# Pembrolizumab and chemotherapy in high-risk, early-stage, ER + /HER2 - breast cancer: a randomized phase 3 trial

Source: https://onco.cc/key-papers/paper-nct03725059-nat-med-2025/  
OnCo record `paper-nct03725059-nat-med-2025` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Published report from the KEYNOTE-756 trial registered as NCT03725059, in Nature Medicine (2025), chosen as the most cited paper whose own text cites the registry id.

## Summary

Addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes in patients with high-risk, early-stage, triple-negative breast cancer. However, whether the addition of neoadjuvant pembrolizumab to chemotherapy would improve outcomes in high-risk, early-stage, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER + /HER2 -) breast cancer remains unclear. We conducted a double-blind, placebo-controlled phase 3 study (KEYNOTE-756) in which patients with previously untreated ER + /HER2 - grade 3 high-risk invasive breast cancer (T1c-2 (≥2 cm), cN1-2 or T3-4, cN0-2) were randomly assigned (1:1) to neoadjuvant pembrolizumab 200 mg or placebo Q3W given with paclitaxel QW for 12 weeks, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide Q2W or Q3W. After surgery (with/without adjuvant radiation therapy), patients received adjuvant pembrolizumab or placebo for nine cycles plus adjuvant endocrine therapy. Dual primary endpoints were pathological complete response and event-free survival in the intention-to-treat population. In total, 635 patients were assigned to the pembrolizumab-chemotherapy arm and 643 to the placebo-chemotherapy arm. At the study's prespecified first interim analysis, the pathological complete response rate was 24.3% (95% confidence interval (CI), 21.0-27.8%) in the pembrolizumab-chemotherapy arm and 15.6% (95% CI, 12.8-18.6%) in the placebo-chemotherapy arm (estimated treatment difference, 8.5 percentage points; 95% CI, 4.2-12.8; P = 0.00005). Event-free survival was not mature in this analysis. During the neoadjuvant phase, treatment-related adverse events of grade ≥3 were reported in 52.5% and 46.4% of patients in the pembrolizumab-chemotherapy and placebo-chemotherapy arms, respectively. In summary, the addition of pembrolizumab to neoadjuvant chemotherapy significantly improved the pathological complete response rate in patients with high-risk, early-stage ER + /HER2 - breast cancer. Safety was consistent with the known profiles of each study treatment. Follow-up continues for event-free survival. ClinicalTrials.gov identifier: NCT03725059.

Indexed on Europe PMC as PubMed record 39838117 (DOI 10.1038/s41591-024-03415-7). Its abstract cites the registry id NCT03725059, which is how it was matched to this trial; no figure has been checked by an editor.

## Fields

- Kind: Key paper
- Last checked: 2026-09-22
- Tags: europepmc-ingest
- Journal: Nature Medicine
- Year: 2025
- DOI: 10.1038/s41591-024-03415-7
- Authors: Cardoso F, O'Shaughnessy J, Liu Z, et al.
- What it means: This is the paper Europe PMC returns for registry id NCT03725059 with the most citations, so it is the natural first reading for anyone following the KEYNOTE-756 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
- Caveats: Matched to the trial by the registry id cited in the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.

## Sources

- Nat Med 2025: https://doi.org/10.1038/s41591-024-03415-7
- PubMed: https://pubmed.ncbi.nlm.nih.gov/39838117/
- Europe PMC: https://europepmc.org/article/MED/39838117
- ClinicalTrials.gov NCT03725059: https://clinicaltrials.gov/study/NCT03725059

## Connected records

- trials: [Study of Pembrolizumab (MK-3475) Versus Placebo in Combination With Neoadjuvant Chemotherapy & Adjuvant Endocrine Therapy in the Treatment of Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Breast Cancer (MK-3475-756/KEYNOTE-756)](https://onco.cc/trials/nct03725059/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)

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