曲妥珠单抗、帕妥珠单抗和化疗新辅助治疗与曲妥珠单抗恩美曲妥珠单抗和帕妥珠单抗联合用于 HER2 阳性乳腺癌患者（KRISTINE）：一项随机、开放标签、多中心、III 期临床试验。
Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial.
机构信息
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CiberOnc, GEICAM, Madrid, Spain.
出版信息
Lancet Oncol. 2018 Jan;19(1):115-126. doi: 10.1016/S1470-2045(17)30716-7. Epub 2017 Nov 23.
BACKGROUND
HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment.
METHODS
We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing.
FINDINGS
Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment.
INTERPRETATION
Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.
FUNDING
F Hoffmann-La Roche and Genentech.
背景
曲妥珠单抗靶向治疗已改善了 HER2 阳性乳腺癌患者在新辅助、辅助和转移性环境中的预后；然而，一些患者在早期疾病治疗后多年仍有复发或死亡的风险。因此，需要新的策略。我们进行了一项 3 期试验，以评估一种新辅助方案，用于治疗 HER2 阳性乳腺癌，该方案用靶向治疗替代传统的系统化疗。
方法
我们在 68 个转化肿瘤学中心（亚洲、欧洲、美国和加拿大的医院和专业癌症中心）进行了一项随机、开放性 3 期 KRISTINE 试验。纳入的患者年龄在 18 岁或以上，经中心确诊为 II-III 期可手术的 HER2 阳性乳腺癌（肿瘤大小>2cm），东部合作肿瘤学组体能状态为 0-1，且基线左心室射血分数至少为 55%（通过超声心动图或多门控采集扫描）。我们以 1:1 的比例随机分配患者（1:1）接受曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗或多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗治疗。我们通过交互式响应系统，根据激素受体状态、诊断时的阶段和地理位置，采用区组随机化（区组大小为 4）进行随机分组。患者接受 6 个周期（每 3 周 1 次）的新辅助曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗（曲妥珠单抗恩美曲妥珠单抗 3·6mg/kg；帕妥珠单抗起始剂量 840mg，维持剂量 420mg）或多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗（多西他赛 75mg/m2；卡铂 AUC 为 6mg/mL×min；曲妥珠单抗起始剂量 8mg/kg，维持剂量 6mg/kg）加帕妥珠单抗[与其他组相同剂量]）。所有治疗均为静脉输注。主要终点是比较两组在意向治疗人群（双侧评估）中达到病理完全缓解（ypT0/is、ypN0）的患者人数，该结果基于新辅助治疗结束后 14 天至 6 周之间进行的乳腺癌手术获取的肿瘤样本进行局部评估。在接受至少一剂研究药物的患者中进行安全性分析。这项试验在 ClinicalTrials.gov 注册，编号为 NCT02131064，辅助阶段的随访仍在进行中。
结果
2014 年 6 月 25 日至 2015 年 6 月 15 日期间，我们随机将 444 名患者分配至接受曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗（n=223）或多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗（n=221）新辅助治疗。曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗组有 99 名（44.4%）患者和多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗组有 123 名（55.7%）患者达到病理完全缓解（绝对差值-11.3 个百分点，95%CI-20.5 至-2.0；p=0.016）。在新辅助治疗期间，与接受多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗治疗的患者相比，接受曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗治疗的患者中，发生 3-4 级不良事件的人数更少（223 例中有 29 例[13%] vs 219 例中有 141 例[64%]）或严重不良事件的人数更少（223 例中有 11 例[5%] vs 219 例中有 63 例[29%]）。曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗组中最常见的 3-4 级不良事件为血小板计数减少（223 例中有 3 例[1%] vs 219 例中有 11 例[5%]接受多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗治疗）、疲劳（223 例中有 3 例[1%] vs 219 例中有 7 例[3%]）、丙氨酸氨基转移酶升高（223 例中有 3 例[1%] vs 219 例中有 4 例[2%]）和低钾血症（223 例中有 3 例[1%] vs 219 例中有 5 例[2%]）。多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗组中最常见的 3-4 级不良事件为中性粒细胞减少症（219 例中有 55 例[25%] vs 223 例中有 1 例[<1%]接受曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗治疗）、腹泻（219 例中有 33 例[15%] vs 223 例中有 2 例[<1%]）和发热性中性粒细胞减少症（219 例中有 33 例[15%] vs 0 例）。新辅助治疗期间未发生死亡。
解释
与传统的新辅助系统化疗加双 HER2 靶向治疗（多西他赛、卡铂和曲妥珠单抗加帕妥珠单抗）相比，HER2 靶向化疗加 HER2 靶向治疗（曲妥珠单抗恩美曲妥珠单抗加帕妥珠单抗）可显著提高病理完全缓解率；然而，化疗加曲妥珠单抗和帕妥珠单抗组发生 3-4 级和严重不良事件的人数更多。进一步努力提高化疗的疗效而不增加更多的毒性是值得的。
资金来源
罗氏公司和基因泰克公司。
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