Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients.
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients.
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DOI：
10.1016/j.neo.2017.01.010
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Morrison SJ
中科院分区：
文献类型：
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作者：
Frankel AE;Eskiocak U;Gill JG;Yuan S;Ramesh V;Froehlich TW;Ahn C;Morrison SJ
这是第一次涉及卡地奈德和MEK抑制剂联合治疗转移性黑色素瘤的前瞻性研究。虽然BRAF突变型黑色素瘤对BRAF和MEK抑制剂的治疗有深刻的反应，但BRAF野生型黑色素瘤的选择较少。在临床前研究中，我们发现，无论BRAF突变状态如何，Cardenolide与MEK抑制剂具有协同作用，可以促进患者来源的异种移植的消退。因此，我们对20例晚期难治性BRAF野生型黑色素瘤患者进行了1B期研究，其中地高辛0.25 mg，曲美替尼2 mg，每天口服一次。最常见的不良反应是皮疹、腹泻、恶心和疲劳。有效率分别为4/20或20%，有效时间分别为2、4、6、8个月。疾病控制率(包括部分应答率和稳定期)为13/20或65%，其中NRAS突变型黑色素瘤为5/6或83%，NRAS野生型黑色素瘤为8/14或57%。病情稳定的患者分别进行2、2、2、4、5、6、7、10、10个月的疾病控制。来自4名患者的异种移植总结了在患者中观察到的治疗反应。基于这些试验结果，对于免疫治疗无效或不耐受的NRAS突变转移性黑色素瘤患者，有必要使用地高辛加MEK抑制剂的扩展臂。地高辛加曲美替尼耐受性良好，在BRAF野生型转移性黑色素瘤患者中实现了高疾病控制率。
This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy. Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.