Addition of pembrolizumab to chemotherapy improves early-stage triple-negative breast cancer survival

1. In this randomized controlled trial, among patients with early-stage triple-negative breast cancer (TNBC), the addition of neoadjuvant and adjuvant pembrolizumab to standard chemotherapy improved overall survival compared to chemotherapy alone.

2. Adverse events were more common in the pembrolizumab group but consistent with its established safety profiles.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Breast cancer is the most common malignancy affecting female adults. TNBC, characterized by the lack of the expression of estrogen, progesterone, and human epidermal growth factor (HER2) receptors, proves challenging to treat as these receptors are therapeutic targets. Furthermore, TNBC has an earlier onset, is more aggressive, and has a higher risk of early recurrence than other subtypes. The programmed death-1 inhibitor pembrolizumab is approved for treating TBNC based on interim analysis of the phase three KEYNOTE-522 trial. This study reported the final outcomes of the KEYNOTE-522 trial. Neoadjuvant and adjuvant pembrolizumab, in addition to standard chemotherapy, resulted in a higher overall survival at 60 months, than chemotherapy alone. Event-free survival and pathological complete response were also higher with pembrolizumab addition. Adverse events, including serious and immune-mediated events, were more common with pembrolizumab but they aligned with established safety profiles of pembrolizumab. The study was not powered to delineate the significance of neoadjuvant against adjuvant phases for pembrolizumab and its efficacy over adjuvant capecitabine is unclear. Nevertheless, these results robustly demonstrated the benefit of adding pembrolizumab to the treatment of TNBC.

Click here to read the study in NEJM

Relevant Reading: Pembrolizumab for Early Triple-Negative Breast Cancer

In-Depth [randomized controlled trial]: This study was a placebo-controlled trial investigating neoadjuvant and adjuvant pembrolizumab in addition to chemotherapy for the treatment of TNBC. Patients who had confirmed TNBC, which was newly diagnosed, previously untreated, locally advanced, and non-metastatic, and had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1, were eligible for inclusion. Exclusion criteria included prior history of another malignancy, recent treatments with chemotherapy or immunotherapy, autoimmune conditions, significant cardiovascular disorders, active infections, and pregnancy. In total, 1,174 patients were randomized 2:1 to receive neoadjuvant therapy with four cycles of pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every three weeks alongside paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo alongside doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. Following surgery, patients in respective groups received adjuvant pembrolizumab or placebo every three weeks for up to nine cycles. The estimated five-year event-free survival was 81.2% (95% Confidence Interval [CI], 78.3-83.8) in the pembrolizumab-chemotherapy group and 72.2% (95% CI, 67.4-76.4) for the placebo-chemotherapy group, with the hazard ratio for event or death being 0.65 (95% CI, 0.51-0.83) favoring the pembrolizumab. Overall survival at five years was 86.6% (95% CI 94.0-88.8) for the pembrolizumab-chemotherapy group and 81.7% (95% CI 77.5-85.2) for placebo-chemotherapy (p=0.002). Treatment-related adverse events of grade three or higher were observed in 77.1% of patients in the pembrolizumab-chemotherapy group and 73.3% in the placebo-chemotherapy group. Serious adverse events occurred in 34.1% and 20.1% of patients, respectively. Immune-related adverse events were significantly more prevalent in the pembrolizumab-chemotherapy group (35.05%) compared to the placebo-chemotherapy group (13.1%), driven by endocrinopathy. These results provided evidence that pembrolizumab, in addition to standard chemotherapy and surgery, was efficacious in the treatment of early-stage TNBC.

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