Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Oncologist. 2019 Jul;24(7):963-972. doi: 10.1634/theoncologist.2018-0296. Epub 2018 Dec 31.
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 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. 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 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.
治疗晚期非小细胞肺癌 (NSCLC) 的方法不断变得更加复杂。化疗正在让位于新的方法，如免疫检查点抑制剂和靶向治疗，以提高疗效和改善结果。达拉非尼联合曲美替尼联合治疗于 2014 年首次被批准用于治疗携带 V600 突变的转移性黑色素瘤。2017 年，美国食品和药物管理局根据 ≈65%的反应率和 10-11 个月的中位无进展生存期批准了该联合治疗方案用于具有相同突变的 NSCLC 患者。 V600 突变是黑色素瘤的高频事件（≈50%），而肺癌的总体发生率约为 2%，但由于疾病的高发病率，其数量相似。作为 NSCLC 治疗的新方法，达拉非尼联合曲美替尼具有独特的毒性特征，这可能是未使用该联合治疗方案治疗黑色素瘤患者的胸科和普通肿瘤学医生所不熟悉的。在接受达拉非尼联合曲美替尼治疗期间，可观察到发热、疲劳、恶心等常见不良反应，以及一系列不太常见的皮肤、眼部和出血事件。以前在转移性黑色素瘤中的经验表明，这些事件可以通过有效的管理来改善患者的生活质量并减少不必要的药物停药。本综述的目的是总结治疗指南，并结合以前在转移性黑色素瘤患者的临床试验和真实世界经验中获得的关键见解，以正确管理与 NSCLC 相关的达拉非尼联合曲美替尼的毒性。 实践意义：达拉非尼联合曲美替尼在 V600E 突变的非小细胞肺癌患者中显示出显著的临床活性，导致美国食品和药物管理局批准。尽管该联合方案具有可管理的安全性特征，但该方案相关的许多毒性可能不为胸科专家或普通肿瘤学家所熟悉。在转移性黑色素瘤患者中广泛的临床经验为识别和管理与达拉非尼联合曲美替尼相关的不良事件提供了丰富的策略。这些策略可由肿瘤内科医生用于增强对毒性的早期识别并促进有效管理，从而提高患者的治疗质量。
