PDF(Pubmed)
Abstract：
National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) is a precision medicine basket trial designed to test the effectiveness of treating cancers based on specific genetic changes in patients\' tumors, regardless of cancer type. Multiple subprotocols have each tested different targeted therapies matched to specific genetic aberrations. Most subprotocols exhibited low rates of tumor shrinkage as evaluated across all tumor types enrolled. We hypothesized that these results may arise because these precision cancer therapies have tumor type-specific efficacy, as is common among other cancer therapies.
To test the hypothesis that certain tumor types are more sensitive to specific therapies than other tumor types, we applied permutation testing to tumor volume change and progression-free survival data from 10 published NCI-MATCH subprotocols (together n = 435 patients). FDR was controlled by the Benjamini-Hochberg procedure.
Six of ten subprotocols exhibited statistically significant evidence of tumor-specific drug sensitivity, four of which were previously considered negative based on response rate across all tumors. This signal-finding analysis highlights potential uses of FGFR tyrosine kinase inhibition in urothelial carcinomas with actionable FGFR aberrations and MEK inhibition in lung cancers with BRAF non-V600E mutations. In addition, it identifies low-grade serious ovarian carcinoma with BRAF v600E mutation as especially sensitive to BRAF and MEK co-inhibition (dabrafenib plus trametinib), a treatment that received accelerated FDA approval for advanced solid tumors with BRAF v600E mutation.
These findings support the value of basket trials because even when precision medicines do not have tumor-agnostic activity, basket trials can identify tumor-specific activity for future study.
To test the hypothesis that certain tumor types are more sensitive to specific therapies than other tumor types, we applied permutation testing to tumor volume change and progression-free survival data from 10 published NCI-MATCH subprotocols (together n = 435 patients). FDR was controlled by the Benjamini-Hochberg procedure.
Six of ten subprotocols exhibited statistically significant evidence of tumor-specific drug sensitivity, four of which were previously considered negative based on response rate across all tumors. This signal-finding analysis highlights potential uses of FGFR tyrosine kinase inhibition in urothelial carcinomas with actionable FGFR aberrations and MEK inhibition in lung cancers with BRAF non-V600E mutations. In addition, it identifies low-grade serious ovarian carcinoma with BRAF v600E mutation as especially sensitive to BRAF and MEK co-inhibition (dabrafenib plus trametinib), a treatment that received accelerated FDA approval for advanced solid tumors with BRAF v600E mutation.
These findings support the value of basket trials because even when precision medicines do not have tumor-agnostic activity, basket trials can identify tumor-specific activity for future study.
摘要：
背景：NCI-MATCH是一项精准医学篮子试验，旨在根据患者肿瘤的特定遗传变化来测试治疗癌症的有效性，无论癌症类型。多个子方案各自测试了与特定遗传畸变匹配的不同靶向疗法。大多数子方案表现出低的肿瘤收缩率，如在所有登记的肿瘤类型中评估的。我们假设这些结果可能是因为这些精确的癌症疗法具有肿瘤类型特异性疗效，这在其他癌症疗法中很常见。
方法：为了检验某些肿瘤类型比其他肿瘤类型对特定疗法更敏感的假设，我们对10个已发表的NCI-MATCH子方案(n=435例)的肿瘤体积变化和无进展生存期数据进行了排列检验.错误发现率由Benjamini-Hochberg程序控制。
结果：十个子方案中有六个显示出肿瘤特异性药物敏感性的统计学显著证据，根据所有肿瘤的缓解率，其中4例以前被认为是阴性的。该信号发现分析突出了FGFR酪氨酸激酶抑制在具有可操作的FGFR畸变的尿路上皮癌中的潜在用途和在具有BRAF非V600E突变的肺癌中的MEK抑制。此外,它鉴定了具有BRAFv600E突变的低度严重卵巢癌，对BRAF和MEK共抑制特别敏感（达拉非尼加曲美替尼），获得FDA加速批准的BRAFv600E突变的晚期实体瘤治疗方法.
结论：这些发现支持篮子试验的价值，因为即使精准药物没有肿瘤无关活性，篮子试验可以确定肿瘤特异性活性,用于未来的研究.
方法：为了检验某些肿瘤类型比其他肿瘤类型对特定疗法更敏感的假设，我们对10个已发表的NCI-MATCH子方案(n=435例)的肿瘤体积变化和无进展生存期数据进行了排列检验.错误发现率由Benjamini-Hochberg程序控制。
结果：十个子方案中有六个显示出肿瘤特异性药物敏感性的统计学显著证据，根据所有肿瘤的缓解率，其中4例以前被认为是阴性的。该信号发现分析突出了FGFR酪氨酸激酶抑制在具有可操作的FGFR畸变的尿路上皮癌中的潜在用途和在具有BRAF非V600E突变的肺癌中的MEK抑制。此外,它鉴定了具有BRAFv600E突变的低度严重卵巢癌，对BRAF和MEK共抑制特别敏感（达拉非尼加曲美替尼），获得FDA加速批准的BRAFv600E突变的晚期实体瘤治疗方法.
结论：这些发现支持篮子试验的价值，因为即使精准药物没有肿瘤无关活性，篮子试验可以确定肿瘤特异性活性,用于未来的研究.
