Office of Medical Student Research, Oklahoma State University Center for Health Sciences, 1111 W 17th St., Tulsa, OK, 74107, USA.
Department of Internal Medicine, University of Vermont Medical Center, Burlington, VT, USA.
Target Oncol. 2024 Mar;19(2):161-173. doi: 10.1007/s11523-024-01040-5. Epub 2024 Mar 11.
Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking.
This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time.
On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint).
Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials.
Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.
化疗药物通常首先在最有前途的适应证中进行测试；然而，在美国食品药品监督管理局（FDA）最初批准后，新的临床试验通常在不太有前途的适应证中启动，这些适应证中患者的获益-风险比更差。目前缺乏关于仑伐替尼在非 FDA 批准适应证中的获益-风险特征的文献。
本研究旨在评估仑伐替尼已发表的临床试验，以确定随着时间的推移患者的获益-风险特征。
在 2023 年 5 月 25 日，我们在 Pubmed/MEDLINE、Embase、Cochrane CENTRAL 和 ClinicalTrials.gov 数据库中搜索了仑伐替尼治疗实体瘤的临床试验。合格的文章为临床试验，包含成年参与者，发表于英文，涉及实体肿瘤。筛查和数据收集以盲法、重复的方式进行。对于每个合格的研究，我们收集了不良事件数据、试验特征、无进展生存期（PFS）、总生存期（OS）和客观缓解率（ORR）。当试验达到主要终点和安全性标准时，被归类为阳性（符合两者标准），否则为阴性（不符合任何标准）或不确定（缺乏预定的主要终点）。
临床试验检测范围扩大到仑伐替尼最初的 FDA 适应证之外，显示累积不良事件不断增加，同时药物疗效下降。仑伐替尼在 16 种癌症适应证中进行了测试，并获得了 FDA 的批准。在 6225 名临床试验参与者中，共发生 5390 例 3-5 级不良事件。扩展适应证测试进一步显示，所有适应证的 ORR（11-69%）、OS（6.2-32 个月）和 PFS（3.6-15.7 个月）差异很大。在美国 FDA 最初批准后，扩展适应证临床试验结果更不可能达到其主要终点，尤其是在非随机临床试验中。
本研究评估了仑伐替尼在其 FDA 批准适应证中的有效性；然而，临床试验扩展到新的适应证的特点是疗效降低，而患者经历了与仑伐替尼既定安全性特征一致的高不良事件负担。此外，在新适应证中进行的临床试验以反复进行的 I 期和 II 期临床试验为标志，且未能进展至 III 期临床试验。未来使用仑伐替尼作为干预措施的临床试验应仔细评估患者可能经历的潜在获益和负担。
