Riess Jonathan W, Lara Matthew S, Luxardi Guillaume, Lopez de Rodas Miguel, Shimoda Michiko, Kelly Karen, Lara Primo N, Beckett Laurel, Monjazeb Arta, Schalper Kurt A, Maverakis Emanual, Gandara David R
University of California Davis Comprehensive Cancer Center, Sacramento, California.
Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut.
JTO Clin Res Rep. 2025 Feb 12;6(6):100806. doi: 10.1016/j.jtocrr.2025.100806. eCollection 2025 Jun.
MEK inhibition (MEKi) combined with programmed death ligand 1 inhibition (immune checkpoint inhibitor [ICI]) modulates the tumor immune microenvironment. This phase 1 study evaluated sequencing schemes of MEKi and ICI with trametinib and pembrolizumab in NSCLC.
In this 3+3 dose escalation study, patients with advanced NSCLC were treated with lead-in trametinib (arm A) or lead-in pembrolizumab (arm B) for cycle 1, followed by a 1.5 to 2 mg oral daily dose of trametinib (d 1-10) with pembrolizumab 200 mg intravenously every 21 days. Eligible patients with progressive disease on or after platinum-based chemotherapy were enrolled. Prior ICI was allowed. Tumor tissue was analyzed with quantitative immunofluorescence. High-parameter flow cytometry was performed on blood. Adverse events were graded using the Common Terminology Criteria for Adverse Events version 4 and efficacy was evaluated by Response Evaluation Criteria in Solid Tumors version 1.1.
Fifteen patients enrolled (nine arm A and six arm B) with 13 (86%) harboring mutations and 10 (66%) receiving prior ICI. Five patients (33%) experienced at least one grade greater than or equal to 3 treatment-related adverse event including one dose-limiting toxicity (grade 3 esophagitis). Two patients had a partial response (ORR = 14%). Trametinib lead-in was associated with decreased T-regulatory cells and myeloid-derived suppressor cells ( = 0.002 and = 0.05, respectively).
The activity of trametinib and pembrolizumab is modest in NSCLC with increased toxicity compared with programmed death ligand 1 blockade alone. The recommended phase 2 dose for the combination is 2 mg of oral trametinib (d 1-10) and 200 mg of intravenous pembrolizumab every 21 days, with lead-in trametinib. Adverse events were comparable with other MEKi and ICI combination studies. Though limited clinical activity was observed, lead-in MEKi may induce favorable immune cell alterations.
丝裂原活化蛋白激酶（MEK）抑制（MEKi）联合程序性死亡配体1抑制（免疫检查点抑制剂[ICI]）可调节肿瘤免疫微环境。这项1期研究评估了MEKi和ICI与曲美替尼和帕博利珠单抗联合用于非小细胞肺癌（NSCLC）的给药方案。
在这项3+3剂量递增研究中，晚期NSCLC患者在第1周期接受导入期曲美替尼治疗（A组）或导入期帕博利珠单抗治疗（B组），随后每日口服1.5至2 mg曲美替尼（第1 - 10天），每21天静脉注射200 mg帕博利珠单抗。纳入在铂类化疗期间或之后出现疾病进展的符合条件的患者。允许既往使用过ICI。采用定量免疫荧光分析肿瘤组织。对血液进行高参数流式细胞术检测。使用《不良事件通用术语标准》第4版对不良事件进行分级，并根据实体瘤疗效评价标准第1.1版评估疗效。
15例患者入组（A组9例，B组6例），其中13例（86%）携带 突变，10例（66%）既往接受过ICI治疗。5例患者（33%）发生至少1次≥3级治疗相关不良事件，包括1例剂量限制性毒性（3级食管炎）。2例患者出现部分缓解（客观缓解率[ORR]=14%）。导入曲美替尼与调节性T细胞和髓源性抑制细胞减少相关（分别为 = 0.002和 = 0.05）。
与单独使用程序性死亡配体1阻断剂相比，曲美替尼和帕博利珠单抗联合用于NSCLC时活性中等，但毒性增加。该联合方案的推荐2期剂量为口服曲美替尼2 mg（第1 - 10天），每21天静脉注射帕博利珠单抗200 mg，导入期使用曲美替尼。不良事件与其他MEKi和ICI联合研究相当。尽管观察到的临床活性有限，但导入MEKi可能诱导有利的免疫细胞改变。
