Trametinib和Dabrafenib对BRAF突变黑色素瘤疗效优于化疗

芝加哥(EGMN)——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。

上述两项研究均由葛兰素史克公司资助。研究者与葛兰素史克等公司存在联系。

CHICAGO (EGMN) –Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib, the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings “show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior,” Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). “Crossover was allowed,” Dr. Robert noted. “That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

“Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable,” she commented. “Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients.”

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. “Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors.”

Dr. Adams, the press briefing moderator, characterized the findings as “exciting” for two reasons. “Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options.”

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

“The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here,” Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

“The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting,” Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

“It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials,” he said. “But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor.���

Dr. Adams, the moderator, commented, “This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [U.S. Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance.”

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.