一线免疫治疗加化疗或不加化疗对brafv600e突变的转移性非小细胞肺癌（FRONT-BRAF）（BRAF + MEK抑制剂）：一项多中心、回顾性队列研究

The Lancet Oncology Pub Date : 2025-09-29 DOI:10.1016/s1470-2045(25)00409-7

Alessandro Di Federico, Kaiwen Wang, Monica F Chen, Adam A Barsouk, Arianna Pagliaro, Lanyi N Chen, Francesca R Ogliari, Paul Stockhammer, Rajat Thawani, Shahm Raslan, Eleonora Gariazzo, Francesca Fusco, Grace M Hambelton, Fabrizio Citarella, David Meyer, Mihaela Aldea, Andrea De Giglio, Joao V Alessi, Federica Pecci, Francesco Gelsomino, Biagio Ricciuti

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引用次数: 0

摘要

BRAFV600E（即Val600Glu）突变的非小细胞肺癌（NSCLC）患者可以用BRAF和丝裂原活化蛋白激酶（MEK）抑制剂或免疫检查点抑制剂（ICIs）治疗，无论是否化疗。我们的目的是调查在这一人群中应该优先考虑哪种初始系统治疗。方法在美国、意大利、法国和巴西的17个中心进行的这项回顾性队列研究中，收集了年龄在18岁及以上的IV期、未治疗、转移性brafv600e突变的非小细胞肺癌患者的临床病理数据，这些患者的东部肿瘤合作组织（Eastern Cooperative Oncology Group）的表现状态为0-3。在2015年1月2日至2024年7月11日期间开始一线治疗的ICIs伴或不伴化疗（PD-1或PD-L1抑制剂伴或不伴铂基化疗）或BRAF和MEK抑制剂（dabrafenib和trametinib或encorafenib和binimetinib）。主要终点是与BRAF和MEK抑制剂相比，接受或不接受化疗的一线ICIs患者的总生存期。研究发现，284名参与者被确定为这项研究，其中88名（31%）接受了联合或不联合化疗的ICIs， 196名（69%）接受了BRAF和MEK抑制剂。参与者的中位年龄为68岁（IQR 61-74），其中女性148人（52%），男性136人（48%）。与BRAF和MEK抑制剂组相比，接受或不接受化疗的ICIs患者有较高的吸烟史（73例[83%]vs 118例[60%]，p= 0.0002）和较高的PD-L1表达（58例[66%]vs 76例[39%]，16例[18%]vs 67例[34%]，1-49%，8例[9%]vs 31例[16%]，p= 0.0003）。在中位随访时间为45.0个月（95% CI为39.0 ~ 55.7）时，与BRAF和MEK抑制剂相比，接受或不接受化疗的ICIs与中位总生存期的改善相关（40.9个月[95% CI为33.3 ~未达到]vs 25.2个月[19.9 ~ 31.1]；风险比[HR] 0.69 [0.49 ~ 0.98], p= 0.039）。在亚组分析中，与BRAF和MEK抑制剂相比，有或没有化疗的ICIs与吸烟史（HR 0.60 [0.40 - 0.90], p= 0.013）、PD-L1肿瘤比例评分≥1% （HR 0.66 [0.45 - 0.98], p= 0.039）、年龄70岁及以上（HR 0.54 [0.31 - 0.94], p= 0.029）、TP53共突变（HR 0.46 [0.27 - 0.79], p= 0.0048）、无脑转移（HR 0.66 [0.45 - 0.99], p= 0.045）的参与者的中位总生存期延长相关。对于BRAF和MEK抑制剂，无论是作为一线治疗还是在ICIs后作为二线治疗（伴或不伴化疗），任何级别和3级及以上不良事件的频率都是相似的。与BRAF和MEK抑制剂相比，在转移性brafv600e突变的非小细胞肺癌患者中，特别是在特定亚群中，接受或不接受化疗的一线ICIs与改善的总生存率相关。这些发现，虽然提示潜在的临床相关性，但仍处于探索性阶段，需要前瞻性研究的证实。

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First-line immunotherapy with or without chemotherapy versus BRAF plus MEK inhibitors in BRAFV600E-mutated metastatic non-small-cell lung cancer (FRONT-BRAF): a multicentre, retrospective cohort study

Background

Patients with BRAF^V600E (ie, Val600Glu)-mutated non-small-cell lung cancer (NSCLC) can be treated with BRAF and mitogen-activated protein kinase (MEK) inhibitors, or with immune checkpoint inhibitors (ICIs) with or without chemotherapy. We aimed to investigate which initial systemic treatment should be prioritised in this population.

Methods

In this retrospective cohort study conducted across 17 centres in the USA, Italy, France, and Brazil, clinicopathological data were collected from participants aged 18 years and older with stage IV, treatment-naive, metastatic BRAF^V600E-mutated NSCLC and with an Eastern Cooperative Oncology Group performance status of 0–3, who started first-line treatment with ICIs with or without chemotherapy (PD-1 or PD-L1 inhibitors with or without platinum-based chemotherapy) or BRAF and MEK inhibitors (dabrafenib and trametinib or encorafenib and binimetinib) between Jan 2, 2015, and July 11, 2024. The primary endpoint was overall survival with first-line ICIs with or without chemotherapy versus with BRAF and MEK inhibitors.

Findings

284 participants were identified for this study, of whom 88 (31%) received ICIs with or without chemotherapy and 196 (69%) received BRAF and MEK inhibitors. The median age of participants was 68 years (IQR 61–74), and 148 (52%) participants were female and 136 (48%) male. Participants in the ICIs with or without chemotherapy group had a higher history of smoking (73 [83%] vs 118 [60%]; p=0·0002) and a higher PD-L1 expression (≥50% in 58 [66%] vs 76 [39%], 1–49% in 16 [18%] vs 67 [34%], and <1% in eight [9%] vs 31 [16%]; p=0·0003) than those in the BRAF and MEK inhibitor group. At a median follow-up time of 45·0 months (95% CI 39·0–55·7), ICIs with or without chemotherapy were associated with improved median overall survival compared with BRAF and MEK inhibitors (40·9 months [95% CI 33·3–not reached] vs 25·2 months [19·9–31·1]; hazard ratio [HR] 0·69 [0·49–0·98], p=0·039). In subgroup analyses, ICIs with or without chemotherapy, compared with BRAF and MEK inhibitors, were associated with longer median overall survival in participants with a history of smoking (HR 0·60 [0·40–0·90], p=0·013), with a PD-L1 tumour proportion score of ≥1% or higher (HR 0·66 [0·45–0·98], p=0·039), aged 70 years or older (HR 0·54 [0·31–0·94], p=0·029), with TP53 co-mutations (HR 0·46 [0·27–0·79], p=0·0048), and without brain metastases (HR 0·66 [0·45–0·99], p=0·045). With BRAF and MEK inhibitors, frequencies of adverse events of any grade and of grade 3 and higher were similar whether administered as first-line therapy or as second-line therapy following ICIs with or without chemotherapy.

Interpretation

First-line ICIs with or without chemotherapy were associated with improved overall survival compared with BRAF and MEK inhibitors in participants with metastatic BRAF^V600E-mutated NSCLC, particularly among specific subpopulations. These findings, although suggesting potential clinical relevance, remain exploratory and require confirmation from prospective studies.