Real-world effectiveness and safety of neoadjuvant pembrolizumab in early-stage triple-negative breast cancer: a systematic review and meta-analysis

Early-stage triple-negative breast cancer (esTNBC) is an aggressive malignancy for which neoadjuvant chemotherapy remains the standard approach. Randomized trials have demonstrated improved pathologic complete response with the addition of pembrolizumab. However, trial populations may not fully reflect routine clinical practice. Evidence describing the real-world effectiveness and safety of neoadjuvant pembrolizumab in early-stage TNBC has not been systematically synthesized. This systematic review and meta-analysis therefore evaluated real-world outcomes associated with pembrolizumab-based neoadjuvant regimens. A systematic search of PubMed, Embase, Scopus, and the Cochrane Library were searched to August 14, 2025 (updated: February 7, 2026). We included prospective and retrospective cohort studies comparing neoadjuvant pembrolizumab plus chemotherapy to chemotherapy alone in patients with esTNBC. Two reviewers independently screened studies, extracted data, and assessed methodological quality using the Newcastle-Ottawa Scale. Meta-analyses were performed using a random-effects model. Certainty of evidence was evaluated using the GRADE approach. Five observational studies (N = 1,501, mean ages 49.5 to 57.8 years) were included. Pooled analysis suggested that compared to chemotherapy alone, neoadjuvant pembrolizumab plus chemotherapy could be associated with a higher likelihood of achieving pathologic complete response (RR:1.52, 95% CI 1.29–1.80). Pembrolizumab use may also reduce the likelihood of undergoing axillary lymph node dissections (RR:0.65, 95% CI 0.50–0.86). No clear differences were observed for time to first adjuvant therapy or postoperative complications. The most frequently reported immune-related adverse events with pembrolizumab included thyroid dysfunction and adrenal insufficiency. Evidence certainty was rated very low for all outcomes. Very-low certainty evidence appears to suggest that in routine clinical practice, the addition of pembrolizumab to neoadjuvant chemotherapy for esTNBC could increase the probability of achieving pathologic complete response and may be associated with a reduced likelihood of axillary lymph node dissection, with no clear increase in perioperative complications. However, confidence in these effect estimates is limited mainly due to inherent limitations in observational studies. These findings, although consistent with randomized trial evidence, should not be interpreted as definitive. This review highlights the need for ongoing safety surveillance and well-designed comparative studies to strengthen the evidence base for real-world use of pembrolizumab in this setting. Not Applicable. Open Science Framework (DOI: 10.17605/OSF.IO/N7YJK). This study provides the first comprehensive synthesis of real-world evidence evaluating the effectiveness and safety of neoadjuvant pembrolizumab in early-stage triple-negative breast cancer. The use of risk ratios and random-effects meta-analysis allows for clinically interpretable effect estimates while accounting for between-study heterogeneity. Certainty of evidence was systematically assessed using the GRADE approach, enhancing transparency in the interpretation of findings. The included evidence was limited to observational studies, which are inherently susceptible to confounding, selection bias, and residual imbalance between treatment groups. Relatively small sample sizes in the included studies, differences in study population, follow-up durations, variable reporting of adverse events, and study-design limitations contributed to very low certainty of evidence across outcomes. The review was restricted to using published data only, and individual participant data were unavailable, which limited the ability to adjust for baseline imbalances or explore subgroup effects.