2017年5月16日，英国《柳叶刀肿瘤学杂志》在线发表美国哈佛大学医学院达纳法伯癌症研究所、韩国蔚山大学医学院首尔峨山医院、西班牙MD安德森癌症中心、美国耶鲁大学医学院癌症中心、法国安托万·拉卡萨涅癌症中心、瑞士罗氏、美国基因泰克、比利时鲁汶大学医院的TH3RESA随机非盲Ⅲ期研究最终总生存结果报告，对T-DM1与医师选择治疗方案用于HER2阳性转移性乳腺癌患者进行了比较。
T-DM1是抗体（曲妥珠单抗）与药物（安坦辛）的共轭物。在随机平行分配非盲Ⅲ期TH3RESA研究中，对于HER2阳性晚期乳腺癌既往治疗失败患者，T-DM1与医师选择的治疗方案相比，无进展生存显著较长。本文报告了TH3RESA研究的最终总生存分析结果。
该研究于2011年9月14日～2012年11月19日从22个国家146个中心入组602例经过中心确认为HER2阳性晚期乳腺癌、既往曲妥珠单抗＋拉帕替尼（晚期病变）和紫杉类（任何病变）治疗失败、晚期病变经过≥2个HER2靶向方案治疗后进展、年龄≥18岁、东部肿瘤协作组（ECOG）体力状态评分≤2、左室射血分数≥50%、器官功能良好的男性和女性患者，通过交互式语音和网络反馈系统，以六区组置换区组随机化，按2∶1随机分配，接受T-DM1（每21天静脉注射3.6mg/kg）或医师根据当地实际情况选择的治疗方案。随机化的分层依据为所在地区、针对晚期乳腺癌的既往治疗方案数量、内脏病变存在与否。2012年9月12日，研究方案进行修改，允许疾病进展患者从医师选择治疗方案组交叉至T-DM1组。主要终点为研究者评定的意向治疗人群无进展生存和总生存。按照计划，当492例预期死亡发生大约67%（330例）时，对总生存进行预设的第二次中期分析并报告结果。本研究在美国政府临床研究网站（ClinicalTrials.gov）的注册编号为：NCT01419197。
结果，被随机分配到T-DM1组、医师选择治疗方案对照组的符合条件患者分别为404、198例：
截至2015年2月13日，对照组198例患者有93例（47%）交叉至T-DM1组。
T-DM1组与对照组相比，中位总生存显著较长（22.7比15.8个月；风险比：0.68，95%置信区间：0.54～0.85，P值：0.0007）。
随着总生存超越预设的总生存有效性分界线，此时的总生存分析作为总生存的最终和确定分析，并根据方案终止研究。
在安全性分析人群中，T-DM1组（403例）与对照组（184例）相比：
≥3级不良事件发生率分别为40%、47%。
发生率相差≥3%的最常见≥3级不良事件（任意一组患者受影响率≥2%）分别为腹泻（1%比4%）、中性粒细胞减少（3%比16%）、发热性中性粒细胞减少（＜1%比4%）、血小板减少症（6%比3%）、任何类型出血（4%比＜1%）。
严重不良事件发生率分别为25%、22%。
不良事件死亡率分别为2.2%（9例）、1.6%（3例），其中分别有3例、1例被判断为与治疗相关。
因此，对于经过≥2个HER2靶向方案治疗后进展的患者，T-DM1与医师选择治疗方案相比，总生存显著改善。这些数据进一步巩固了T-DM1在HER2阳性晚期乳腺癌既往治疗失败患者中的地位，并且验证了即使经过既往多线疗法，HER2仍可作为治疗靶点。
对此，意大利皮埃蒙特肿瘤学基金会坎迪奥洛癌症研究所的临床肿瘤学研究者发表同期评论：T-DM1用于HER2阳性转移性乳腺癌。
Lancet Oncol. 2017 May 16. [Epub ahead of print]
Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial.
Ian E Krop, Sung-Bae Kim, Antonio Gonzalez Martin, Patricia M LoRusso, Jean-Marc Ferrero, Tanja Badovinac-Crnjevic, Silke Hoersch, Melanie Smitt, Hans Wildiers.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; MD Anderson Cancer Center, Madrid, Spain; Yale Cancer Center, Yale University Medical Center, New Haven, CT, USA; Centre Antoine Lacassagne, Nice, France; F Hoffmann La-Roche Ltd, Basel, Switzerland; Genentech Inc, South San Francisco, CA, USA; University Hospitals Leuven, Leuven, Belgium.
BACKGROUND: In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial.
METHODS: Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3.6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197.
FINDINGS: Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22.7 months [95% CI 19.4-27.5] vs 15.8 months [13.5-18.7]; hazard ratio 0.68 [95% CI 0.54-0.85]; p=0.0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).
INTERPRETATION: In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.
FUNDING: F Hoffman-La Roche/Genentech.
DOI: 10.1016/S1470-2045(17)30313-3
Lancet Oncol. 2017 May 16. [Epub ahead of print]
Trastuzumab emtansine in HER2-positive metastatic breast cancer.
Filippo Montemurro.
Investigative Clinical Oncology, Fondazione del Piemonte per l'Oncologia, Candiolo Cancer Institute, 10060 Candiolo, Torino, Italy.
DOI: 10.1016/S1470-2045(17)30303-0
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