Abstract:
The acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable and heterogeneous. The strategies to overcome acquired resistance are significant. For patients with secondary T790M-positive after early generation EGFR-TKIs, osimertinib is the standard second-line therapy. In patients resistant to prior early generation EGFR-TKIs, the acquired T790M mutation overlaps with other driver gene resistance, such as HER2-and MET amplification, accounting for 4-8%. The efficacy of osimertinib is unclear in patients with concurrent multiple driver gene resistance. We here report a patient who acquired EGFR T790M, STRN-ALK fusion, and EGFR amplification after gefitinib progression and subsequent MET amplification acquired from osimertinib. The other patient acquired EGFR T790M and MET amplification post-dacomitinib and acquired CCDC6-RET fusion after osimertinib treatment. Besides, subsequent new bypass activations were the possible resistance mechanisms to second-line osimertinib. Both patients had progression-free survival (PFS) less than 4 months and limited benefits from osimertinib second-line therapy. The T790M accompanying driver gene resistance will be a new subtype after EGFR-TKIs progression, needing effective treatment options.
摘要:
表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)的获得性耐药是不可避免的和异质性的。克服获得性抗性的策略是重要的。对于早期产生EGFR-TKIs后继发T790M阳性的患者,奥希替尼是标准的二线治疗药物.在对早期产生EGFR-TKIs耐药的患者中,获得的T790M突变与其他驱动基因抗性重叠,如HER2和MET扩增,占4-8%。奥希替尼在并发多驱动基因耐药患者中的疗效尚不清楚。我们在这里报告一名获得EGFRT790M的患者,STRN-ALK融合,吉非替尼进展后的EGFR扩增以及随后从奥希替尼获得的MET扩增。另一名患者在达克替尼后获得EGFRT790M和MET扩增,并在奥希替尼治疗后获得CCDC6-RET融合。此外,随后新的旁路激活是二线奥希替尼可能的耐药机制.两名患者的无进展生存期(PFS)均小于4个月,奥希替尼二线治疗的获益有限。伴随驱动基因耐药的T790M将是EGFR-TKIs进展后的新亚型,需要有效的治疗方案。