Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Geneplus-Beijing, Beijing, China.
Ann Palliat Med. 2021 Jun;10(6):7051-7056. doi: 10.21037/apm-20-1477. Epub 2021 Feb 2.
Tyrosine kinase inhibitor (TKI) has greatly improved the survival of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-TKI sensitive mutations. However, TKI resistance constantly occur, although multiple lines of different generations of TKIs are adopted during the progression. For example, in the case when T790M, which is the most common resistance mechanism of first generation TKIs, occurs, alteration to osimertinib (the third generation TKI) could always be effective. Unfortunately, some cases gradually become resistant even to osimertinib leaving limited therapy choice for clinical practitioners. Few cases have been reported in the situation after EGFR tertiary mutations occurred, such as C797S, G724S, etc. Herein, we report the first clinical evidence that sequential therapy with erlotinib, osimertinib, afatinib plus endostar, brigatinib plus cetuximab, almonertinib, almonertinib plus afatinib achieved long-term control in a NSCLC patient demonstrating EGFR 19Del/T790M/G724S/cis-C797Sevolution in response to TKI treatment. EGFR targeted therapy introduced successful management for more than 36 months until now. ctDNA NGS was performed at the time of important clinical event. The EGFR 19Del was discovered in October 2017, and erlotinib was administered for 10 months with PR in the beginning. Then T790M was detected and osimertinib was used for 9 months with SD condition. Subsequently, EGFR G724S was identified in ctDNA with the remaining 19Del and loss of T790M. Afatinib plus endostar was administered and PR was achieved after 1.5 months. PD occurred 6 months later with the emergence of EGFR cis-C797S. Then brigatinib plus cetuximab was chosen and lasted for 4 months with the best response of SD. And then EGFR 19Del and T790M were still detected with loss of G724S and C797S. Almonertinib, another third-generation TKI, was administered for 3 months with SD condition. Finally, 19Del/T790M/G724S/cis-C797S recurred, and whole dose of almonertinib plus afatinib was prescribed until now with a PR at 2 months until now. The side effect was acceptable during the whole period of therapies. Plasma ctDNA NGS provided information of EGFR mutation evolution and inform appropriate therapy regimen during the progression.
酪氨酸激酶抑制剂（TKI）显著改善了具有表皮生长因子受体（EGFR）-TKI 敏感突变的非小细胞肺癌（NSCLC）的生存。然而，尽管在进展过程中采用了多种不同代的 TKI，但 TKI 耐药性仍不断发生。例如，当第一代 TKI 最常见的耐药机制 T790M 发生时，改用奥希替尼（第三代 TKI）总是有效。不幸的是，即使对奥希替尼，有些病例也逐渐产生耐药性，这使得临床医生的治疗选择有限。在 EGFR 三级突变（如 C797S、G724S 等）发生后，很少有病例有报道。在此，我们报告了首例临床证据，即一例 NSCLC 患者在接受 TKI 治疗后出现 EGFR 19Del/T790M/G724S/cis-C797S 演变，采用厄洛替尼、奥希替尼、阿法替尼联合恩度、布加替尼联合西妥昔单抗、阿美替尼、阿美替尼联合阿法替尼序贯治疗，长期控制病情。EGFR 靶向治疗已成功管理超过 36 个月。ctDNA NGS 在重要临床事件时进行。2017 年 10 月发现 EGFR 19Del，给予厄洛替尼治疗 10 个月，初显 PR。然后检测到 T790M，使用奥希替尼治疗 9 个月，病情稳定。随后，在 ctDNA 中发现 EGFR G724S，同时仍存在 19Del 和 T790M 缺失。给予阿法替尼联合恩度治疗，1.5 个月后 PR。6 个月后出现 PD，出现 EGFR cis-C797S。然后选择布加替尼联合西妥昔单抗治疗，4 个月后病情稳定，为最佳反应。然后仍检测到 EGFR 19Del 和 T790M，同时 G724S 和 C797S 缺失。另一种第三代 TKI 阿美替尼治疗 3 个月，病情稳定。最后，19Del/T790M/G724S/cis-C797S 复发，直至现在仍全剂量给予阿美替尼联合阿法替尼治疗，2 个月时 PR。整个治疗过程中，副作用可耐受。血浆 ctDNA NGS 提供了 EGFR 突变演变的信息，并在进展过程中提供了合适的治疗方案。
