曲妥珠单抗-美坦新偶联物（T-DM1）用于 HER2 扩增型肿瘤患者（不包括乳腺癌和胃/胃食管交界处[GEJ]腺癌）：NCI-MATCH 试验（EAY131）子方案 Q 的结果。
Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.
机构信息
Department of Medicine, Memorial Sloan-Kettering Center, New York.
Biostatistics, E-A Biostatistical Center, Boston.
出版信息
Ann Oncol. 2019 Nov 1;30(11):1821-1830. doi: 10.1093/annonc/mdz291.
BACKGROUND
The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors.
METHODS
Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed.
RESULTS
Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay.
CONCLUSION
T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.
背景
国家癌症研究所-分子分析用于治疗选择（NCI-MATCH）是一项全国性的精准医学研究，纳入了集中的基因组检测，以指导难治性癌症患者接受分子靶向治疗亚方案。该治疗亚方案旨在筛选除乳腺癌和胃食管肿瘤以外的 HER2 扩增组织学中 ado-trastuzumab emtansine（T-DM1）潜在疗效信号。
方法
符合条件的患者根据靶向下一代测序（NGS）采用定制的 Oncomine AmpliSeq™（ThermoFisher Scientific）面板，HER2 扩增倍数（CN）>7。排除先前接受过曲妥珠单抗、帕妥珠单抗或 T-DM1 治疗的患者。患者接受 3.6mg/kg 静脉注射 T-DM1，每 3 周一次，直至出现毒性或疾病进展。每三个周期进行肿瘤评估。主要终点是中心评估的客观缓解率（ORR）。探索性终点包括通过 NGS 检测与 HER2 CN 相关的反应。还评估了共发生的基因组改变和免疫组织化学检测到的 PTEN 缺失的影响。
结果
共入组 38 例患者，36 例纳入疗效分析。转移性疾病中既往治疗中位数为 3 次（范围 0-9；1 例患者未知）。中位 HER2 CN 为 17（范围 7-139）。两名患者（5.6%）观察到部分缓解：一名腮腺黏液表皮样癌和一名腮腺鳞状细胞癌。17 名患者（47%）疾病稳定，包括 10 名卵巢和子宫癌患者中的 8 名（80%），中位持续时间为 4.6 个月。6 个月无进展生存率为 23.6%[90%置信区间 14.2%至 39.2%]。常见的毒性包括疲劳、贫血、发热和血小板减少，没有新的安全信号。通过 NGS 检测，肿瘤缩小与基因 CN 水平升高呈趋势相关。
结论
T-DM1 耐受良好。虽然在这一预先治疗过的多样化患者人群中，该亚方案未达到 ORR 的主要终点，但在唾液腺肿瘤中观察到临床活性，这需要在专门的试验中对这种肿瘤类型进行进一步研究。
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