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HER2阳性晚期乳腺癌难以治愈，亟需新的治疗方法。恩美曲妥珠单抗（缩写T-DM1，商品名赫赛莱）为HER2靶向单克隆抗体＋肿瘤细胞毒性药物，对于曲妥珠单抗＋紫杉类一线治疗失败患者，为二线治疗可选方案之一。阿替利珠单抗（俗称T药，商品名泰圣奇）为T淋巴细胞程序性死亡蛋白配体PD-L1抑制剂，可能增强抗癌免疫力、增强恩美曲妥珠单抗的HER2靶向＋肿瘤细胞毒性作用。
2020年9月29日，英国《柳叶刀》肿瘤学分册在线发表美国匹兹堡大学癌症中心、纽约大学癌症中心、南加利福尼亚基因泰克、英国巴斯大学皇家联合医院、西班牙巴塞罗纳大学肿瘤研究所、意大利那不勒斯肿瘤研究所、韩国蔚山大学首尔峨山医院、首尔大学癌症研究所、罗氏（中国）投资有限公司、比利时安特卫普医院、瑞士罗氏、澳大利亚墨尔本大学癌症中心的KATE2研究报告，比较了赫赛莱＋泰圣奇、赫赛莱＋安慰剂对HER2阳性晚期乳腺癌曲妥珠单抗＋紫杉类治疗失败患者的有效性和安全性。
KATE2: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab and Taxane Based Therapy (NCT02924883)
该国际多中心随机双盲安慰剂对照二期临床研究于2016年9月26日～2017年8月7日从亚洲、澳大利亚、北美、西欧9个国家地区68个中心入组年龄≥18岁、美国东部肿瘤学协作组体力状态评分为0或1、曲妥珠单抗＋紫杉类治疗失败、经过集中确认病灶可测量HER2阳性晚期乳腺癌202例，按2∶1随机分为两组：
赫赛莱＋泰圣奇组133例：每3周静脉注射恩美曲妥珠单抗3.6毫克/公斤体重＋阿替利珠单抗1200毫克赫赛莱＋安慰剂组 69例：每3周静脉注射恩美曲妥珠单抗3.6毫克/公斤体重＋安慰剂
按PD-L1表达状态、所在地区、是否肝转移对患者进行分层。患者、研究者和研究团队成员对治疗分配双盲。主要终点为研究者评定的意向治疗患者无进展生存。
结果，由于赫赛莱＋泰圣奇组患者的无效和不良事件发生比例较高，根据独立数据监察委员会的推荐意见，治疗分配于2017年12月11日揭盲，该日期被设为主要分析的临床截止日期。
赫赛莱＋泰圣奇组133例与赫赛莱＋安慰剂组69例意向治疗患者相比：
中位随访时间：8.5个月比8.4个月（四分位：6.1～11.5、5.3～11.1）中位无进展生存：8.2个月比6.8个月（95%置信区间：5.8～10.7、4.0～11.1）进展或死亡风险：减少18%（分层风险比：0.82，95%置信区间：0.55～1.23，P=0.33）
对于PD-L1阳性亚组患者，赫赛莱＋泰圣奇组76例与赫赛莱＋安慰剂42例意向治疗患者相比：
中位无进展生存：8.5个月比4.1个月（95%置信区间：5.7～未达终点、2.7～11.1）进展或死亡风险：减少40%（分层风险比：0.60，95%置信区间：0.32～1.11，P=0.099）
对于PD-L1阴性亚组患者，赫赛莱＋泰圣奇组57例与赫赛莱＋安慰剂27例意向治疗患者相比：
中位无进展生存：6.8个月比8.2个月（95%置信区间：5.4～未达终点、4.2～未达终点）进展或死亡风险：增加2%（分层风险比：1.02，95%置信区间：0.60～1.74，P=0.099）
赫赛莱＋泰圣奇组132例与赫赛莱＋安慰剂组68例实际治疗患者相比，≥3级不良事件发生比例：
血小板减少：13%比4%谷草转氨酶升高：8%比3%中性粒细胞减少：5%比4%谷丙转氨酶升高：5%比3%贫血：5%比0严重不良事件：33%比19%治疗相关死亡：1例（噬血细胞综合征）比0例
因此，该研究结果表明，对于HER2阳性晚期乳腺癌曲妥珠单抗＋紫杉类治疗失败患者，赫赛莱＋泰圣奇与赫赛莱＋安慰剂相比，无进展生存并未显著改善、不良事件发生比例显著较高。对于PD-L1阳性HER2阳性晚期乳腺癌亚组患者，有必要进一步开展大样本研究探讨恩美曲妥珠单抗＋阿替利珠单抗的有效性。
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该研究负责人、美国匹兹堡大学蕾莎·艾蒙斯教授访谈
Lancet Oncol. 2020 Oct;21(10):1283-1295.
Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial.
Leisha A Emens, Francisco J Esteva, Mark Beresford, Cristina Saura, Michelino De Laurentiis, Sung-Bae Kim, Seock-Ah Im, Yifan Wang, Roberto Salgado, Aruna Mani, Jigna Shah, Chiara Lambertini, Haiying Liu, Sanne L de Haas, Monika Patre, Sherene Lo.
University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA; Perlmutter Cancer Center at New York University Langone Health, New York, NY, USA; Royal United Hospital, Bath, UK; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Roche (China) Holding, Shanghai, China; Gasthuis Zusters Antwerpen-Ziekenhuis Netwerk Antwerpen Hospitals, Antwerp, Belgium; Genentech, South San Francisco, CA, USA; F Hoffmann-La Roche, Basel, Switzerland; Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
BACKGROUND: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane.
METHODS: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3.6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed.
FINDINGS: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8.5 months (IQR 6.1-11.5) for patients assigned atezolizumab and 8.4 months (5.3-11.1) for those assigned placebo. Median progression-free survival was 8.2 months (95% CI 5.8-10.7) for patients assigned atezolizumab versus 6.8 months (4.0-11.1) for those assigned placebo (stratified hazard ratio 0.82, 95% CI 0.55-1.23; p=0.33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome).
INTERPRETATION: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer.
FUNDING: F Hoffman-La Roche
DOI: 10.1016/S1470-2045(20)30465-4
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发表于 2020-10-1 12:19:58
