Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

小分子激酶抑制剂 (SMKI) 是治疗具有基因驱动突变的非小细胞肺癌 (NSCLC) 患者的基石。由于在过去几十年中引入了 SMKI，治疗结果有了显着改善。它们的治疗效果、耐药性的发展以及不良毒性都受到患者变异性大的影响。这种变异性至少部分可以通过它们的口服给药途径来解释，这导致基于吸收差异的患者间和患者体内的生物利用度差异很大。此外，经常报道药物-药物和食物-药物相互作用。这些相互作用可以调节 SMKI 功效和/或不良毒性。此外，较大的患者变异性可以通过靶受体结构域、代谢酶和药物流出转运体中存在种系变异来解释。关于这些预测变量的知识对于在临床实践中处理 SMKI 和选择最佳疗法至关重要。在本次审查中，文献检索包括截至 2022 年 3 月 24 日由美国食品和药物管理局 (FDA) 或欧洲药品管理局 (EMA) 注册用于局部晚期和转移性 NSCLC 的所有 SMKI。BIM缺失显示东亚地区接受吉非替尼治疗的患者的 PFS 和 OS 显着降低，并且可能与其他 SMKI 有临床相关性。此外，我们预计厄洛替尼和吉非替尼治疗期间ABCG2 34 G>A 和CYP1A1变异的相关性最高。也可以考虑在开始吉非替尼治疗之前进行先发制人的CYP2D6检测，以预防严重的药物相关毒性。总结和讨论了这些和其他种系变异，以便为临床实践提供明确的建议。