Magios Nikolaus, Bozorgmehr Farastuk, Volckmar Anna-Lena, Kazdal Daniel, Kirchner Martina, Herth Felix J, Heussel Claus-Peter, Eichhorn Florian, Meister Michael, Muley Thomas, Elshafie Rami A, Fischer Jürgen R, Faehling Martin, Kriegsmann Mark, Schirmacher Peter, Bischoff Helge, Stenzinger Albrecht, Thomas Michael, Christopoulos Petros
Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg.
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Ther Adv Med Oncol. 2021 Mar 24;13:1758835921996509. doi: 10.1177/1758835921996509. eCollection 2021.
Epidermal growth factor receptor-mutated (EGFR) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging.
EGFR NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib.
A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months 24 and 21 months for patients with alternative and no subsequent therapies ( = 0.003).
Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR NSCLC in the future.
表皮生长因子受体突变（EGFR）的非小细胞肺癌（NSCLC）患者在酪氨酸激酶抑制剂（TKI）治疗失败后可从二线靶向治疗中获益，但实施起来具有挑战性。
回顾性分析在我们机构接受第一代/第二代（1G/2G）TKI治疗且在奥希替尼获批后（2016年2月）进行最后一次随访的EGFR NSCLC患者，并将结果与奥希替尼治疗下已发表的数据进行比较。
共有207例患者接受了厄洛替尼（37%）、吉非替尼（16%）或阿法替尼（47%）治疗。中位年龄为66岁，女性占多数（70%），从不吸烟/轻度吸烟者占69%。在174/202例病情进展的病例（86%）中进行了T790M检测，其中93/174例（53%）呈阳性，87/93例（94%）随后接受了奥希替尼治疗。在135例死亡患者中，94例（70%）接受了后续的全身治疗（43%为化疗，39%为奥希替尼），而30%的患者未接受治疗即死亡，其中4%在病情进展前死亡，22%因临床快速恶化死亡，2%因患者拒绝进一步治疗死亡，2%因严重合并症死亡。未接受后续治疗与未进行T790M检测显著相关（4.5倍，<0.001），其最常见的原因（约50%的病例）也是临床快速恶化。在2015年11月后开始接受1G/2G TKI治疗失败的127例连续患者中，47例（37%）接受了奥希替尼治疗，接受替代治疗和未接受后续治疗的患者的中位总生存期分别为36个月、24个月和21个月（P = 0.003）。
1G/2G TKI治疗失败后使用奥希替尼可延长生存期，但分别约有15%和30%的患者未进行分子复测和后续治疗，主要原因是临床快速恶化。这是EGFR NSCLC序贯TKI治疗的一个重要且可补救的障碍。这也适用于在1G/2G抑制剂或奥希替尼治疗下出现的其他可靶向的耐药机制，其未接受二线治疗的比例相似（在FLAURA/AURA3试验中约为35%），并凸显了未来对接受TKI治疗的EGFR NSCLC进行更密切监测以及更广泛分析的必要性。
