Abstract：
BACKGROUND: Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response.
METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%.
RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%).
CONCLUSIONS: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.
METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%.
RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%).
CONCLUSIONS: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.
摘要：
背景：恩科拉非尼联合比米替尼（EB）是晚期BRAFV600突变黑色素瘤的标准治疗方法。我们评估了恩可拉非尼联合比米替尼治疗BRAFV600突变黑色素瘤和脑转移（BM）患者的疗效和安全性，并探讨了放疗是否可以改善缓解时间。
方法：E-BRAIN/GEM1802是一种前瞻性，多中心，单臂,纳入黑色素瘤BRAFV600突变体和BM患者的II期试验。患者接受恩科非尼450mg，每日一次，加比米替尼45mgBID，和那些在第一次肿瘤评估时获得部分缓解或疾病稳定的人接受放射治疗。继续治疗直至进展。主要终点是EB术后2个月的颅内反应率（icRR），建立60%的徒劳门槛。
结果：该研究包括25例无BM症状的患者和23例有BM症状的患者，无论是否使用皮质类固醇。其中,31例(64.6%)接受序贯放疗。两个月后,icRR为70.8%（95%CI：55.9-83.1）；10.4%完全缓解。颅内PFS和OS中位数分别为8.5(95%CI:6.4-11.8)和15.9(95%CI:10.7-21.4)个月,（icPFS分别为8.3个月，接受RDT的患者为13.9个月OS）。最常见的3-4级治疗相关的不良事件是丙氨酸转氨酶（ALT）增加（10.4％）。
结论：恩科拉非尼联合比尼在icRR方面显示了有希望的临床益处，具有低频率的高等级TRAE，在BRAFV600突变黑色素瘤和BM患者中，包括那些有症状和需要类固醇的人。序贯放疗是可行的，但似乎并不能延长反应。
方法：E-BRAIN/GEM1802是一种前瞻性，多中心，单臂,纳入黑色素瘤BRAFV600突变体和BM患者的II期试验。患者接受恩科非尼450mg，每日一次，加比米替尼45mgBID，和那些在第一次肿瘤评估时获得部分缓解或疾病稳定的人接受放射治疗。继续治疗直至进展。主要终点是EB术后2个月的颅内反应率（icRR），建立60%的徒劳门槛。
结果：该研究包括25例无BM症状的患者和23例有BM症状的患者，无论是否使用皮质类固醇。其中,31例(64.6%)接受序贯放疗。两个月后,icRR为70.8%（95%CI：55.9-83.1）；10.4%完全缓解。颅内PFS和OS中位数分别为8.5(95%CI:6.4-11.8)和15.9(95%CI:10.7-21.4)个月,（icPFS分别为8.3个月，接受RDT的患者为13.9个月OS）。最常见的3-4级治疗相关的不良事件是丙氨酸转氨酶（ALT）增加（10.4％）。
结论：恩科拉非尼联合比尼在icRR方面显示了有希望的临床益处，具有低频率的高等级TRAE，在BRAFV600突变黑色素瘤和BM患者中，包括那些有症状和需要类固醇的人。序贯放疗是可行的，但似乎并不能延长反应。
