Anticancer drugs are frequently used off-label for tumours that are genetically similar to the approved indication. However, outcomes are rarely captured systematically, limiting evidence-based decision-making and risking repeated futile treatment. The Drug Rediscovery Protocol (DRUP; ClinicalTrials.gov ID: NCT02925234) prospectively evaluates such off-label use in patients in the Netherlands with advanced solid tumours who lack standard treatment options and harbour actionable genomic alterations1. Here we present results of 1,610 patients who began treatment with 37 different off-label drugs between July 2016 and May 2024 in the DRUP trial. Of these patients, 1,363 were response-evaluable, including 533 (39.1%) with rare cancers. The clinical benefit rate (confirmed response or stable disease for at least 16 weeks) was 34.9% (95% confidence interval, 32.2–37.6) and the objective response rate was 15.7% (95% confidence interval, 13.7–17.9). Median progression-free and overall survival were 3.4 months (95% confidence interval, 2.8–3.5) and 8.2 months (95% confidence interval, 7.6–8.8), respectively. Grade 3 or higher treatment-related adverse events occurred in 28.4% of patients. Notably, evidence generated in DRUP was used for reimbursement decisions by the regulatory bodies in the Netherlands2. Although activity across all tumour–drug combinations was modest, defined molecular subgroups and exceptional responders (7.0%) achieved meaningful benefit. To maximize patient benefit, we recommend that off-label precision medicines should be used only within frameworks that systematically evaluate efficacy and toxicity, support biomarker refinement and enable stepwise assessment toward potential future label expansion. These frameworks should prioritize high-confidence targets, early intervention, regulatory-aligned end-points and international collaboration.
抗癌药物常被超说明书用于与批准适应症基因相似的肿瘤。然而，这些治疗结果很少被系统记录，限制了基于证据的决策，并可能导致无效治疗的重复。荷兰的“药物再发现方案”（DRUP；ClinicalTrials.gov ID: NCT02925234）前瞻性地评估了这种超说明书用药在无标准治疗选择且携带可干预基因变异的晚期实体瘤患者中的应用。本文展示了2016年7月至2024年5月期间参与DRUP试验的1610名患者（接受37种不同超说明书药物）的治疗结果。其中1363名患者可进行疗效评估，包括533名（39.1%）罕见癌症患者。临床获益率（确认缓解或疾病稳定≥16周）为34.9%（95%置信区间，32.2–37.6），客观缓解率为15.7%（95%置信区间，13.7–17.9）。中位无进展生存期为3.4个月（95%置信区间，2.8–3.5），中位总生存期为8.2个月（95%置信区间，7.6–8.8）。28.4%的患者发生了3级或以上的治疗相关不良事件。值得注意的是，DRUP产生的证据已被荷兰监管机构用于报销决策。尽管所有肿瘤-药物组合的总体疗效有限，但特定分子亚组和 exceptional responders（7.0%）获得了有意义的获益。为使患者获益最大化，我们建议超说明书精准药物仅在能够系统评估疗效和毒性、支持生物标志物优化、并为未来可能的适应症扩展提供逐步评估的框架内使用。这些框架应优先考虑高置信度靶点、早期干预、符合监管要求的终点以及国际合作。
Prospective evaluation of genomics-guided off-label treatment
肿瘤(癌症)患者之家