Neoadjuvant treatment with the HER2-targeted monoclonal antibody inetetamab in combination with the irreversible pan-HER tyrosine kinase inhibitor pyrotinib (inhibits HER1, HER2, HER4) and chemotherapy produced high pathologic response rates in patients in China with HER2-positive locally advanced breast cancer, according to results from the prospective, multicenter, single-arm phase II neoPICD trial presented during the 2026 ASCO Breakthrough Meeting in Singapore.¹

Among 108 patients who received neoadjuvant therapy and were included in the primary analysis, the total pathologic complete response rate was 60.2%, and the breast pathologic complete response rate was 65.7%. The objective response rate was 92.6%, and the disease control rate was 100%.

Rationale for Dual HER2 Targeting

Taxane-based neoadjuvant chemotherapy plus trastuzumab and pertuzumab is a standard treatment strategy for patients with HER2-positive locally advanced breast cancer before surgery. Dr. Yang noted that prior pivotal studies of trastuzumab/pertuzumab-containing neoadjuvant regimens have produced pathologic complete response rates of approximately 45% to 68%. However, a substantial proportion of patients still do not achieve pathologic complete response, which may indicate a higher risk of recurrence.

Chenghui Yang, PhD: Photo by Todd Buchanan

The neoPICD trial evaluated a different HER2-targeted strategy using two agents developed in China: inetetamab and pyrotinib. Inetetamab is a HER2-targeted monoclonal antibody with a modified Fc region designed to enhance antibody-dependent cellular cytotoxicity. Pyrotinib is an irreversible pan-HER tyrosine kinase inhibitor targeting HER1, HER2, and HER4. Neither drug is currently approved by the U.S. Food and Drug Administration.

Dr. Yang described the rationale for the combination as dual HER2 targeting, with inetetamab blocking HER2 extracellularly and pyrotinib inhibiting HER signaling intracellularly. Both agents have shown activity in HER2-positive metastatic breast cancer, but their combined use as neoadjuvant therapy in nonmetastatic HER2-positive breast cancer had not been well established.

Trial Design and Patient Population

The prospective, multicenter, single-arm phase II neoPICD trial enrolled 124 patients with stage II to III nonmetastatic HER2-positive locally advanced breast cancer and high tumor burden across seven centers in China. The primary endpoint was total pathologic complete response. Secondary endpoints in the trial included breast pathologic complete response rate, objective response rate, safety, and longer-term outcomes including event-free survival, disease-free survival, and overall survival.

Patients received six cycles of neoadjuvant therapy every 3 weeks. The regimen consisted of inetetamab at an 8-mg/kg loading dose followed by 6 mg/kg every 3 weeks, pyrotinib at 400 mg orally once daily, docetaxel at 75 mg/m², and carboplatin at an area under the curve of 6. Surgery was performed 2 to 4 weeks after the last neoadjuvant cycle. After surgery, patients continued HER2-targeted treatment with inetetamab and pyrotinib to complete 1 year of therapy.

Of the 124 enrolled patients, 108 received neoadjuvant treatment and were included in the primary analysis. Sixteen patients discontinued treatment: 6 patients discontinued treatment because of adverse events and 10 discontinuted treatment because of noncompliance. The median age was 52 years. Overall, 37.1% of patients had stage II disease, and 62.9% had stage III disease. HER2 immunohistochemistry 3+ disease was reported in 83.1% of patients, 52.4% had hormone receptor–negative disease, and 76.6% had Ki-67 expression of at least 30%.

Pathologic Response and Subgroup Findings

After a median follow-up of 22.9 months, total pathologic complete response—defined as no invasive disease in the breast and lymph nodes—was achieved in 60.2% of patients. Breast pathologic complete response was achieved in 65.7%. Tumor shrinkage was common, with an objective response rate of 92.6%, and all patients had disease control.

Responses differed by hormone receptor status. Among patients with hormone receptor–negative tumors, the total pathologic complete response rate was 73.3%, compared with 43.8% among patients with hormone receptor–positive tumors. Breast pathologic complete response rates were 76.7% vs 52.1%, respectively.

Exploratory subgroup analyses also suggested higher total pathologic complete response rates among patients with HER2 immunohistochemistry 3+ disease. In multivariable logistic regression analysis, hormone receptor–negative status and HER2 immunohistochemistry 3+ status were identified as independent predictors of total pathologic complete response.

Adverse Events and Diarrhea

No treatment-related deaths were reported. Dr. Yang said most adverse events were grade 1 or 2 and manageable, and no new safety signals were observed.

Diarrhea was the most common adverse event, occurring in 73.1% of patients. Although diarrhea was frequent, Dr. Yang noted that grade 3 or higher diarrhea was uncommon. Other common toxicities were consistent with chemotherapy and HER2-targeted therapy and included anemia, nausea/vomiting, and decreased appetite.

Limitations and Next Steps

Dr. Yang acknowledged several limitations of the neoPICD trial, including its single-arm design, which limits direct comparison with current standard neoadjuvant regimens. Median follow-up was also relatively short, and longer-term outcomes such as event-free survival, disease-free survival, and overall survival remain immature. The high incidence of diarrhea was also noted as a limitation.

The investigators concluded that the regimen warrants evaluation in a larger randomized phase III trial. The research team plans longer-term follow-up to evaluate survival outcomes and further study the mechanism of the combination in HER2-positive breast cancer.

Expert Perspective

Rebecca Alexandra Dent, MD, MSc, FRCP, FASCO, Deputy Chief Executive Officer (Clinical) and Senior Consultant at the National Cancer Centre Singapore, and an ASCO Expert in breast cancer, said the prospective, multicenter, single-arm phase II neoPICD trial highlights “a promising new HER2-targeted combination” with notably high pathologic complete response rates in patients with locally advanced HER2-positive breast cancer.

Rebecca Alexandra Dent, MD, MSc, FRCP, FASCO

“While these results are encouraging, particularly for patients with high tumor burden and hormone receptor-negative disease, they come from a single-arm phase 2 trial,” Dr. Dent said. “Randomized studies comparing this approach with current standards, such as trastuzumab and pertuzumab-based regimens as well as the more recently approved trastuzumab deruxtecan, will be essential before this strategy can be widely adopted.” 

DISCLOSURE: Dr. Yang reported no conflicts of interest. Dr. Dent reported honoraria from AstraZeneca, BioNTech SE, Daiichi Sankyo/AstraZeneca, DKSH, Eisai, Gilead Sciences, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles with AstraZeneca, Daiichi Sankyo/AstraZeneca, Eisai, Gilead Sciences, MSD, Novartis, Pfizer, and Roche; institutional research funding from AstraZeneca and Roche; and travel, accommodations, or expenses from AstraZeneca, Daiichi Sankyo/AstraZeneca, Eisai, MSD, Novartis, Pfizer, and Roche. The study was funded by Wenzhou Medical University.

REFERENCE

1. Yang C, Xu Y, Wang O: Inetetamab combined with pyrotinib for neoadjuvant treatment of HER2-positive locally advanced breast cancer (neoPICD): A prospective, multicenter, single-arm phase II trial. 2026 ASCO Breakthrough Meeting. Abstract 27. Published June 23, 2026.