“Although each study arm had a pCR rate over 60 percent, suggesting the potential efficacy of the SHR-A1811-based regimen, a prospective phase III study should be conducted,” the researchers said.

In addition, some features of the HER2-positive patients who stand to benefit more from HER2-directed ADC or ADC combined with TKIs remained hazy. Thus, the number of cycles and drug dosage need to be explored, according to the researchers.

Another limitation was the different treatment cycles between groups, which could have influenced the pCR rate. Finally, the appropriate adjuvant treatment for patients receiving the SHR-A1811-based regimen must be further analysed, both in those who achieved pCR and those who did not.

“HER2-positive breast cancer is an inherently aggressive subtype that accounts for [approximately] 15 percent to 20 percent of all breast cancers, and neoadjuvant therapy is routinely recommended for stage II and III disease,” the researchers said. [Lancet 2017;389:2415-2429]