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 University Hospital Marburg, Marburg (C.D.), the Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, LMU University Hospital, Munich (N.H.), and the Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, University Hospital Erlangen, Erlangen (P.A.F.) - all in Germany; the Department of Oncology-Pathology, Karolinska Institutet, and Breast Cancer Center, Cancer Theme, Karolinska University Hospital, Karolinska Comprehensive Cancer Center, Solna, Sweden (J.B.); Samsung Medical Center, Sungkyunkwan University School of Medicine (Y.H.P.), Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (S.-A.I.), and Asan Medical Center, University of Ulsan College of Medicine (J.-H.A.) - all in Seoul, South Korea; Westmead Breast Cancer Institute, Westmead Hospital and the University of Sydney (R.H.), and Royal North Shore Hospital (S.B.-H.) - both in Sydney; Hokkaido Cancer Center, Sapporo, Japan (M.T.); the Breast Unit, Champalimaud Clinical Center-Champalimaud Foundation, Lisbon (F.C.), and Instituto Português de Oncologia do Porto Francisco Gentil, Porto (M.F.) - both in Portugal; Compass Oncology, U.S. Oncology Network, Portland, OR (J.A.); Virginia Oncology Associates, U.S. Oncology Network, Norfolk (M.D.); Centre Jean-Perrin, Clermont-Ferrand, France (M.-A.M.-R.); McGill University, Segal Cancer Centre, Jewish General Hospital, Montreal (J.-F.B.); and Merck, Kenilworth, NJ (Y.D., K.T., G.A., V.K.).
N Engl J Med. 2022 Feb 10;386(6):556-567. doi: 10.1056/NEJMoa2112651.
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.
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.
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.
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.).
在这项新辅助和辅助治疗的 3 期试验的早期分析中，与新辅助化疗相比，帕博利珠单抗联合新辅助化疗显著提高了早期三阴性乳腺癌患者在确定性手术时病理完全缓解（定义为乳房和淋巴结中无浸润性癌）的比例。该试验中关于无事件生存的主要结果尚未报告。
我们以 2:1 的比例随机分配既往未经治疗的 II 期或 III 期三阴性乳腺癌患者接受新辅助治疗，每 3 周接受 4 个周期的帕博利珠单抗（剂量 200mg）或安慰剂联合紫杉醇和卡铂，随后接受 4 个周期的帕博利珠单抗或安慰剂联合多柔比星-环磷酰胺或表柔比星-环磷酰胺。在确定性手术后，患者接受辅助性帕博利珠单抗（帕博利珠单抗-化疗组）或安慰剂（安慰剂-化疗组）每 3 周治疗，最多 9 个周期。主要终点为病理完全缓解（之前已报道过结果）和无事件生存，定义为从随机分组到疾病进展导致确定性手术无法进行、局部或远处复发、发生第二原发性癌症或任何原因死亡的时间。还评估了安全性。
在接受随机分组的 1174 名患者中，784 名患者被分配至帕博利珠单抗-化疗组，390 名患者被分配至安慰剂-化疗组。此次计划中的第四次中期分析（数据截止日期为 2021 年 3 月 23 日）时的中位随访时间为 39.1 个月。在 36 个月时，帕博利珠单抗-化疗组的无事件生存估计为 84.5%（95%置信区间[CI]，81.7 至 86.9），而安慰剂-化疗组为 76.8%（95%CI，72.2 至 80.7）（事件或死亡风险比，0.63；95%CI，0.48 至 0.82；P<0.001）。不良事件主要发生在新辅助阶段，与帕博利珠单抗和化疗的既定安全性特征一致。
在早期三阴性乳腺癌患者中，与新辅助化疗相比，帕博利珠单抗联合新辅助化疗，随后在手术后给予辅助性帕博利珠单抗治疗，可显著延长无事件生存时间。（由默克公司的子公司默沙东资助；KEYNOTE-522 临床试验.gov 编号，NCT03036488。）
