Cybulska-Stopa Bożena, Rogala Paweł, Czarnecka Anna M, Galus Łukasz, Dziura Robert, Rajczykowski Marcin, Kubiatowski Tomasz, Wiśniewska Magdalena, Gęga-Czarnota Adrianna, Teterycz Paweł, Ziobro Marek, Suwiński Rafał, Mackiewicz Jacek, Rutkowski Piotr
Clinical Oncology Clinic, Maria Sklodowska-Curie National Research Institute of Oncology, Cracow Branch, Krakow.
Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology.
Melanoma Res. 2020 Oct;30(5):465-471. doi: 10.1097/CMR.0000000000000662.
Despite considerable progress made in the treatment of patients with advanced melanoma, the majority of the patients treated with BRAF and mitogen-activated protein inhibitors (BRAFi and MEKi) experience a disease progression due to acquired resistance. Currently, ongoing studies explore the possibility to overcome or reverse this process. Our multicenter retrospective analysis included 51 patients with metastatic BRAF-mutated melanoma who had previously progressed on BRAFi/MEKi than had progressed on immunotherapy (anti-progression disease-1 or anti-cytotoxic T-lymphocyte-associated protein 4) and next were rechallenged with BRAFi/MEKi. Median age at BRAFi/MEKi rechallenge was 56 (range: 31-82 y/o). Median overall survival from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 29.7 and 9.3 months, respectively, whereas median progression-free survival was 10.5 and 5.9 months, respectively. Six-month, annual, and 2-year overall survival rates on both treatments were: 98% and 55%, 92% and 29%, and 69% and 2%, respectively. A response rate to treatment was higher in the group receiving BRAFi/MEKi for the first time as compared with the group receiving BRAFi/MEKi rechallenge and was overall response rate 72% and 27%; disease control rate 92% and 63%. Time interval between the end of the first BRAFi/MEKi treatment and the beginning of BRAFi/MEKi rechallenge did not influence median overall survival or progression-free survival. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. BRAFi/MEKi rechallenge treatment remains clinically important and is associated with the lower toxicity. BRAFi/MEKi rechallenge efficacy is higher in patients who are in good performance status, with normal lactate dehydrogenase, and without brain metastases.
尽管晚期黑色素瘤患者的治疗取得了显著进展，但大多数接受BRAF和丝裂原活化蛋白抑制剂（BRAFi和MEKi）治疗的患者由于获得性耐药而出现疾病进展。目前，正在进行的研究探索克服或逆转这一过程的可能性。我们的多中心回顾性分析纳入了51例转移性BRAF突变黑色素瘤患者，这些患者先前在BRAFi/MEKi治疗中进展，之后在免疫治疗（抗疾病进展-1或抗细胞毒性T淋巴细胞相关蛋白4）中进展，随后再次接受BRAFi/MEKi治疗。再次接受BRAFi/MEKi治疗时的中位年龄为56岁（范围：31-82岁）。从首次BRAFi/MEKi治疗开始和再次接受BRAFi/MEKi治疗的中位总生存期分别为29.7个月和9.3个月，而中位无进展生存期分别为10.5个月和5.9个月。两种治疗的6个月、1年和2年总生存率分别为：98%和55%、92%和29%、69%和2%。首次接受BRAFi/MEKi治疗的组的治疗缓解率高于接受BRAFi/MEKi再次治疗的组，总体缓解率分别为72%和27%；疾病控制率分别为92%和63%。首次BRAFi/MEKi治疗结束至再次接受BRAFi/MEKi治疗开始之间的时间间隔不影响中位总生存期或无进展生存期。再次接受BRAFi/MEKi治疗时的毒性率较低。再次接受BRAFi/MEKi治疗在临床上仍然很重要，且与较低的毒性相关。在体能状态良好、乳酸脱氢酶正常且无脑转移的患者中，再次接受BRAFi/MEKi治疗的疗效更高。
