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  • Title: Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib.
    Author: Chalmers A, Cannon L, Akerley W.
    Journal: Oncologist; 2019 Jul; 24(7):963-972. PubMed ID: 30598499.
    Abstract:
    Therapies for advanced non-small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600-mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression-free survival of 10-11 months. BRAF mutations are a high-frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical-trial and real-world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. IMPLICATIONS FOR PRACTICE: The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E-mutant non-small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients. 摘要 晚期非小细胞肺癌 (NSCLC) 的治疗不断变得更加复杂。化学疗法正在被更新的方法所替代，如旨在提高疗效和改善预后的免疫检查点抑制剂和靶向治疗。达拉非尼和曲美替尼联合疗法于 2014 年首次被批准用于治疗含有 BRAF V600 突变的转移性黑色素瘤。2017 年，基于 ≈ 65% 的反应率和 10–11 个月的中位无进展生存期，美国食品和药品管理局批准将此联合疗法用于患有相同突变的 NSCLC 患者。BRAF 突变是黑色素瘤中的一种高频事件 (≈ 50%)，而它在肺癌中的总发病率 ≈ 2%，不过，由于肺癌的发病率很高，因而在数量方面十分相似。作为一种新的 NSCLC 治疗方法，达拉非尼和曲美替尼联合治疗具有独特的毒性特征，在胸腔肿瘤科和普通肿瘤科中尚未利用此联合疗法治疗黑色素瘤患者的医疗服务提供者可能对此还不太熟悉。在达拉非尼和曲美替尼联合治疗期间，可以观察到诸如发热、疲劳和恶心等常见的不良反应以及一些较不频繁发生的皮肤、眼睛和出血反应。既往在转移性黑色素瘤方面积累的经验表明，我们可以有效地管理这些反应，以便改善患者的生活质量和减少不必要的药物停用。本次研究旨在总结治疗指南以及从既往的临床试验和真实世界经验中获取的关于转移性黑色素瘤患者的重要见解，以便正确地管理与达拉非尼和曲美替尼联合治疗 NSCLC 相关的毒性。 实践意义:达拉非尼和曲美替尼联合治疗已在 BRAF V600E 突变型非小细胞肺癌患者中显示出重要的临床活性，从而导致美国食品和药品管理局给予批准。虽然此联合疗法具有可管理的安全特性，但是，胸科专家或普通科肿瘤专家可能对与此治疗方案相关的许多毒性还不太熟悉。关于将此联合疗法用于转移性黑色素瘤患者的大量临床经验提供了丰富的策略，以供我们识别和管理与达拉非尼和曲美替尼联合治疗相关的不良反应。内科肿瘤学家可以将它们用于提高毒性的早期识别和促进有效的管理，从而改善患者的治疗质量。
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