SHR-A1811 Monotherapy Generates Similar pCR Rate as PCbHP in HER2+ Breast Cancer

Neoadjuvant SHR-A1811 monotherapy, a third-generation HER2-directed antibody-drug conjugate (ADC), demonstrated a similar pathologic complete response (pCR) rate compared with both SHR-A1181 plus pyrotinib and nab-paclitaxel (Abraxane) plus carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta; PCbHP) in patients with stage II or III HER2-positive breast cancer, according to data from the phase 2 FASCINATE-N trial (NCT05582499).¹

Data published in the Annals of Oncology revealed that among patients evaluated for pCR in the intent-to-treat population (ITT; n = 265), the pCR rate was 63.2% (90% CI, 53.9%-71.8%) in the SHR-A1811 arm (n = 87; hormone receptor (HR) positive, 50%; HR negative, 74.5%), 62.5% (90% CI, 53.2%-71.1%) in the SHR-A1811 plus pyrotinib arm (n = 88; 44.7%; 76%), and 64.4% (90% CI, 55.3%-72.8%) in the PCbHP arm (n = 90; 54.1%; 71.7%).

“The pCR rates observed with the ADC-based regimens were comparable to those achieved with the combination of taxane, platinum, trastuzumab, and pertuzumab,” lead study author Junjie Li, MD, deputy chief physician and associate professor in the Department of Breast Surgery at Fudan University Shanghai Cancer Center in China, and coauthors wrote in the publication. “Nevertheless, the substantial activity observed with SHR-A1811 monotherapy suggests that it may serve as a backbone for new therapeutic strategies. The combination with other treatments, including immunotherapy and other targeted therapies, warrants further investigation in future trials.”

Diving Into the Background and Design of FASCINATE-N

Previously, in a global, first-in-human phase 1 study (NCT04446260), SHR-A1811 demonstrated acceptable tolerability and preliminary antitumor activity for the treatment of patients with HER2-expressing or -mutated unresectable, advanced, or metastatic solid tumors that were refractory or intolerant to standard therapies.² Of note, the overall response rate (ORR) in evaluable patients with solid tumors (n = 307) was 59.9% (95% CI, 54.2%-65.5%).

The randomized, open-label, single-center FASCINATE-N study in China included patients at least 18 years of age with pathologically confirmed HER2-positive breast cancer defined by an immunohistochemistry (IHC) score of 3+ or 2+ with in situ hybridization amplification on the primary tumor, according to the ASCO/College of American Pathologists guidelines.¹ Furthermore, patients were required to have an ECOG performance status of 0 or 1, a left ventricular ejection fraction of at least 55%, and no exposure to prior systemic therapy. A primary tumor measuring at least 2 cm, histologically confirmed early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0) breast cancer was also mandated.

Patients on the study were randomly assigned 1:1:1 to either receive SHR-A1811 alone, SHR-A1811 plus pyrotinib, or the PCbHP regimen. Those in the SHR-A1811 arms were treated with the ADC at a dose of 4.8 mg/kg every 3 weeks for 8 cycles with or without the irreversible dual pan-HER2 receptor TKI pyrotinib at a dose of 240 mg once daily. Patients treated with the PCbHP regimen received 100 mg/m² of nab-paclitaxel on days 1, 8, and 15 in a 28-day cycle for 6 cycles; carboplatin at an area under the curve of 1.5 mg/mL/min on days 1, 8, and 15 in a 28-day cycle for 6 cycles; trastuzumab at an initial dose of 8 mg/kg plus a subsequent dose at 6 mg/kg every 3 weeks; and pertuzumab at an initial dose of 840 mg plus a subsequent dose of 420 mg every 3 weeks.

The primary end point was pCR; secondary end points included invasive disease-free survival, ORR, and safety.

In the ITT population, most patients were 35 to 59 years of age (76.2%), and 56.6% of patients had HR-negative status. Additionally, the most common clinical nodal stage was N1 (40.0%), and most patients had stage III disease at baseline (69.8%). Represented clinical tumor sizes were T1 (3.0%), T2 (50.9%), T3 (50.9%), T4 (24.5%), and Tx (2.3%). Locally advanced breast cancer was also the most common stage (63.8%). Moreover, most patients had Ki-67 expression of 30% or greater (87.9%), an IHC score of 3+ (87.9%), and a HER2 copy number of 6 or greater (89.8%).

Tumor Regression Rates and Safety Data

Every 2 cycles, a tumor evaluation was conducted using breast MRI, of which the best percentage changes from baseline diameters were reported. Notably, the tumor regression rates were similar across the 3 arms. The median best percentage reduction from baseline in the sum of diameters of target lesions following 2, 4, and 6 cycles of treatment was 55.6%, 74.5%, and 84.2% in the SHR-A1811 monotherapy arm; 55.6%, 74.3%, and 84.2% in the SHR-A1811 plus pyrotinib arm; and 56.0%, 74.5%, and 84.0% in the PCbHP arm, respectively.

Regarding safety, grade 3/4 treatment-related adverse effects (TRAEs) were observed in 44.8%, 71.6%, and 38.8% of patients in the SHR-A1811 monotherapy, SHR-A1811/pyrotinib, and PCbHP arms, respectively. Treatment discontinuation rates due to TRAEs were reported in 5.7%, 29.9%, and 16.7% of patients in the respective arms.

Of note, a higher incidence of grade 3 diarrhea was observed in the SHR-A1811 plus pyrotinib arm (9.1%). Additionally, the incidence of several non-hematologic AEs, including alopecia, diarrhea, and peripheral sensory neuropathy was lower in the SHR-A1811 arm compared with the PCbHP arm. Furthermore, the incidence of grade 4 neutropenia was 10.3% in the SHR-A1811 arm, 25% in the SHR-A1811/pyrotinib arm, and 2.2% in the PCbHP arm.

“In this study, 45% of the SHR-A1811 [monotherapy] AEs were grade 3 [or greater],” the study authors stated. “Consistent with the findings from previous studies of third-generation HER2-targeted ADCs, the safety profile with SHR-A1811 was generally manageable.”

References

1. Li JJ, Wang ZH, Chen L, et al. Efficacy and safety of neoadjuvant SHR-A1811 with or without pyrotinib in women with locally advanced or early HER2-positive breast cancer: a randomized, open-label, phase II trial. Ann Oncol. 2025;36(6):651-659. doi:10.1016/j.annonc.2025.02.011
2. Yao H, Yan M, Tong Z, et al. Safety, efficacy, and pharmacokinetics of SHR-A1811, a human epidermal growth factor receptor 2-directed antibody-drug conjugate, in human epidermal growth factor receptor 2-expressing or mutated advanced solid tumors: a global phase I trial. J Clin Oncol. 2024;42(29):3453-3465. doi:10.1200/JCO.23.02044