Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial
Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial
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DOI：
10.1001/jamaoncol.2020.4643
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发表时间：
2020-12-01
期刊：
影响因子：
28.4
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Hayashi, Hidetoshi;Takiguchi, Yuichi;Nakagawa, Kazuhiko
关键点问题位点特异性治疗，包括基于基因表达谱和新一代测序基因改变的分子靶向治疗，是否可以临床用于原发部位不明的癌症患者？结果这项对 97 名原发部位不明的癌症患者进行的 2 期非随机临床试验显示，1 年生存概率为 53.1%，在具有可操作基因改变的患者中观察到了对靶向治疗的持久反应。意义：针对原发部位不明的癌症患者，包括基于下一代测序的引导靶向治疗在内的位点特异性治疗是一种很有前景的策略，值得在随机临床试验中进行进一步研究。 重要性虽然通过下一代测序（NGS）分析基因表达和基因改变来预测原发肿瘤部位并指导分子靶向治疗可能有望改善原发部位不明的癌症（CUP）的临床结果，但据我们所知，之前没有临床试验评估过这种方法。目的评估针对 CUP 患者的位点特异性治疗（包括基于 NGS 结果的分子靶向治疗）的临床应用。设计、设置和参与者这项 2 期临床试验在日本 19 家机构进行，2015 年 3 月至 2018 年 1 月期间入组了 111 名先前未接受治疗的 CUP 不利子集患者，其中 97 名患者纳入疗效分析。资格标准包括在强制性检查后诊断为不利的 CUP，包括免疫组织化学病理评估、胸腹骨盆计算机断层扫描和正电子发射断层扫描。干预措施 同时对所选基因进行 RNA 和 DNA 测序，分别评估基因表达和基因改变。应用新建立的算法根据这些数据预测肿瘤起源。根据预测的位点和检测到的基因改变，患者接受位点特异性治疗，包括分子靶向治疗。主要结果和措施 主要终点是 1 年生存概率。次要终点包括无进展生存期（PFS）、总生存期（OS）、客观缓解率、安全性、根据预测位点的疗效以及基因改变的频率。结果 97 名参与者中，49 名（50.5%）为女性，中位（范围）年龄为 64（21-81）岁。最常预测的癌症类型是肺癌 (21 [21%])、肝癌 (15 [15%])、肾癌 (15 [15%]) 和结直肠癌 (12 [12%])。最常见的基因改变是 TP53 (45 [46.4%])、KRAS (19 [19.6%]) 和 CDKN2A (18 [18.6%])。 1 年生存概率、中位 OS 和中位 PFS 分别为 53.1%（95% CI，42.6%-62.5%）、13.7 个月（95% CI，9.3-19.7 个月）和 5.2 个月（95% CI，3.3-7.1 个月）。在 5 名预计患有非小细胞肺癌的患者 (5.2%) 中检测到肿瘤标本中的靶向 EGFR 突变，其中 4 名患者接受了阿法替尼治疗；其中 2 名患者实现了超过 6 个月的持久 PFS。结论和相关性本研究的结果表明，位点特异性治疗，包括基于 NGS 分析基因表达和基因改变的分子靶向治疗，有助于治疗患有 CUP 不利亚型的患者。试验注册UMIN 标识符：UMIN000016794 该临床试验评估了针对原发部位不明的日本癌症患者的特定部位治疗的临床应用，包括基于下一代测序结果的分子靶向治疗。
Key PointsQuestionDoes site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by next-generation sequencing, have clinical use for patients with cancer of unknown primary site? FindingsThis phase 2 nonrandomized clinical trial of such site-specific treatment in 97 patients with cancer of unknown primary site revealed a 1-year survival probability of 53.1%, with a durable response to targeted therapy being observed in patients with actionable genetic alterations. MeaningSite-specific treatment, including guided targeted therapy based on next-generation sequencing, is a promising strategy for patients with cancer of unknown primary site and warrants further investigation in a randomized clinical trial.ImportanceAlthough profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. ObjectiveTo assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and ParticipantsThis phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. InterventionsRNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And MeasuresThe primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. ResultsOf 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and RelevanceThis study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial RegistrationUMIN Identifier: UMIN000016794This clinical trial assesses the clinical use of site-specific treatment, including molecularly targeted therapy based on next-generation sequencing results, for Japanese patients with cancer of unknown primary site.