Abstract：
BACKGROUND: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome.
METHODS: The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon\'s optimal two stage design. The primary end point of the study is 2 months PFS rate.
CONCLUSIONS: By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further.
BACKGROUND: EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.
METHODS: The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon\'s optimal two stage design. The primary end point of the study is 2 months PFS rate.
CONCLUSIONS: By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further.
BACKGROUND: EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.
摘要：
背景：BRAFV600E突变的转移性结直肠癌（mCRC）患者预后不良。采用恩科拉非尼的BRAF靶向治疗和每周施用西妥昔单抗已显示出改善的生存期，中位无进展生存期（PFS）为4.3个月。然而,每2周给予西妥昔单抗的方案可能具有相当的疗效,并且对患者更方便.虽然BRAF靶向治疗是治疗前BRAFV600E突变mCRC患者的新标准治疗方法，抵抗总是会发生，并且是一个新兴的挑战。这项研究的目的是研究西妥昔单抗每两周联合每日恩科拉非尼的疗效和耐受性，并探讨耐药标志物与结局之间的相关性。
方法：这项研究是一个开放的标签，单臂,第二阶段研究，研究在BRAFV600E突变的mCRC患者中,每两周给予西妥昔单抗联合恩科拉菲尼的疗效和耐受性.此外，我们将通过对肿瘤组织和血液进行全面的基因组分析以进行循环肿瘤DNA分析，研究针对BRAF靶向治疗的应答和耐药机制。根据Simon的最佳两阶段设计，共纳入53名患者（19+34分两步）。研究的主要终点是2个月的PFS率。
结论：与目前批准的每周西妥昔单抗方案相比，每两周联合使用BRAF抑制剂与西妥昔单抗，我们可以将医院就诊次数减半。这似乎在一组中位总生存期为9.3个月的患者中特别相关。对靶向治疗的初始反应后的抗性可以是适应性的(例如，表观遗传,或转录组改变)或获得性(选择性遗传改变-例如，激活从头突变)抗性。在BRAFV600E突变的mCRC患者中解开这些复杂的耐药机制以在未来可能甚至进一步改善治疗策略非常重要。
背景：欧盟临床试验注册，不。2020-003283-10。于2020年11月11日注册。
方法：这项研究是一个开放的标签，单臂,第二阶段研究，研究在BRAFV600E突变的mCRC患者中,每两周给予西妥昔单抗联合恩科拉菲尼的疗效和耐受性.此外，我们将通过对肿瘤组织和血液进行全面的基因组分析以进行循环肿瘤DNA分析，研究针对BRAF靶向治疗的应答和耐药机制。根据Simon的最佳两阶段设计，共纳入53名患者（19+34分两步）。研究的主要终点是2个月的PFS率。
结论：与目前批准的每周西妥昔单抗方案相比，每两周联合使用BRAF抑制剂与西妥昔单抗，我们可以将医院就诊次数减半。这似乎在一组中位总生存期为9.3个月的患者中特别相关。对靶向治疗的初始反应后的抗性可以是适应性的(例如，表观遗传,或转录组改变)或获得性(选择性遗传改变-例如，激活从头突变)抗性。在BRAFV600E突变的mCRC患者中解开这些复杂的耐药机制以在未来可能甚至进一步改善治疗策略非常重要。
背景：欧盟临床试验注册，不。2020-003283-10。于2020年11月11日注册。
