Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial
Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial
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DOI：
10.1016/s1470-2045(18)30015-9
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发表时间：
2018-02-01
期刊：
影响因子：
51.1
通讯作者：
Wargo, Jennifer A.
中科院分区：
文献类型：
--
作者：
Amaria, Rodabe N.;Prieto, Peter A.;Wargo, Jennifer A.
背景：BRAF和MEK双重抑制在大量IV期BRAF突变黑色素瘤患者中产生应答。临床III期黑色素瘤患者的现有护理标准是前期手术和考虑辅助治疗，这不足以治愈大多数患者。BRAF和MEK抑制剂（如达非尼和曲美替尼）的新辅助靶向治疗可能在这一高危人群中提供临床益处。方法：我们在德克萨斯大学MD安德森癌症中心（Houston， TX， USA）进行了这项单中心、开放标签、随机2期试验。符合条件的参与者是组织学或细胞学证实可手术切除的临床III期或寡转移IV期BRAF（V600E）或BRAF(V600K)（即Val600Glu或Val600Lys）突变黑色素瘤的成年患者（年龄>= 18岁）。符合条件的患者必须具有东部肿瘤合作组的表现状态为0或1，预期寿命超过3年，以前没有接触过BRAF或MEK抑制剂。排除标准包括转移到骨、脑或其他不能完全手术切除的部位。我们随机将患者（1:2）分配到术前手术和考虑辅助治疗（标准护理组）或新辅助加辅助达非尼和曲美替尼（8周新辅助口服达非尼150毫克，每天2次，口服曲美替尼2毫克，术后1周开始，达非尼加曲美替尼辅助治疗44周，共52周治疗）。随机化没有被掩盖，并由试验中心维护的临床试验实施网站实施。患者按疾病分期分层。主要终点是研究者评估的意图治疗人群12个月时的无事件生存期（即无疾病进展的患者）。该试验已在ClinicalTrials注册。网址：NCT02231775。在2014年10月23日至2016年4月13日期间，我们随机分配了7名患者接受标准治疗，14名患者接受新辅助加辅助达非尼和曲美替尼治疗。在四分之一的参与者累积后进行了预先指定的中期安全性分析，结果显示新佐剂加佐剂dabrafenib和trametinib的无事件生存期明显长于标准护理后，试验提前停止。中位随访18.6个月（IQR为14.6-23.1）后，接受新辅助加辅助dabrafenib和trametinib治疗的患者比接受标准治疗的患者存活无疾病进展明显更多（标准治疗组14例患者中有10例[71%]，7例患者中没有1例；中位无事件生存期为19.7个月[16.2-不可估计]vs 2.9个月[95% CI为1.7-不可估计]；风险比为0.016,95% CI为0.00012-0.14,p< 0.0001）。新佐剂加佐剂达非尼和曲美替尼耐受性良好，未发生4级不良事件或治疗相关死亡。新佐剂加佐剂达非尼和曲美替尼组最常见的不良事件是预期的1-2级毒性，包括寒战（12例[92%]）、头痛（12例[92%]）和发热（10例[77%]）。最常见的3级不良事件是腹泻（2例[15%]）。与标准治疗相比，新辅助加辅助达非尼和曲美替尼显著提高了高风险、可手术切除的临床III-IV期黑色素瘤患者的无事件生存率。虽然试验结束得较早，限制了结果的普遍性，但研究结果提供了概念证明，并支持进一步研究新辅助方法治疗该疾病的基本原理。这
Background Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation.Methods We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged >= 18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAF(V600E) or BRAF(V600K) (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1: 2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials. gov, number NCT02231775.Findings Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18.6 months (IQR 14.6-23.1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19.7 months [16.2-not estimable] vs 2.9 months [95% CI 1.7-not estimable]; hazard ratio 0.016, 95% CI 0.00012-0.14, p< 0.0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]).Interpretation Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This