Promising New Drug Combination Shows High Efficacy in Advanced HER2+ breast Cancer
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A novel antibody-drug conjugate, SHR-A1811, combined with pertuzumab, is demonstrating significant promise in the treatment of patients with HER2-positive (HER2+) unresectable metastatic breast cancer (mBC), according to data presented at the European Society For Medical Oncology (ESMO) 2025 Congress in Berlin, Germany, on October 17-21, 2025.The phase 1b/2 trial (NCT05353361) revealed compelling efficacy and a manageable safety profile.
HER2-positive breast cancer,the most common subtype of the disease,accounts for nearly 70% of all diagnoses. This aggressive form of breast cancer requires continuous innovation in treatment strategies. antibody drug conjugates (ADCs) have become a cornerstone of therapy for patients with HER2 alterations, and ongoing research is crucial to improve outcomes.
SHR-A1811: A Novel Targeted Therapy
SHR-A1811 is a new ADC designed to target HER2. It consists of trastuzumab,linked to a topoisomerase I inhibitor payload via a cleavable linker. Prior to the combination study, SHR-A1811 demonstrated encouraging antitumor activity as a single agent (NCT04446260). The recent ESMO presentation focused on the results of combining SHR-A1811 with pertuzumab.
Phase 1b/2 Trial Results: efficacy and Safety
The phase 1b/2 open-label, multicenter trial evaluated the safety and efficacy of SHR-A1811 plus pertuzumab in patients with HER2+ unresectable or mBC. The study was divided into a dose-escalation phase (1b) and a phase 2 expansion.
In the dose-escalation phase, ten patients who had previously received trastuzumab with chemotherapy and at least one prior metastatic-setting therapy received intravenous SHR-A1811 at doses of 3.2 mg/kg, 4.8 mg/kg,or 6.4 mg/kg every three weeks, alongside standard-dose pertuzumab. Importantly, no dose-limiting toxicities where observed, supporting the evaluation of all three dose levels.
The phase 2 expansion involved 65 patients with either de novo metastatic disease or relapse occurring more than 12 months after completing (neo)adjuvant therapy. As of March 31, 2025, with a median follow-up of 22.2 months (range, 3.1-31.8 months), the results were compelling:
- Overall Response rate (ORR): 63.6% in the 3.2 mg/kg group, 86.4% in the 4.8 mg/kg group, and 84.4% in the 6.4 mg/kg group.
- Twelve-Month Progression-Free Survival: 100% in the 3.2 mg/kg group, 90.5% in the 4.8 mg/kg group, and 96.4% in the 6.4 mg/kg group.
Manageable Toxicity Profile
The combination of SHR-A1811 and pertuzumab demonstrated a manageable toxicity profile. The most common treatment-related adverse event was a decreased neutrophil count, occurring in 86.7% of patients, with over half experiencing grade 3 or higher neutropenia. Notably, no treatment-related deaths or cases of interstitial lung disease were reported.
Future Directions
“Findings from this phase 1b/2 study suggest that SHR-A1811 combined with pertuzumab produces high response rates and durable disease control, with a safety profile consistent with known ADC-based regimens,” stated a lead researcher involved in the study. the strong efficacy signals observed across all dose levels support continued inquiry of this combination as a potential new therapeutic option for patients with advanced HER2+ disease. Further research will be critical to confirm these findings in larger, randomized trials and to determine the optimal dose and schedule for this promising new regimen.
