晚期乳腺癌曲妥、帕妥、恩美失败后
HER2阳性晚期乳腺癌通常无法治愈，尤其对于曲妥珠单抗、帕妥珠单抗、恩美曲妥珠单抗治疗失败后患者，最佳治疗方案尚未确定。人鼠嵌合抗体马格妥昔单抗与曲妥珠单抗相比，虽然HER2抗原结合片段相同，但是免疫细胞结合片段经过基因工程改造，抗肿瘤免疫激活作用大大增强。
2021年1月22日，《美国医学会杂志》肿瘤学分册在线发表旧金山加利福尼亚大学、斯坦福大学、佛罗里达肿瘤医院、新墨西哥大学、萨拉坎农研究所、田纳西肿瘤医院、芝加哥西北大学、韩国首尔大学、蔚山大学首尔峨山医院、葡萄牙尚帕利莫基金会临床中心、西班牙凯龙医疗集团肿瘤研究所、巴塞罗纳大学肿瘤研究所、意大利米兰大学欧洲肿瘤研究所、帕尔马大学、那不勒斯帕斯卡基金会国家癌症研究所、法国巴克莱斯癌症中心诺曼塞纳研究所、蔚蓝海岸大学安托万拉卡萨涅癌症中心、荷兰马斯特里赫特大学、捷克马萨里克纪念癌症研究所、加拿大麦克劳林达勒姆地区癌症中心、丹麦瓦埃勒医院、以色列查姆示巴医疗中心、拉宾医疗中心、德国埃尔朗根纽伦堡大学的SOPHIA研究报告，比较了马格妥昔单抗＋化疗或曲妥珠单抗＋化疗对HER2阳性晚期乳腺癌抗HER2治疗失败患者的临床疗效。
SOPHIA (Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in the Treatment of HER2+ Metastatic Breast Cancer): A Phase 3, Randomized Study of Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in the Treatment of Patients With HER2+ Metastatic Breast Cancer Who Have Received Prior Anti-HER2 Therapies and Require Systemic Treatment (NCT02492711)
该国际多中心非盲随机对照三期临床研究于2015年8月26日～2018年10月10日从17个国家或地区166家医院入组≥2种抗HER2药物1～3线治疗失败的晚期乳腺癌患者536例（中位年龄56岁，范围27～86岁），按1∶1随机分为2组，给予随机分组前由研究者选择的化疗方案＋马格妥昔单抗（266例，每3周15mg/kg）或曲妥珠单抗（270例，每3周6mg/kg，首次8mg/kg）。对转移部位（≤2、>2）、治疗方案（≤2、>2）和化疗选择进行分层分析。主要终点为集中盲法分析的无进展生存和总生存，次要终点为研究者评定的无进展生存和集中盲法分析的客观缓解率。数据分析于2019年2月～2019年10月进行。
结果，马格妥昔单抗组266例全部（100%）为女性，曲妥珠单抗组267例（98.9%）为女性，两组患者的人口统计学特征和疾病特征分布均衡。
535例患者（99.8%）接受过帕妥珠单抗治疗，489例患者（91.2%）接受过恩美曲妥珠单抗治疗。
截至2018年10月10日，中位随访2.8个月，马格妥昔单抗与曲妥珠单抗相比：
根据集中盲法分析
进展或死亡事件：130例比135例
进展或死亡风险：减少24%（多因素比例风险回归模型分层风险比：0.76，95%置信区间：0.59～0.98，分层对数秩P=0.03）
中位无进展生存：5.8个月比4.9个月（95%置信区间：5.5～7.0、4.2～5.6）
根据研究者评定
进展或死亡事件：160例比177例
进展或死亡风险：减少30%（多因素比例风险回归模型分层风险比：0.70，95%置信区间：0.56～0.87，分层对数秩P=0.001）
中位无进展生存：5.6个月比4.2个月（95%置信区间：5.06～6.67、3.98～5.39）
根据集中盲法分析
客观缓解率：22%比16%（P=0.06）
截至2019年9月10日，中位随访15.6个月，对270例死亡事件进行第二次计划中期分析，马格妥昔单抗与曲妥珠单抗相比：
总死亡事件：131例比139例
总死亡风险：减少11%（多因素比例风险回归模型分层风险比：0.89，95%置信区间：0.69～1.13，分层对数秩P=0.33）
中位总生存：21.6个月比19.8个月（95%置信区间：18.86～24.05、17.54～22.28）
根据研究者评定
进展或死亡风险：减少29%（多因素比例风险回归模型分层风险比：0.71，95%置信区间：0.58～0.86，分层对数秩P<0.001）
中位无进展生存：5.7个月比4.4个月（95%置信区间：5.22～6.97、4.14～5.45）
根据集中盲法分析
客观缓解率：25%比14%（P<0.001）
截至2019年6月10日，马格妥昔单抗与曲妥珠单抗相比：
实际用药患者：264例、266例
输注相关反应：35例比9例（13.3%比3.4%，P<0.001，主要集中于第1周期）
黏膜炎症反应：26例比8例（9.8%比3.0%，P=0.001）
中性粒细胞减少：74例比52例（28.4%比20.7%，P=0.04）
三级中性粒细胞减少：52例比33例（19.7%比12.4%，P=0.02）
其他不良事件发生率：相似
因此，该研究结果表明，对于≥2种抗HER2药物1～3线治疗失败的晚期乳腺癌患者，马格妥昔单抗＋化疗与曲妥珠单抗＋化疗头对头相比，安全性可接受，无进展生存显著改善。最终总生存分析预计将于2021年完成。据悉，中国再鼎医药已于2018年11月29日获得马格妥昔单抗在中国的独家开发推广许可，美国食品药品监督管理局已于2020年12月16日批准马格妥昔单抗＋化疗用于≥2种抗HER2药物1～3线治疗失败的晚期乳腺癌患者。
相关链接
JAMA Oncol. 2021 Jan 22. Online ahead of print.
Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group.
University of California San Francisco Helen Diller Family Comprehensive Cancer Center; Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, California; Florida Cancer Specialists & Research Institute, New Port Richey; University of New Mexico Comprehensive Cancer Center, Albuquerque; Sarah Cannon Research Institute, Tennessee Oncology PLLC, Nashville; MacroGenics, Inc, Rockville, Maryland; Northwestern University, Chicago, Illinois; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Asan Medical Center, Seoul, Korea; Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal; IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; European Institute of Oncology, University of Milano, Milan, Italy; University of Parma, University Hospital of Parma, Parma, Italy; Istituto Nazionale Tumori "Fondazione Pascale", Naples, Italy; Centre Francois Baclesse, Institut Normand du Sein, Caen, France; Centre Antoine Lacassagne, University Cote d'Azur, Nice, France; Maastricht University Medical Center, GROW-School of Oncology and Developmental Biology, Maastricht, the Netherlands; Masaryk Memorial Cancer Institute, Brno, Czech Republic; RS McLaughlin Durham Regional Cancer Centre, Lakeridge Health, Oshawa, Ontario, Canada; Vejle Hospital, Vejle, Denmark; Chaim Sheba Medical Center, Breast Oncology Institute, Ramat Gan, Israel; Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
This phase 3 randomized clinical trial compares the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive advanced breast cancer.
QUESTION: Does margetuximab plus chemotherapy prolong progression-free survival and/or overall survival of patients with pretreated ERBB2-positive advanced breast cancer, relative to trastuzumab plus chemotherapy?
FINDINGS: In the SOPHIA phase 3 randomized clinical trial of 536 patients with pretreated ERBB2-positive advanced breast cancer, margetuximab plus chemotherapy generated a statistically significant 24% relative risk reduction in the hazard of progression vs trastuzumab plus chemotherapy. After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab, and final analysis of OS will be reported subsequently.
MEANING: This trial demonstrates a head-to-head advantage of margetuximab (an Fc-engineered ERBB2-targeted antibody) compared with trastuzumab in a pretreated ERBB2-positive advanced breast cancer population.
IMPORTANCE: ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation.
OBJECTIVE: To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC.
DESIGN, SETTING, AND PARTICIPANTS: The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019.
INTERVENTIONS: Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice.
MAIN OUTCOMES AND MEASURES: Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis.
RESULTS: A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable.
CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02492711
PMID: 33480963
DOI: 10.1001/jamaoncol.2020.7932