Muto Yusuke, Ng William, Namikawa Kenjiro, Takahashi Akira, Tsutsumida Arata, Nishida Makiko, Yamazaki Naoya
Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Melanoma Res. 2018 Apr;28(2):151-154. doi: 10.1097/CMR.0000000000000424.
The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.
丝裂原活化蛋白激酶途径调节细胞生长和分化，并由BRAF突变激活。BRAF突变存在于约40%-50%的皮肤黑色素瘤中。超过90%的BRAF突变是V600E型。BRAF抑制剂（达拉非尼或维莫非尼）和MEK抑制剂（曲美替尼或考比替尼）联合疗法对BRAF突变的晚期黑色素瘤有效。联合疗法已观察到多种副作用，包括发热、疲劳、恶心和呕吐。横纹肌溶解是最严重的不良事件之一，但非常罕见。临床试验中仅报告了两例横纹肌溶解病例。一名41岁的日本皮肤黑色素瘤女性在免疫检查点治疗失败后开始接受达拉非尼和曲美替尼联合治疗。一个月后，她主诉肌痛和疲劳，随后转诊至我院。她被诊断为曲美替尼诱导的横纹肌溶解，仅通过大量补液后症状有所改善。我们停止了联合治疗，但对她没有有效的治疗选择。在恢复使用达拉非尼，随后再使用曲美替尼后，她没有出现任何问题。这是首例转移性皮肤黑色素瘤患者在曲美替尼相关横纹肌溶解后能够重新开始联合治疗的病例。我们推测并非所有曲美替尼诱导的横纹肌溶解患者都会出现横纹肌溶解复发。由于报告的病例较少，需要更多信息。如果重新挑战联合治疗，我们必须仔细评估安全性。
