Addition of Pembrolizumab to Neoadjuvant Chemotherapy in Early-Stage HER2-Negative Breast Cancer

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As reported in JAMA Oncology by Rita Nanda, MD, and colleagues, findings from the ongoing phase II I-SPY 2 trial indicated that the addition of pembrolizumab to standard neoadjuvant chemotherapy improved pathologic complete response rates in patients with high-risk stage II/III HER2-negative breast cancer.

Rita Nanda, MD

Rita Nanda, MD

I-SPY 2 is an ongoing, open-label, multicenter, adaptively randomized phase II platform trial for high-risk stage II/III breast cancer that is evaluating multiple investigational groups in parallel, with standard taxane- and anthracycline-based neoadjuvant chemotherapy serving as the control treatment. Patients were classified into subtypes based on hormone receptor (HR)-positive, HER2-positive, and MammaPrint high-risk status, based on biomarker assessments (70-gene MammaPrint and TargetPrint ERBB2 gene expression assays) performed at baseline. Investigational arms are “graduated” if they demonstrate an 85% predictive probability of success in a hypothetical confirmatory phase III trial. Patients with MammaPrint low-risk status or HER2-negative disease were excluded from I-SPY 2 because escalation of therapy is not justified in these subgroups. Those patients with HER2-negative disease are eligible for randomization to the pembrolizumab arm.

Study Details

In the current component of the trial, 181 women were randomly assigned to the standard neoadjuvant chemotherapy group (weekly paclitaxel followed by doxorubicin/cyclophosphamide) and 69 were randomly assigned, between November 2015 and November 2016, to receive four cycles of pembrolizumab in addition to neoadjuvant chemotherapy followed by definitive surgery. In the pembrolizumab group, 40 patients had HR-positive disease and 29 had triple-negative disease.

Pathologic Complete Response Rates

The final estimated pathologic complete response rates were 44% vs 17%, 30% vs 13%, and 60% vs 22% for the pembrolizumab vs control group among all HER2-negative patients, patients with HR-positive/HER2-negative disease, and patients with triple-negative disease, respectively, with pembrolizumab being considered graduated in each of the three biomarker signatures evaluated. Residual cancer burden distribution was shifted to a lower burden level in the pembrolizumab group in each of the biomarker cohorts.

Median follow-up was 2.8 years in the pembrolizumab group and 3.5 years in the control group. An exploratory analysis showed no significant difference in 3-year event-free survival between groups. The investigators stated that patients with pathologic complete response in both groups had excellent 3-year event-free survival (eg, 93% in the pembrolizumab group).


  • Estimated pathologic complete response rates were 44% in the pembrolizumab group vs 17% in the control group among all HER2-negative patients.
  • Estimated pathologic complete response rates were 30% vs 13% and 60% vs 22% for the pembrolizumab vs control group among patients with HR-positive/HER2-negative disease and patients with triple-negative disease, respectively.

Adverse Events

Adverse events were consistent with established safety profiles of the treatment components in both groups. Immune-mediated adverse events were more common in the pembrolizumab group. The most common were endocrinopathies; thyroid dysfunction (hypothyroidism and hyperthyroidism) was the most common of these, occurring in 13.0% of patients. Adrenal insufficiency was observed in 8.7% of patients, with five of the six reported cases occurring more than 30 days after last dose of pembrolizumab. A number of other immune-related adverse events, excluding pruritus, were observed to occur more than 30 days after the final pembrolizumab dose.

The investigators concluded, “When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pathologic complete response rates for both HR-positive/HER2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, HER2-negative breast cancer is highly likely to succeed in a phase III trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/HER2-negative signature.”

Dr. Nanda, of The University of Chicago, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Quantum Leap Healthcare Collaborative, the National Institutes of Health, the National Cancer Institute, and others. For full disclosures of the study authors, visit