ASCO 2012：两大新药治疗BRAF突变黑色素瘤疗效显著
2012-06-09 卢秀玲 ：爱唯医学网
美国临床肿瘤学会(ASCO)年会公布的两项III期临床研究显示，与化疗相比，trametinib和dabrafenib这两种通过干扰BRAF通路信号发挥作用的新型口服靶向药物，分别使携带BRAF突变的晚期黑色素瘤患者的进展或死亡风险降低55%和70%。此外，这些药物的安全性也较好。因此，trametinib和dabrafenib有望与vemur
美国临床肿瘤学会(ASCO)年会公布的两项III期临床研究显示，与化疗相比，trametinib和dabrafenib这两种通过干扰BRAF通路信号发挥作用的新型口服靶向药物，分别使携带BRAF突变的晚期黑色素瘤患者的进展或死亡风险降低55%和70%。此外，这些药物的安全性也较好。因此，trametinib和dabrafenib有望与vemurafenib比肩，后者是目前唯一被批准专门用于治疗BRAF突变黑色素瘤的靶向药物。
在第1项研究(METRIC)中，法国Gustave Roussy研究所皮肤科主任Caroline Robert博士及其同事纳入322例V600E或V600K BRAF突变的局部晚期或转移性黑色素瘤患者，对MEK(位于BRAF下游)口服选择性抑制剂trametinib与化疗(氮烯咪胺或紫杉醇)进行了比较。
结果显示，trametinib组≥3级高血压(12% vs. 3%)和皮疹(8% vs. 0%)的发生率较高。与trametinib相关的射血分数降低或心室功能障碍(7%)和脉络膜视网膜病变(＜1%)可逆。值得指出的是，接受trametinib治疗的患者无1例发生皮肤鳞状细胞癌，这与在vemurafenib用药者中观察到的不同。trametinib组的中位无进展生存期长于化疗组[4.8个月 vs. 1.5 个月；危险比(HR)=0.45；P＜0.0001]。此外，trametinib还降低了死亡风险(HR=0.54；P=0.01)。该研究允许交叉治疗，这无疑对总生存结果产生了一定影响，但即使化疗组有47%的患者交叉至trametinib组，仍观察到两组在总生存方面存在差异。
在第2项研究(BREAK-3)中，德国基尔大学医院皮肤科教授Axel Hauschild博士及其同事纳入250例局部晚期或转移性V600E BRAF突变黑色素瘤患者，对BRAF口服抑制剂dabrafenib与化疗(氮烯咪胺)进行了比较。在该研究中，化疗组有68%的患者最终交叉至另一组。
结果显示，dabrafenib组的中位无进展生存期长于化疗组(5.1个月 vs. 2.7个月；HR=0.30；P＜0.0001)。dabrafenib组的完全或部分应答率是化疗组的2倍多(53% vs. 19%)。总生存数据还非常不成熟；目前仅观察到12%的患者死亡，因此会上未公布总生存结果。dabrafenib组≥3级角化过度(2% vs. 0%)和鳞状细胞癌(5% vs. 0%)发生率较高，而化疗组≥3级血液学不良事件的发生率较高。Hauschild博士表示，鉴于目前BRAF靶向治疗已经可供使用，所有黑色素患者均应进行BRAF突变检测。下一步要探讨dabrafenib与trametinib联合治疗IV期黑色素瘤的效果及作为辅助治疗的效果。
纽约大学Langone医学中心的Sylvia Adams博士评论指出，以MEK通路为靶点的治疗(trametinib)对转移性黑色素瘤的效果非常好，不仅可使肿瘤缩小且可延长生存期。以BRAF为靶点的治疗(dabrafenib)对突变黑色素瘤的效果也非常好，可使约半数患者的肿瘤缩小，与vemurafenib的疗效相当，并且dabrafenib引起的皮肤不良反应程度较轻。另外，BRAF抑制剂和MEK抑制剂合用的研究结果令人期待。
题目：METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM)（Abstract LBA8509）
作者：Caroline Robert, Keith T. Flaherty, Peter Hersey, et al.
英文摘要：
作者：Caroline Robert, Keith T. Flaherty, Peter Hersey, et al.
英文摘要：
Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-sided α = 0.025 to detect 57% reduction in the risk of PD or death in pts treated with T vs C. Results: Between Dec 2010 and Jul 2011, 322 pts were randomized to T (n=214) or C (n=108); 273 pts were BRAFV600E mutation-positive with no prior brain mets. HR for primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; p<0.0001) in favor of T with a median PFS of 4.8 mo vs 1.4 mo with C. PFS benefit in favor of T was observed in ITT; this was confirmed by an independent review. The confirmed ORR was 24% with T and 7% with C. HR for interim OS was 0.53 (95% CI 0.30–0.94; p=0.0181), in favor of T in primary population. OS benefit was consistent in ITT pop despite 51 pts crossover from C to T. The most frequent AEs with T were skin rash, diarrhea, edema, hypertension, fatigue. Known MEKi class effects were observed, e.g. chorioretinopathy (<1%) and decreased ejection fraction (7%). Grade 3 AEs in T arm were hypertenstion (12%) and rash (7%). Conclusions: T is the first in class MEKi associated with a significant improvement of PFS and OS compared to C in pts with BRAFV600E/K mutant MM.
题目：Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.(Abstract LBA8500^)
作者：Axel Hauschild, Jean Jacques Grob, Lev V. Demidov, et al.
英文摘要：
作者：Axel Hauschild, Jean Jacques Grob, Lev V. Demidov, et al.
英文摘要：
Background: Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety profile in phase I/II studies in patients (pts) with BRAFV600E-mutated metastatic melanoma (MM). This phase III trial (NCT01227889) compared progression-free survival (PFS) in pts with advanced MM treated either with dabrafenib or dacarbazine (DTIC). Methods: Pts with previously untreated, unresectable stage III or IV BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w). Primary endpoint was investigator-assessed PFS. Primary analysis for PFS was planned after 102 events. Pts on the DTIC arm were allowed to cross over once progression was confirmed by independent review (IR). Secondary endpoints included PFS by IR, overall survival (OS), response rate (RR), duration of response, safety and pharmacokinetics. Results: 250 pts were enrolled at 93 centers globally from February to September 2011. 187 were randomized to dabrafenib and 63 to DTIC. 141pts were on study treatment at the data cut-off at December 19, 2011 (dabrafenib n = 127; DTIC n = 14), including 21/28 DTIC pts crossed over to dabrafenib. Median age was 52 years, 31% of pts were ECOG >1, 66% M1c, 33% LDH > ULN. Demographics were well balanced between the two arms. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18–0.53; p < 0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Common adverse events (AEs) on the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%). Serious AEs (> 1%) on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new primary melanomas (2%). Conclusions: Dabrafenib demonstrated a significant improvement in PFS and ORR over DTIC with an acceptable safety profile.
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#色素#
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#ASC#
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#BRAF#
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#BRAF突变#
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#黑色素#
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#黑色素#
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