Trédan Olivier, Pouessel Damien, Penel Nicolas, Chabaud Sylvie, Gomez-Roca Carlos, Delord Jean-Pierre, Pannier Diane, Brahmi Mehdi, Fabbro Michel, Garcia Marie-Eve, Larrieu-Ciron Delphine, Ray-Coquard Isabelle, Viala Marie, Italiano Antoine, Tosi Diego, Cassier Philippe, Dufresne Armelle, Attignon Valery, Boyault Sandrine, Treilleux Isabelle, Viari Alain, Pérol David, Blay Jean Yves
Centre Léon Bérard, Lyon, France.
Cancer Research Center of Lyon, Lyon, France.
Nat Med. 2025 May;31(5):1502-1508. doi: 10.1038/s41591-025-03613-x. Epub 2025 Apr 7.
Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs). Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with an MBRT identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to MBRT identification, the number of patients with and without MBRTs initiated, progression-free survival, best overall response, duration of response and safety. Among the 741 patients screened, 45.7% had quality-checked tumor samples. MBRTs were identified with F1CDX in 175 (51.6%) patients and with CTL in 125 (36.9%) patients, translating to a significant increase of 14.8 percentage points (P < 0.001) with the more comprehensive gene panel versus the more limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations. These findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded MBRTs. ClinicalTrials.gov registration: NCT03163732 .
大型基因组计划有助于改善癌症药物研发。为评估使用更大的基因检测板指导基于分子的治疗的潜在益处，我们对晚期和/或转移性实体癌患者开展了一项多中心随机试验。使用一组324个癌症相关基因（Foundation OneCDX（F1CDX））或一组有限的87个单核苷酸/插入缺失基因及全基因组拷贝数变异（CTL）来确定分子改变，并由分子肿瘤委员会进行审查以确定基于分子的推荐疗法（MBRTs）。利用每位患者两组检测板的配对数据，主要终点是确定有MBRT的患者比例。主要次要终点包括至少有一个可导致确定MBRT的可操作改变的患者数量、启动和未启动MBRT的患者数量、无进展生存期、最佳总体缓解率、缓解持续时间和安全性。在741名筛查的患者中，45.7%有经过质量检查的肿瘤样本。175名（51.6%）患者通过F1CDX确定了MBRT，125名（36.9%）患者通过CTL确定了MBRT，与更有限的检测板相比，更全面的基因检测板使确定MBRT的比例显著增加了14.8个百分点（P < 0.001），达到了主要终点。然而，在这些需要标准基因组改变以外治疗的晚期和/或转移性癌症患者中，未观察到临床结局的差异。这些发现表明更大的基因检测板有增加分子匹配疗法数量的潜力。需要开展更大规模的研究来评估扩展MBRT的临床益处。ClinicalTrials.gov注册号：NCT03163732 。
