Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia; Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
J Thorac Oncol. 2017 Nov;12(11):1728-1732. doi: 10.1016/j.jtho.2017.08.006. Epub 2017 Aug 24.
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has demonstrated efficacy in tumors harboring the EGFR T790M resistance mutation. Inevitably, resistance to third-generation inhibitors results in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. On the basis of preclinical data, we report what is the first known case of a patient harboring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib.
On development of progressive disease after multiple therapies, the patient's plasma was sequenced using the Oncomine Lung cfDNA Assay (Thermo Fisher Scientific, Waltham, MA). Subsequent monitoring of circulating tumor DNA in plasma was performed by droplet digital polymerase chain reaction.
Sequencing showed that the T790M and C797S mutations were in trans. Within 2 weeks of commencement of combination therapy, rapid clinical improvement occurred. Accompanying this, a rapid decline in the C797S mutation subclone in plasma was detected. However, the levels of the EGFR exon 19 deletion driver mutation and the T790M resistance mutation in the circulating tumor DNA continued to rise and the patient died from progressive disease 6 weeks after commencement of combination therapy. There were no adverse events seen with the combination therapy.
This is, to the best of our knowledge, the first reported case of combination EGFR tyrosine kinase inhibitor therapy tailored to the allelic conformation of T790M and C797S mutation that resulted in brief clinical improvement without toxicity.
奥希替尼是第三代 EGFR 酪氨酸激酶抑制剂，在携带 EGFR T790M 耐药突变的肿瘤中显示出疗效。不可避免的是，第三代抑制剂的耐药会导致疾病进展，目前已经确定了 EGFR C797S 突变是几种耐药途径之一。基于临床前数据，我们报告了首例已知的 T790M 和 C797S 突变顺式患者接受吉非替尼和奥希替尼联合治疗的病例。
在经过多种治疗后疾病进展时，使用 Oncomine Lung cfDNA 检测（Thermo Fisher Scientific，马萨诸塞州沃尔瑟姆）对患者的血浆进行测序。随后通过液滴数字聚合酶链反应对血浆中的循环肿瘤 DNA 进行监测。
测序显示 T790M 和 C797S 突变是顺式的。联合治疗开始后 2 周内，患者的临床状况迅速改善。与此同时，在血浆中检测到 C797S 突变亚克隆的迅速下降。然而，循环肿瘤 DNA 中的 EGFR 外显子 19 缺失驱动突变和 T790M 耐药突变的水平继续上升，患者在联合治疗开始后 6 周死于疾病进展。联合治疗没有观察到不良反应。
据我们所知，这是首例报道的针对 T790M 和 C797S 突变等位基因构象的 EGFR 酪氨酸激酶抑制剂联合治疗的病例，该治疗导致短暂的临床改善而无毒性。
