Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Oncology Department, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau, and Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
BMJ. 2024 Aug 20;386:e079126. doi: 10.1136/bmj-2023-079126.
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).
Cross sectional study.
PARTICIPANTS/SETTING: Genome targeted cancer drugs recommended by NCCN guidelines in the advanced setting.
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.
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.
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.
评估美国国家综合癌症网络（NCCN）推荐的用于临床实践的基因组靶向癌症药物的分子靶标临床获益和可操作性。
横断面研究。
参与者/设置：NCCN 指南中晚期推荐的基因组靶向癌症药物。
使用欧洲肿瘤内科学会（ESMO）分子靶标临床可操作性量表（ESCAT）评估分子靶标可操作性。使用 ESMO 临床获益量表（ESMO-MCBS）评估基因组靶向肿瘤疗法的临床获益。将 ESCAT 类别 1 级别的与 ESMO-MCBS （等级 4-5）显示出实质性临床获益的研究相关的分子靶点指定为高获益，而与 ESMO-MCBS 等级为 3 的研究相关的分子靶点则归类为有希望但未经证实的获益。
共研究了 74 种针对 50 种驱动基因突变的基因组靶向药物的 411 项建议。大多数建议（346/411；84%）与各种阶段的临床试验有关，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缓解率（271/346；78%）而不是生存。ESCAT 1 级靶标涵盖了 60%（246/411）的靶标建议，35%（142/411）为 2 级或 3 级，6%（23/411）的相关性尚待确定（4 级至 10 级）。当将 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（等级 4-5），45%（121/267）为等级 3。当结合这两个框架时，12%（32/267）的试验支持确定高获益，33%（88/267）表明有希望但未经证实的获益。在 NCCN 作者推荐的 118 种干预措施中，有 62 种（53%）适用于具有高或有希望但未经证实的获益的治疗方法。
根据 ESCAT 和 ESMO-MCBS 框架，约有八分之一的实体瘤基因组治疗方法被认为可能为患者带来高获益，而约三分之一的治疗方法被认为具有有希望但未经证实的实质性获益。确保 NCCN 建议与预期的临床获益保持一致对于促进知情、基于证据、基于基因组的治疗决策至关重要。
