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Cited by 1,274Breast Cancer Treatment StudiesCancer Immunotherapy and BiomarkersMRI in cancer diagnosis

Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer

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Schmid, Peter, Cortes, Javier, Dent, Rebecca, Pusztai, Lajos, McArthur, Heather, Kümmel, Sherko, Bergh, Jonas, Denkert, Carsten +22 more·2022·New England Journal of Medicine
DOI 10.1056/nejmoa2112651
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Abstract

BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

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  • In perioperative HCC, no surrogate endpoint has been validated, unlike pathological complete response in NSCLC and breast cancer.

    “Given the lack of successful trials in the perioperative space in HCC, no surrogate end point has been validated yet, as is the case for pCR in patients with NSCLC20,120 and breast cancer8.”

    From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [8]

    The End Points section lists pathological complete response (pCR) as a primary endpoint in a breast-cancer trial, and the Efficacy section reports event-free survival by pCR status. Neither section says pCR is a validated surrogate endpoint in breast cancer; the paper measures event-free survival separately. The HCC and NSCLC portions of the citing sentence are not attributed to this source. (LLM, conf=0.84)

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Authors
Schmid, P., Cortes, J., Dent, R., Pusztai, L., McArthur, H., Kümmel, S., Bergh, J., Denkert, C., Park, Y. H., Hui, R., Harbeck, N., Takahashi, M., Untch, M., Fasching, P. A., Cardoso, F., Andersen, J., Patt, D., Danso, M., Ferreira, M., Mouret-Reynier, M.-A., Im, S.-A., Ahn, J.-H., Gion, M., Baron-Hay, S., Boileau, J.-F., Ding, Y., Tryfonidis, K., Aktan, G., Karantza, V., & O’Shaughnessy, J.
Affiliations
  • National University of Singapore (SG)
  • From Barts Cancer Institute, Queen Mary University of London, London (P.S.); International Breast Cancer Center, Quironsalud Group, and Vall d’Hebron Institute of Oncology, Barcelona (J.C.), and the Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid (J.C.), and Ramon y Cajal University Hospital (M.G.), Madrid; the National Cancer Center Singapore, Duke–National University of Singapore Medical School, Singapore (R.D.); Yale School of Medicine, Yale Cancer Center, New Haven, CT (L.P.); the University of Texas Southwestern Medical Center (H.M.), and Baylor University Medical Center, Texas Oncology, U.S. Oncology Network (J.O.), Dallas, and Texas Oncology, U.S. Oncology Network, Austin (D.P.); the Breast Unit, Kliniken Essen-Mitte, Essen, Charité–Universitätsmedizin Berlin, the Department of Gynecology with Breast Center (S.K.) and the Breast Cancer Center, Helios Klinikum Berlin–Buch (M.U.), Berlin, the Institute of Pathology, Philipps–University Marburg and Unive...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2022-02-10
Volume
386
Issue
6
Pages
556-567
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2112651
OpenAlex
W4210957314
Cited by
1,274
References
35
Citations by year
2026: 251 · 2025: 267 · 2024: 318 · 2023: 278 · 2022: 158
FWCI
107.48
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
Merck & Co., Inc. (Not applicable)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › MRI in cancer diagnosis
Keywords
pembrolizumab, triple-negative breast cancer, early breast cancer, event-free survival, neoadjuvant immunotherapy, immune checkpoint inhibitors, paclitaxel, carboplatin, doxorubicin-cyclophosphamide, epirubicin-cyclophosphamide, adjuvant therapy, pathological complete response, local recurrence, distant recurrence, secondary malignancies
MeSH terms
Antineoplastic Agents, Immunological, Progression-Free Survival, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Middle Aged, Chemotherapy, Adjuvant, Neoadjuvant Therapy, Kaplan-Meier Estimate, Intention to Treat Analysis, Antibodies, Monoclonal, Humanized, Triple Negative Breast Neoplasms

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