在非小细胞肺癌中发生频率≤5％的癌基因被定义为“罕见”；尽管如此，这种频率可能与每年诊断出的大量患者相对应。在罕见的癌基因中，较少见的变异（例如HRAS，NRAS，RIT1，ARAF，RAF1和MAP2K1突变，或ERBB家族，LTK和RASGRF1融合）可以与更常见的变异（例如KRAS，BRAF，MET和ERBB家族突变，或ALK，RET和ROS1融合）共享某些结构或致癌特征。在过去的五年中，罕见癌基因驱动的肺癌的识别数量激增，挑战了传统临床分级诊断测定和分析算法的限制。与此同时，针对罕见分子亚型肺癌的批准靶向治疗药物的数量也大幅上升。理性药物设计不断改进小分子治疗剂的质量，引入了一系列基于抗体的治疗剂，扩大了在肺癌治疗中可操作的新陈代谢和耐药突变列表。在更多的国家为罕见癌基因驱动的肺癌获得额外的分子定制治疗药物将需要持续的利益相关者合作。患者倡导者、医疗机构、调查员和对诊断、治疗和现实世界证据感兴趣的公司已经采取了措施，克服了与低频驱动因素研究相关的挑战。© 2023 Springer Nature Limited。

Oncogenes that occur in ≤5% of non-small-cell lung cancers have been defined as 'rare'; nonetheless, this frequency can correspond to a substantial number of patients diagnosed annually. Within rare oncogenes, less commonly identified alterations (such as HRAS, NRAS, RIT1, ARAF, RAF1 and MAP2K1 mutations, or ERBB family, LTK and RASGRF1 fusions) can share certain structural or oncogenic features with more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions). Over the past 5 years, a surge in the identification of rare-oncogene-driven lung cancers has challenged the boundaries of traditional clinical grade diagnostic assays and profiling algorithms. In tandem, the number of approved targeted therapies for patients with rare molecular subtypes of lung cancer has risen dramatically. Rational drug design has iteratively improved the quality of small-molecule therapeutic agents and introduced a wave of antibody-based therapeutics, expanding the list of actionable de novo and resistance alterations in lung cancer. Getting additional molecularly tailored therapeutics approved for rare-oncogene-driven lung cancers in a larger range of countries will require ongoing stakeholder cooperation. Patient advocates, health-care agencies, investigators and companies with an interest in diagnostics, therapeutics and real-world evidence have already taken steps to surmount the challenges associated with research into low-frequency drivers.© 2023. Springer Nature Limited.