背景:MEK抑制剂单一疗法在晚期NRASQ61R/K/L突变型黑色素瘤中具有活性,但与剂量限制性皮肤毒性相关。BRAF-与MEK抑制剂在其全剂量下的组合(如在BRAFV600E/K突变黑色素瘤中)具有低的皮肤毒性。尚不清楚低剂量BRAF抑制剂是否可以减轻晚期NRASQ61R/K/L突变型黑色素瘤患者与全剂量MEK抑制剂治疗相关的皮肤毒性。
方法:这项两阶段2期临床试验研究了接受免疫检查点抑制剂预处理的晚期NRASQ61R/K/L突变型黑色素瘤患者每天2mg曲美替尼。在曲美替尼相关的皮肤毒性的情况下,添加低剂量dabrafenib(50mg,每日2次)以防止复发性皮肤毒性(修正前).经过修改,曲美替尼预先与低剂量达拉非尼合用(修正后).客观反应率(ORR)是主要终点。
结果:所有6例患者在治疗前出现曲美替尼相关皮肤毒性,需要中断治疗。曲美替尼与低剂量达拉非尼联合使用可预防此后复发性皮肤毒性。在所有10例患者治疗后,曲美替尼相关皮肤毒性均得到有效缓解。在所有16名患者中,ORR和疾病控制率分别为6.3%(1部分缓解)和50.0%,分别。审判在第一阶段后停止。
结论:将全剂量曲美替尼与低剂量达拉非尼联合使用可以减轻MEK抑制剂相关的皮肤毒性,但在该患者人群中活性不足。该组合对于MEK抑制剂敏感性肿瘤的治疗可以是进一步感兴趣的。
BACKGROUND: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma.
METHODS: This two-stage phase 2 clinical
trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint.
RESULTS: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The
trial was halted after the first stage.
CONCLUSIONS: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.