Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.
Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.
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DOI：
10.1038/sj.bjc.6603291
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发表时间：
2006-09-04
影响因子：
8.8
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中科院分区：
文献类型：
--
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索拉非尼是一种靶向肿瘤和肿瘤血管系统的口服多激酶抑制剂，在一项大型多疾病II期随机停药试验（RDT）中对晚期黑色素瘤患者进行了评价。入组患者接受为期12周的索拉非尼400 mg每日两次（b.i.d.）导入。然后将二维肿瘤测量值较基线变化<25%的患者随机分配至索拉非尼或安慰剂组，持续12周（即至第24周）。导入后肿瘤缩小> 25%的患者继续接受开放标签索拉非尼治疗，而肿瘤生长> 25%的患者则停止治疗。该分析重点关注次要RDT终点：12周后二维肿瘤测量值较基线的变化和第24周时的总体肿瘤缓解（WHO标准）、无进展生存期（PFS）、安全性和生物标志物（BRAF、KRAS和NRAS突变状态）。在导入期接受治疗的37例黑色素瘤患者中，34例可评价反应：1例肿瘤缩小> 25%，并继续接受开放标签索拉非尼治疗; 6例（16%）肿瘤生长<25%，并接受随机分配（安慰剂，n=3;索拉非尼，n=3）; 27例肿瘤生长> 25%，并停药。所有3例随机化索拉非尼患者在第24周时均发生进展; 1例患者继续接受索拉非尼治疗以缓解症状。所有3例安慰剂组患者在第24周时均出现进展，并重新开始接受索拉非尼治疗; 1例患者出现疾病重新稳定。总体而言，接受索拉非尼治疗的37例黑色素瘤患者中，每例患者的确认最佳缓解率为19%疾病稳定（SD）（即n=1开放标签; n=6随机化），62%（n=23）疾病进展（PD）和19%（n=7）不可评估。总体中位PFS为11周。6例随机化SD患者的总体PFS值范围为16 - 34周。最常见的药物相关不良事件为皮肤病（如皮疹/脱屑，51%;手足皮肤反应，35%）。V600 E BRAF状态与疾病稳定性之间无相关性。从17/22例患者的活检组织中提取DNA。6例V600 E阳性肿瘤（n=4例PD; n=1例SD; n =1例无法评价缓解），11例肿瘤含有野生型BRAF（n=9例PD; n=1例SD; n=1例无法评价缓解）。总之，索拉非尼耐受性良好，但在评估剂量（400 mg b.i.d.）下作为单药治疗晚期黑色素瘤患者时几乎没有或没有抗肿瘤活性。正在进行的晚期黑色素瘤试验正在评估索拉非尼联合治疗。
The effects of sorafenib – an oral multikinase inhibitor targeting the tumour and tumour vasculature – were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with ⩾25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with ⩾25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had ⩾25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had ⩾25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.
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