帕博利珠单抗治疗早期三阴性乳腺癌。

Pembrolizumab for Early Triple-Negative Breast Cancer.

机构信息

From Barts Cancer Institute, Queen Mary University of London, London (P.S.); International Oncology Bureau Institute of Oncology, Quirón Group, Madrid, and Vall d'Hebron Institute of Oncology, Barcelona (J.C.) - both in Spain; Yale School of Medicine, Yale Cancer Center, New Haven, CT (L.P.); Cedars-Sinai Medical Center, Los Angeles (H.M.); Kliniken Essen-Mitte, Essen (S.K.), the Institute of Pathology, Philipps-University Marburg and University of Marburg, Marburg (C.D.), the Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Ludwig Maximilian University of Munich, University of Munich, Munich (N.H.), University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Erlangen (P.A.F.), and the Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin (M.U.) - all in Germany; the Department of Oncology-Pathology, Karolinska Institutet and Breast Cancer Center, Theme Cancer, Karolinska University Hospital, Solna, Sweden (J.B., T.F.); Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (Y.H.P.); Westmead Breast Cancer Institute, Westmead Hospital and the University of Sydney, Sydney (R.H.); Department of Breast Surgery, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan (M.T.); the Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal (F.C.); Merck, Kenilworth, NJ (L.J., V.K., J.Z., G.A.); the National Cancer Center Singapore, Duke-National University of Singapore Medical School, Singapore (R.D.); and Baylor University Medical Center, Texas Oncology and US Oncology, Dallas (J.O.).

出版信息

N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549.

DOI:10.1056/NEJMoa1910549

PMID:32101663

Abstract

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.).

摘要

背景

先前的试验显示，在早期三阴性乳腺癌患者中，与安慰剂相比，帕博利珠单抗联合新辅助化疗具有较好的抗肿瘤活性和可接受的安全性。帕博利珠单抗联合新辅助化疗是否会显著增加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）的比例尚不清楚。

方法

在这项 3 期临床试验中，我们按 2:1 的比例随机分配未经治疗的 II 期或 III 期三阴性乳腺癌患者接受新辅助治疗，治疗方案为每 3 周静脉输注 200mg 帕博利珠单抗联合紫杉醇和卡铂（784 例患者；帕博利珠单抗联合化疗组）或安慰剂联合紫杉醇和卡铂（390 例患者；安慰剂联合化疗组）；两组随后均接受另外 4 个周期的帕博利珠单抗或安慰剂治疗，两组均接受多柔比星-环磷酰胺或表柔比星-环磷酰胺治疗。在确定性手术后，患者接受每 3 周一次的辅助帕博利珠单抗或安慰剂治疗，最多 9 个周期。主要终点是确定性手术时的病理完全缓解率和意向治疗人群的无事件生存。

结果

在首次中期分析中，在接受随机分组的 602 例患者中，帕博利珠单抗联合化疗组有 64.8%（95%置信区间[CI]，59.9%至 69.5%）的患者达到病理完全缓解，安慰剂联合化疗组有 51.2%（95%CI，44.1%至 58.3%）（估计治疗差异为 13.6 个百分点；95%CI，5.4 至 21.8；P<0.001）。在中位随访 15.5 个月（范围，2.7 至 25.0）后，帕博利珠单抗联合化疗组中有 784 例患者（7.4%）发生了疾病进展而无法进行确定性手术，有 46 例（11.8%）发生了局部或远处复发或第二原发肿瘤，或因任何原因死亡（风险比，0.63；95%CI，0.43 至 0.93）。在所有治疗阶段，帕博利珠单抗联合化疗组中有 78.0%的患者发生了 3 级或更高级别的治疗相关不良事件，安慰剂联合化疗组中有 73.0%的患者发生了这种情况，包括分别有 0.4%（3 例）和 0.3%（1 例）的患者死亡。