The treatment of non small cell lung cancer (NSCLC) has been revolutionized in the last decade with the advent of oncogene specific tyrosine kinase inhibitors (TKIs). Although the responses to these TKIs are good, resistance is almost inevitable and there are very few patients who are cured of their disease. This happens due to the development of bypass signaling or resistance pathways.Osimertinib is one such standard of care TKI in the treatment of epidermal growth factor receptor (EGFR) mutant NSCLC. There are no dominant pathways to explain the resistance to osimertinib, and research is ongoing to find out such targetable mechanisms. A possible strategy is to perform a repeat biopsy and next generation sequencing (NGS) at progression. This case is being presented as it showcases the development of one such targetable mutation which responded to combination dual therapy. Our patient was initially treated with afatinib and developed a T790M resistance mutation for which he was then started on osimertinib. He developed echinoderm microtubule associated protein like 4 – anaplastic lymphoma kinase(EML4- ALK) fusion as a resistance mechanism on progression and was further treated with a combination of osimertinib and alectinib. He had clinical and radiological response to the therapy, with disappearance of symptomatic intracranial metastases. Sequential biopsies may represent a potential strategy to find novel management options and help in delaying chemotherapy for some patients who progress on osimertinib.

在过去十年中，随着癌基因特异性酪氨酸激酶抑制剂 (TKI) 的出现，非小细胞肺癌 (NSCLC) 的治疗发生了革命性的变化。尽管对这些 TKI 的反应良好，但耐药性几乎是不可避免的，而且治愈疾病的患者很少。这是由于旁路信号或抗性通路的发展而发生的。 奥希替尼是治疗表皮生长因子受体 ( EGFR) 的TKI 护理标准之一突变型非小细胞肺癌。没有主要途径来解释对奥希替尼的耐药性，并且正在进行研究以找出此类可靶向机制。一种可能的策略是在进展时进行重复活检和下一代测序 (NGS)。这个案例展示了一个这样的可靶向突变的发展，该突变对联合双重治疗有反应。我们的患者最初接受了阿法替尼治疗，并出现了 T790M 耐药突变，然后他开始接受奥希替尼治疗。他开发了棘皮动物微管相关蛋白，如 4-间变性淋巴瘤激酶(EML4-ALK)融合作为进展的一种耐药机制，并用奥希替尼和艾乐替尼的组合进一步治疗。他对治疗有临床和放射学反应，症状性颅内转移消失。序贯活检可能代表一种潜在的策略，可以找到新的治疗方案，并有助于延迟一些在奥希替尼治疗中进展的患者的化疗。