Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France.
Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France; Pharmacology Department, National Research Centre, Cairo, Egypt.
Eur J Cancer. 2019 Oct;120:40-46. doi: 10.1016/j.ejca.2019.08.002. Epub 2019 Aug 31.
Determining the optimal biological dose (OBD) has been described as an alternative strategy to the maximum tolerated doses (MTDs) for identifying the recommended phase II trial doses (RP2Ds) of phase I anti-cancer therapies. However, the clinical relevance is still unknown. An extensive review was performed to assess if the OBDs defined in early-phase trials were useful for subsequent drug development and approvals.
All the molecular targeted therapies approved by the Food and Drug Administration (FDA) in solid oncology or in haematological malignancies before July 2018 were listed through the National Cancer Institute Database. The early-phase trial publications investigating these drugs as single agents were retrieved and analysed to identify the drugs for which OBDs were reported. The publications of subsequent pivotal efficacy clinical trials leading to the approvals were retrieved, and OBDs compared with the final labelled doses and dosing schedules.
A total of 87 early-phase trial publications were analysed, corresponding to 81 FDA-approved targeted therapies. OBDs were reported for 40% (32/81) of these drugs (19 small molecules, 13 monoclonal antibodies). MTDs were not identified for 59% (19/32) of molecules. When the OBDs were selected as the RP2Ds (18/32 molecules), the final FDA-approved doses were consistent with the OBDs for 83% of the drugs, which is much higher than the previously reported 58% rate when MTDs were chosen as the RP2Ds.
Although still poorly investigated, the OBD may be a relevant and complementary end-point for early-phase trials of targeted therapies.
确定最佳生物学剂量（OBD）已被描述为替代最大耐受剂量（MTD）的策略，用于确定 I 期抗癌治疗的推荐 II 期试验剂量（RP2D）。然而，其临床相关性仍不清楚。进行了广泛的综述，以评估在 I 期试验中定义的 OBD 是否对后续药物开发和批准有用。
通过国家癌症研究所数据库，列出了 2018 年 7 月前在实体瘤或血液恶性肿瘤中获得美国食品和药物管理局（FDA）批准的所有分子靶向治疗药物。检索并分析了研究这些药物作为单一药物的 I 期试验出版物，以确定报告 OBD 的药物。检索了导致批准的后续关键疗效临床试验的出版物，并将 OBD 与最终标签剂量和给药方案进行比较。
共分析了 87 篇 I 期试验出版物，对应于 81 种 FDA 批准的靶向治疗药物。这些药物中有 40%（32/81）报告了 OBD（19 种小分子，13 种单克隆抗体）。对于 59%（19/32）的分子，未确定 MTD。当 OBD 被选为 RP2D（32 个分子中的 18 个）时，最终 FDA 批准的剂量与 OBD 一致的药物为 83%，这明显高于先前报道的当 MTD 被选为 RP2D 时的 58%的比率。
尽管研究仍不充分，但 OBD 可能是靶向治疗 I 期试验的一个相关且互补的终点。
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