Global Drug Development Division, Novartis Pharma K.K., Tokyo, Japan.
Medical Affairs Department, Innovative Medicines International Japan, Novartis Pharma K.K., Tokyo, Japan.
J Dermatol. 2023 Jun;50(6):727-738. doi: 10.1111/1346-8138.16759. Epub 2023 Mar 8.
Targeted therapy with a combination of dabrafenib and trametinib has been developed and widely used for treatment of melanoma. However, data regarding its safety and efficacy in Japanese patients with malignant melanoma are limited. A post-marketing surveillance (PMS) study was conducted to investigate the safety and efficacy of combination therapy in a Japanese clinical setting with a surveillance period of June 2016 to March 2022; 326 patients with unresectable malignant melanoma with BRAF mutation were enrolled. The interim results were published in July 2020. Herein, we report the results of the final analysis based on the data collected until the completion of the PMS study. The safety analysis population included 326 patients, the majority of whom had stage IV disease (79.14%) and Eastern Cooperative Oncology Group performance status 0 or 1 (85.28%). All patients were treated with the approved dose of dabrafenib, while 99.08% were treated with the approved dose of trametinib. Adverse events (AEs) occurred in 282 patients (86.50%) and the major AEs (incidence ≥5%) were pyrexia (47.85%), malignant melanoma (33.44%), hepatic function abnormal (9.82%), rash and blood creatine phosphokinase increased (8.59% each), malaise (6.44%), nausea (5.52%), and diarrhea and rhabdomyolysis (5.21% each). The incidences rates of adverse drug reactions of safety specifications were 45.71% for pyrexia, 15.95% for hepatic impairment, 12.58% for rhabdomyolysis, 4.60% for cardiac disorders, and 3.07% for eye disorders. In the efficacy analysis population of 318 patients, the objective response rate was 58.18% (95% confidence interval [CI] 52.54%-63.66%). The progression-free survival rates at 90, 180, and 360 days were 88.14% (95% CI 84.00%-91.26%), 69.53% (63.85%-74.50%), and 52.07% (45.71%-58.03%), respectively. Consistent with previous interim results, no new safety or efficacy concerns were observed in this final analysis of a PMS study conducted in a Japanese real-world clinical setting.
达拉非尼联合曲美替尼的靶向治疗已经开发并广泛用于治疗黑色素瘤。然而，关于其在日本黑色素瘤患者中的安全性和疗效的数据有限。一项上市后监测（PMS）研究旨在调查日本临床环境中联合治疗的安全性和疗效，监测期为 2016 年 6 月至 2022 年 3 月；共纳入 326 例不可切除的有 BRAF 突变的恶性黑色素瘤患者。中期结果于 2020 年 7 月公布。在此，我们根据 PMS 研究完成时收集的数据报告最终分析结果。安全性分析人群包括 326 例患者，其中大多数为 IV 期疾病（79.14%）和东部合作肿瘤学组表现状态 0 或 1（85.28%）。所有患者均接受批准剂量的达拉非尼治疗，而 99.08%的患者接受批准剂量的曲美替尼治疗。282 例患者（86.50%）出现不良事件（AE），主要不良事件（发生率≥5%）为发热（47.85%）、黑色素瘤（33.44%）、肝功能异常（9.82%）、皮疹和血肌酸磷酸激酶升高（各 8.59%）、乏力（6.44%）、恶心（5.52%）和腹泻及横纹肌溶解（各 5.21%）。安全性规范中不良药物反应的发生率为发热 45.71%、肝损伤 15.95%、横纹肌溶解 12.58%、心脏疾病 4.60%和眼部疾病 3.07%。在 318 例疗效分析人群中，客观缓解率为 58.18%（95%置信区间[CI]52.54%-63.66%）。90、180 和 360 天的无进展生存率分别为 88.14%（95%CI84.00%-91.26%）、69.53%（63.85%-74.50%）和 52.07%（45.71%-58.03%）。与之前的中期结果一致，在日本真实世界临床环境中进行的这项 PMS 研究的最终分析中未观察到新的安全性或疗效问题。
