Pembrolizumab for Early Triple-Negative Breast Cancer
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Pembrolizumab for Early Triple-Negative Breast Cancer. / Schmid, Peter; Cortes, Javier; Pusztai, Lajos; McArthur, Heather; Kümmel, Sherko; Bergh, Jonas; Denkert, Carsten; Park, Yeon Hee; Hui, Rina; Harbeck, Nadia; Takahashi, Masato; Foukakis, Theodoros; Fasching, Peter A; Cardoso, Fatima; Untch, Michael; Jia, Liyi; Karantza, Vassiliki; Zhao, Jing; Aktan, Gursel; Dent, Rebecca; O'Shaughnessy, Joyce; KEYNOTE-522 Investigators.
In: NEW ENGL J MED, Vol. 382, No. 9, 27.02.2020, p. 810-821.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Pembrolizumab for Early Triple-Negative Breast Cancer
AU - Schmid, Peter
AU - Cortes, Javier
AU - Pusztai, Lajos
AU - McArthur, Heather
AU - Kümmel, Sherko
AU - Bergh, Jonas
AU - Denkert, Carsten
AU - Park, Yeon Hee
AU - Hui, Rina
AU - Harbeck, Nadia
AU - Takahashi, Masato
AU - Foukakis, Theodoros
AU - Fasching, Peter A
AU - Cardoso, Fatima
AU - Untch, Michael
AU - Jia, Liyi
AU - Karantza, Vassiliki
AU - Zhao, Jing
AU - Aktan, Gursel
AU - Dent, Rebecca
AU - O'Shaughnessy, Joyce
AU - KEYNOTE-522 Investigators
AU - Witzel, Isabell
N1 - Copyright © 2020 Massachusetts Medical Society.
PY - 2020/2/27
Y1 - 2020/2/27
N2 - BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).
AB - BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antibodies, Monoclonal, Humanized/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage
KW - Carboplatin/administration & dosage
KW - Cyclophosphamide/administration & dosage
KW - Doxorubicin/administration & dosage
KW - Epirubicin/administration & dosage
KW - Female
KW - Humans
KW - Intention to Treat Analysis
KW - Kaplan-Meier Estimate
KW - Middle Aged
KW - Neoadjuvant Therapy
KW - Neoplasm Staging
KW - Paclitaxel/administration & dosage
KW - Triple Negative Breast Neoplasms/drug therapy
U2 - 10.1056/NEJMoa1910549
DO - 10.1056/NEJMoa1910549
M3 - SCORING: Journal article
C2 - 32101663
VL - 382
SP - 810
EP - 821
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 9
ER -