SHR-A1811, a novel anti-HER2 antibody-drug conjugate (ADC), has demonstrated promising anti-tumor activity and an acceptable safety profile in patients with HER2-expressing breast cancer, according to data presented at the 2024 San Antonio Breast Cancer Symposium (SABCS). The findings come from two separate phase 2 trials evaluating SHR-A1811 in different breast cancer subtypes.
Activity in HR-Positive/HER2-Low Breast Cancer
In a single-arm phase 2 trial (NCT05911958), SHR-A1811 was evaluated as neoadjuvant treatment in 35 patients with hormone receptor (HR)-positive/HER2-low breast cancer. The primary endpoint was objective response rate (ORR). The study met its primary endpoint, with 26 of 35 evaluable patients achieving a response, resulting in an ORR of 74.3%. This included 26 partial responses and 9 instances (25.7%) of stable disease. No patients achieved a pathological complete response (pCR) in this stage of the trial.
As of the data cutoff date of June 17, 2024, 34 patients had completed the treatment regimen of 6.4 mg/kg of intravenous SHR-A1811 once every 3 weeks for 8 cycles, followed by surgery. The median age of patients was 49 years (range, 35-63), with the majority having an ECOG performance status of 0. Most patients (74.3%) had node-positive disease and a baseline HER2 expression of IHC 2+.
Treatment-related adverse events (TRAEs) occurred in all patients, with grade 3 or greater TRAEs reported in 65.7% of patients. Common grade 3 or higher TRAEs included neutropenia (48.6%), leukopenia (28.6%), and anemia (22.9%). The most common any-grade TRAEs included nausea (88.6%), asthenia (82.9%), vomiting (77.1%), leukopenia (65.7%), neutropenia (62.9%), and anemia (60.0%). No interstitial lung disease (ILD) or treatment-related deaths were observed.
FASCINATE-N Trial in HER2-Positive Breast Cancer
Results from the randomized (1:1:1) phase 2 FASCINATE-N trial (NCT05582499) evaluating neoadjuvant SHR-A1811 alone or in combination with other agents in adult patients with HER2-positive breast cancer were also presented at SABCS. Patients were randomized to receive SHR-A1811 monotherapy, SHR-A1811 plus pyrotinib (a tyrosine kinase inhibitor approved in China), or nab-paclitaxel combined with carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta; PCbHP).
The primary endpoint of the FASCINATE-N study was pCR. The pCR rate was 63.2% in the SHR-A1811 arm, 62.5% in the SHR-A1811 plus pyrotinib arm, and 64.4% in the PCbHP arm. Junjie Li, MD, associate chief physician, Fudan University Cancer Hospital, Shanghai, China, noted that there was no significant difference in pCR rate among the three groups. In HR-negative patients, pCR rates were 74.5%, 76.0%, and 71.7% in the respective arms. In HR-positive patients, pCR rates were 50.0%, 44.7%, and 54.1%, respectively.
Grade 3 to 4 TRAEs were observed in 44.8% of patients in the SHR-A1811 arm, 71.6% in the SHR-A1811 plus pyrotinib arm, and 38.8% in the PCbHP arm. AEs leading to dose reductions and treatment discontinuation were also reported, with the combination arm showing higher rates of discontinuation.
"In the era of the ADC combinations, whether that’s immune therapy or endocrine therapy, we hope SHR-A1811 can serve as a backbone for future treatment," Li concluded.
