Li Hong-Shuai, Wang Shou-Zheng, Xu Hai-Yan, Yan Xiang, Zhang Jin-Yao, Lei Si-Yu, Li Teng, Hao Xue-Zhi, Zhang Tao, Yang Guang-Jian, Zhou Li-Qiang, Liu Peng, Wang Yu-Ying, Hu Xing-Sheng, Xing Pu-Yuan, Wang Yan
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Medical Oncology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing 101149, China.
Cancers (Basel). 2022 Oct 28;14(21):5307. doi: 10.3390/cancers14215307.
(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene () mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 ( = 0.006), but fewer G3 ( = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon mutations.
(1) 背景：阿法替尼已被批准用于携带主要罕见表皮生长因子受体基因（）突变的非小细胞肺癌（NSCLC）患者。另一种第二代酪氨酸激酶抑制剂达可替尼，对于罕见突变也显示出有前景的潜力。然而，尚未进行比较研究。(2) 方法：采用了两个队列：AFANDA队列，一个回顾性队列，包括在中国两家三级医院收治的121例携带罕见突变的患者；以及一个外部验证阿法替尼队列（ex - AC），从阿法替尼罕见突变数据库中提取（N = 1140）。AFANDA队列被分为阿法替尼队列（AC）和达可替尼队列（DC）用于内部探索。评估客观缓解率（ORR）、无进展生存期（PFS）和不良事件（AE）以进行比较。探索进展模式和耐药机制。(3) 结果：总共纳入了286例接受阿法替尼或达可替尼治疗的携带罕见突变的晚期NSCLC患者，包括AFANDA队列中的79例（DC组44例，AC组35例）和ex - AC队列中的207例。在内部探索中，DC组的ORR显著高于AC组（60.5%对26.7%，= 0.008），但DC组和AC组的中位PFS无显著差异（12.0个月对10.0个月，= 0.305）。多因素分析证实达可替尼对PFS有独立的有利影响（风险比（HR），1.909；= 0.047）。在外部验证中，多因素分析证实达可替尼在PFS方面有独立的预后作用（HR，1.953；= 0.029）。倾向评分匹配分析证实，在单因素和多因素分析中，达可替尼在PFS方面均优于阿法替尼。毒性分析表明，DC组的G1级不良事件更多（= 0.006），但G3级不良事件少于AC组（= 0.036）。进展模式显示，AC组的颅内进展发生率显著高于DC组（50%对21.1%，= 0.002）。耐药分析表明，AC组和DC组之间T790M的发生率无显著差异（11.8%对15.4%，= 0.772）。(4) 结论：与阿法替尼相比，达可替尼在携带罕见突变的NSCLC患者中表现出更有利的活性，毒性可控且进展模式不同。
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