Objective To assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN). Design Cross sectional study. Participants/setting Genome targeted cancer drugs recommended by NCCN guidelines in the advanced setting. Main outcome measures Molecular target actionability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit of genome targeted oncology therapies was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT category level I associated with studies showing substantial clinical benefit by ESMO-MCBS (grades 4-5) were designated as high benefit, and those linked to studies achieving an ESMO-MCBS grade of 3 were categorized as being of promising but unproven benefit. Results 411 recommendations related to 74 genome targeted drugs targeting 50 driver alterations were examined. Most recommendations (346/411; 84%) were associated with clinical trials of various phases, but 16% (65/411) relied on only case reports or pre-clinical studies. However, clinical trials mostly comprised phase I or phase II (271/346; 78%), single arm (262/346; 76%) studies. The primary endpoint assessed in most trials was overall response rate (271/346; 78%) rather than survival. ESCAT tier I targetability encompassed 60% (246/411) of target recommendations, 35% (142/411) were classified as tier II or III, and 6% (23/411) had their relevance yet to be determined (tiers IV to X). When ESMO-MCBS was applied to 267 scorable trials, only 12% (32/267) showed substantial clinical benefit (grades 4-5) and 45% (121/267) were grade 3. When both frameworks were combined, 12% (32/267) of trials supported a determination of high benefit and 33% (88/267) indicated promising but unproven benefit. Of the 118 interventions endorsed by NCCN authors as preferred, 62 (53%) applied to treatments with high or promising but unproven benefit. Conclusion According to the ESCAT and ESMO-MCBS frameworks, about one eighth of genome based treatments for solid cancer were rated as likely to offer a high benefit to patients, whereas around a third were identified as offering a promising but unproven substantial benefit. Ensuring that NCCN recommendations are aligned with expected clinical benefits is crucial for promoting informed, evidence based, genomic guided treatment decisions. Data are publicly available.

中文翻译：

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指南推荐的分子靶点和基因组靶向癌症治疗的临床价值：横断面研究


目的 评估国家综合癌症网络（NCCN）推荐用于临床实践的基因组靶向癌症药物的分子靶点的临床益处和可操作性。设计横断面研究。参与者/环境 NCCN 指南在高级环境中推荐的基因组靶向癌症药物。主要结果指标 使用欧洲肿瘤内科学会 (ESMO) 分子靶点临床可操作性量表 (ESCAT) 评估分子靶点可操作性。使用 ESMO 临床获益量表 (ESMO-MCBS) 评估基因组靶向肿瘤治疗的临床获益。 ESCAT 类别 I 级的分子靶标与显示 ESMO-MCBS（4-5 级）显着临床效益的研究相关，被指定为高效益，而与实现 ESMO-MCBS 3 级的研究相关的分子靶标被归类为有希望但未经证实的好处。结果 审查了与针对 50 个驱动基因改变的 74 种基因组靶向药物相关的 411 条建议。大多数建议（346/411；84%）与不同阶段的临床试验相关，但 16%（65/411）仅依赖于病例报告或临床前研究。然而，临床试验主要包括 I 期或 II 期（271/346；78%）、单臂（262/346；76%）研究。大多数试验评估的主要终点是总体缓解率（271/346；78%）而不是生存率。 ESCAT 第一级目标性涵盖了 60% (246/411) 的目标建议，35% (142/411) 被归类为第二级或第三级，6% (23/411) 的相关性尚未确定（第四级到第三级） X）。当 ESMO-MCBS 应用于 267 项可评分试验时，只有 12% (32/267) 显示出实质性临床获益（4-5 级），45% (121/267) 为 3 级。 当两个框架结合起来时，12% (32/267) 的试验支持高效益的确定，33% (88/267) 表明有希望但未经证实的效益。在 NCCN 作者认可的 118 项首选干预措施中，有 62 项 (53%) 适用于具有高效益或有希望但未经证实效益的治疗。结论 根据 ESCAT 和 ESMO-MCBS 框架，大约八分之一的基于基因组的实体癌治疗被认为可能为患者带来很高的益处，而大约三分之一的治疗被认为可以提供有希望但未经证实的实质性益处。确保 NCCN 建议与预期的临床效益保持一致对于促进知情、基于证据、基因组指导的治疗决策至关重要。数据是公开的。