Fuchs Vered, Roisman Laila, Kian Waleed, Daniel Levin, Dudnik Julia, Nechushtan Hovav, Goldstein Iris, Dvir Addie, Soussan-Gutman Lior, Grinberg Roxana, Gillis Roni, Peled Nir
Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka University Medical Center, Beer-Sheva, Israel.
Lung Cancer. 2021 Mar;153:126-133. doi: 10.1016/j.lungcan.2020.12.039. Epub 2021 Jan 14.
Resistance mechanisms following 1st line therapy with osimertinib in EGFR + NSCLC have become focus of investigation. This retrospective study aims to deepen the understanding and clarify possible mechanisms of osimertinib 1st line resistance in comparison to the 2nd line by examining NGS results of 30 patients who developed resistance to osimertinib. Furthermore, we followed clinical outcomes of select patients who received combined therapy following EGFR resistance, a novel strategy not yet widely tested.
Liquid biopsy technique (Guardant360) was used to monitor tumor dynamics in patients who were treated with osimertinib as 1st-line therapy (Group A, N = 15) and patients who received osimertinib as 2nd-line therapy (Group B, N = 15).
At the time of progression under osimertinib all but one patient preserved the primary EGFR mutation. While the C797S mutation was relatively common in the 2nd-line osimertinib setting (5/15), it did not develop in group A patients. TP53 was the most common detected mutation among all patients accounting for 11/15 in group A (73.33 %) and 10/15 in group B (66.67 %). In group A MET amplification was found in 3/15 patients (20 %) whereas MET mutation appeared in only one patient from group B. The outcomes of different treatment approaches post osimertinib resistance is reported including chemotherapy with/without osimertinib for maintaining control of brain metastases, drug combination such as osimertinib with crizotinib, chemo-immunotherapy and others. Overall survival in this cohort ranged from 12 to80 months.
Mechanisms of resistance to osimertinib as 1st-line therapy differ from those which develop in the 2nd-line setting and commonly include MET amplification. C797S is not a main resistance mechanism in the 1st-line setting, whereas it is more common in the 2nd-line setting. Combined therapy was effective and well tolerated, making it an acceptable choice in patients for whom there is a reasonable rationale for such treatment, however this approach deserves further investigation.
表皮生长因子受体（EGFR）阳性的非小细胞肺癌（NSCLC）患者一线使用奥希替尼治疗后的耐药机制已成为研究重点。本回顾性研究旨在通过检测30例对奥希替尼产生耐药的患者的二代测序（NGS）结果，加深对奥希替尼一线耐药的理解，并阐明其与二线耐药相比可能的机制。此外，我们跟踪了部分在EGFR耐药后接受联合治疗患者的临床结局，这是一种尚未得到广泛验证的新策略。
采用液体活检技术（Guardant360）监测接受奥希替尼一线治疗的患者（A组，N = 15）和接受奥希替尼二线治疗的患者（B组，N = 15）的肿瘤动态变化。
在奥希替尼治疗进展时，除1例患者外，所有患者均保留了原发性EGFR突变。虽然C797S突变在二线奥希替尼治疗中相对常见（5/15），但在A组患者中未出现。TP53是所有患者中最常见的检测到的突变，A组占11/15（73.33%），B组占10/15（66.67%）。A组15例患者中有3例（20%）检测到MET扩增，而B组仅1例患者出现MET突变。报告了奥希替尼耐药后不同治疗方法的结局，包括使用/不使用奥希替尼进行化疗以维持对脑转移的控制、奥希替尼与克唑替尼等药物联合治疗、化疗免疫治疗等。该队列的总生存期为12至80个月。
奥希替尼一线治疗的耐药机制与二线治疗不同，常见的包括MET扩增。C797S不是一线治疗的主要耐药机制，而在二线治疗中更常见。联合治疗有效且耐受性良好，对于有合理治疗依据的患者是一个可接受的选择，然而这种方法值得进一步研究。
