Targeted Therapies, Novel Antibodies, and Immunotherapies in Advanced Non-Small Cell Lung Cancer: Clinical Evidence and Drug Approval Patterns.

IF 10 1区 医学 Q1 ONCOLOGY Clinical Cancer Research Pub Date : 2024-11-01 DOI:10.1158/1078-0432.CCR-24-0741
Marén U Koban, Markus Hartmann, Georgios Amexis, Pedro Franco, Laura Huggins, Imran Shah, Niki Karachaliou
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Abstract

Since 2011, the US FDA has approved 30 new drugs for use in advanced non-small cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small-molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the United States, based on single-cohort or multicohort trials. Confirmatory clinical evidence was subsequently provided through postmarketing trials. In NSCLC without such driver alterations, regulatory agencies in both the United States and the European Union set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small-molecule inhibitors that target driver alterations, as well as biologics. The latter include mAbs inhibiting immune checkpoints like PD-(L)1 or cell surface receptors and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.

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晚期非小细胞肺癌的靶向疗法、新型抗体和免疫疗法:临床证据和药物审批模式。
自2011年以来,美国FDA已批准了30种用于晚期非小细胞肺癌(NSCLC)的新药,主要包括酪氨酸激酶抑制剂和免疫检查点抑制剂。有癌基因驱动基因改变的 NSCLC 适合使用靶向药物(通常是小分子抑制剂)进行治疗。在这些病例中,由于总体反应率高,且反应持续时间长,因此美国根据单个或多个队列试验加速批准了这些药物。随后又通过上市后试验提供了确证的临床证据。对于没有发生此类驱动因素改变的 NSCLC,美国和欧盟的监管机构都设定了临床证据预期,促进开展以随机对照试验设计为基础、主要侧重于确定生存期或无事件生存期的研究。本综述分析了 NSCLC 新型疗法的审批模式,重点关注靶向驱动基因改变的小分子抑制剂以及生物制剂。后者包括抑制 PD-(L)1 等免疫检查点或细胞表面受体的单克隆抗体,以及抗体-药物共轭物,即与细胞毒性化合物相连的高效生物制剂。将 NSCLC 分为癌基因亚型和非癌基因亚型决定了药物开发策略、临床开发计划的范围、获得孤儿药开发奖励的机会以及监管审批策略。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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