Abstract：
Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study of a BRAF-MEK inhibitor combination therapy (encorafenib + binimetinib) in patients with BRAF V600-mutated stage IIB/IIC melanoma.
Melanoma is a type of skin cancer. Although most stage II melanomas (cancer affecting the first two layers of skin) can be cured with surgery, the risk of the cancer returning and spreading to other areas of the body is high in some patients with stage IIB/IIC melanoma. Furthermore, once the melanoma has spread, it is much more difficult to treat successfully and remove all the cancer cells from the body. Some melanomas have a DNA alteration (or mutation) in what is known as the BRAF gene. This mutation can be identified by testing a sample of the tumor tissue removed during a biopsy or surgery. Testing for BRAF mutations at diagnosis can help ensure that patients receive the most appropriate treatment for their cancer. In some countries, surgery is the only option for patients with stage II melanoma, while in other countries, patients may be offered additional (adjuvant) anticancer treatment with immunotherapy (agents that work with the immune system to kill cancer cells). While immunotherapy can reduce the risk of melanoma recurrence, persistent, long-term toxicities are common and the use of this treatment in all stage IIB/IIC melanoma patients is not always possible. Here, we describe the rationale and design of an ongoing clinical trial (COLUMBUS-AD), which will be the first study (to our knowledge) to investigate the efficacy and safety of a treatment that specifically targets cancers with BRAF mutations (i.e., the BRAF-MEK inhibitor combination of the drugs encorafenib and binimetinib) in patients with BRAF-mutated stage IIB/IIC melanoma. Clinical Trial Registration: NCT05270044 (ClinicalTrials.gov).
Melanoma is a type of skin cancer. Although most stage II melanomas (cancer affecting the first two layers of skin) can be cured with surgery, the risk of the cancer returning and spreading to other areas of the body is high in some patients with stage IIB/IIC melanoma. Furthermore, once the melanoma has spread, it is much more difficult to treat successfully and remove all the cancer cells from the body. Some melanomas have a DNA alteration (or mutation) in what is known as the BRAF gene. This mutation can be identified by testing a sample of the tumor tissue removed during a biopsy or surgery. Testing for BRAF mutations at diagnosis can help ensure that patients receive the most appropriate treatment for their cancer. In some countries, surgery is the only option for patients with stage II melanoma, while in other countries, patients may be offered additional (adjuvant) anticancer treatment with immunotherapy (agents that work with the immune system to kill cancer cells). While immunotherapy can reduce the risk of melanoma recurrence, persistent, long-term toxicities are common and the use of this treatment in all stage IIB/IIC melanoma patients is not always possible. Here, we describe the rationale and design of an ongoing clinical trial (COLUMBUS-AD), which will be the first study (to our knowledge) to investigate the efficacy and safety of a treatment that specifically targets cancers with BRAF mutations (i.e., the BRAF-MEK inhibitor combination of the drugs encorafenib and binimetinib) in patients with BRAF-mutated stage IIB/IIC melanoma. Clinical Trial Registration: NCT05270044 (ClinicalTrials.gov).
摘要：
IIB/IIC期黑色素瘤在手术切除后复发的风险很高。同时,几十年来,在大多数国家，手术是高危II期疾病的唯一选择，辅助疗法现在已经存在。与安慰剂相比，抗程序性细胞死亡蛋白1（PD-1）抗体显着改善了完全切除的IIB/IIC期黑色素瘤患者的无复发生存率。BRAFMEK抑制剂联合治疗在高危III期和晚期疾病中显示出益处；然而，其在完全切除阶段BRAF突变的IIB/IIC黑色素瘤患者中的作用尚不清楚.在这里，我们描述了正在进行的随机化的基本原理和设计，安慰剂对照哥伦布-AD试验，首次对BRAFV600突变IIB/IIC期黑色素瘤患者进行BRAF-MEK抑制剂联合治疗(恩可拉非尼+比尼)的研究.
黑色素瘤是一种皮肤癌。尽管大多数II期黑色素瘤（影响前两层皮肤的癌症）可以通过手术治愈，在一些IIB/IIC期黑色素瘤患者中,癌症复发并扩散到身体其他部位的风险很高.此外，一旦黑色素瘤扩散，成功治疗和从体内清除所有癌细胞要困难得多。一些黑色素瘤在所谓的BRAF基因中具有DNA改变(或突变)。该突变可以通过测试在活检或手术期间移除的肿瘤组织的样品来鉴定。在诊断时测试BRAF突变可以帮助确保患者接受最适当的癌症治疗。在一些国家,手术是II期黑色素瘤患者的唯一选择，而在其他国家,患者可以接受免疫疗法（与免疫系统一起杀死癌细胞的药物）的额外（辅助）抗癌治疗。虽然免疫疗法可以降低黑色素瘤复发的风险，持久性,长期毒性是常见的,并且在所有IIB/IIC期黑色素瘤患者中使用这种治疗并不总是可能的.这里,我们描述了正在进行的临床试验（COLUMBUS-AD）的基本原理和设计，这将是第一项研究（据我们所知），以调查疗效和安全性的治疗，专门针对具有BRAF突变的癌症（即，BRAF-MEK抑制剂联合应用恩可拉非尼和比米替尼）治疗BRAF突变的IIB/IIC期黑色素瘤患者。临床试验注册：NCT05270044（ClinicalTrials.gov）。
黑色素瘤是一种皮肤癌。尽管大多数II期黑色素瘤（影响前两层皮肤的癌症）可以通过手术治愈，在一些IIB/IIC期黑色素瘤患者中,癌症复发并扩散到身体其他部位的风险很高.此外，一旦黑色素瘤扩散，成功治疗和从体内清除所有癌细胞要困难得多。一些黑色素瘤在所谓的BRAF基因中具有DNA改变(或突变)。该突变可以通过测试在活检或手术期间移除的肿瘤组织的样品来鉴定。在诊断时测试BRAF突变可以帮助确保患者接受最适当的癌症治疗。在一些国家,手术是II期黑色素瘤患者的唯一选择，而在其他国家,患者可以接受免疫疗法（与免疫系统一起杀死癌细胞的药物）的额外（辅助）抗癌治疗。虽然免疫疗法可以降低黑色素瘤复发的风险，持久性,长期毒性是常见的,并且在所有IIB/IIC期黑色素瘤患者中使用这种治疗并不总是可能的.这里,我们描述了正在进行的临床试验（COLUMBUS-AD）的基本原理和设计，这将是第一项研究（据我们所知），以调查疗效和安全性的治疗，专门针对具有BRAF突变的癌症（即，BRAF-MEK抑制剂联合应用恩可拉非尼和比米替尼）治疗BRAF突变的IIB/IIC期黑色素瘤患者。临床试验注册：NCT05270044（ClinicalTrials.gov）。
