奥西替尼+赛沃替尼在表皮生长因子受体突变的MET扩增非小细胞肺癌中克服获得性MET介导的耐药：TATTON

SCI 1 November 2022

Osimertinib+Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor Mutated METAmplified Non-Small Cell Lung Cancer: TATTON

 (Cancer Discovery, IF: 38.272)

Hartmaier RJ, Markovets AA, Ahn MJ, et al. Osimertinib+Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor Mutated MET-Amplified Non-Small Cell Lung Cancer: TATTON. Cancer Discov 2022. DOI: 10.1158/2159-8290.CD-22-0586.

Corresponding author: Ryan Hartmaier, 35 Gatehouse Dr, Waltham, MA 02451.  Phone: 781-839-4264; E-mail: ryan.hartmaier@astrazeneca.com

Abstract 摘要

MET-inhibitor and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final PhIb TATTON (NCT02143466) analysis (Part B, n=138/Part D, n=42) assessing oral savolitinib 600 mg/300 mg once daily (QD) + osimertinib 80 mg QD in patients with MET amplified EGFR mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33-67% and 62%, and median progression-free survival (PFS) was 5.5-11.1 and 9.0 months. Increased antitumor activity may occur with MET copy-number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib+savolitinib were mediated by MET, EGFR, or KRAS alterations.

MET-抑制剂和表皮生长因子受体(EGFR)-酪氨酸激酶抑制剂(TKI)联合治疗可克服MET介导的获得性奥西替尼耐药。我们提出了最终的PhIb TATTON (NCT02143466)分析(B部分，n=138/ D部分，n=42)，评估MET扩增EGFR突变(EGFRm)晚期非小细胞肺癌(NSCLC)患者口服赛沃替尼600 mg/300 mg每日一次(QD) +奥西替尼80 mg QD的疗效及先前EGFR- TKI进展情况。观察到可接受的安全效果。在B部分和D部分，客观有效率分别为33-67%和62%，中位无进展生存期(PFS)分别为5.5-11.1和9.0个月。MET拷贝数≥10可增加抗肿瘤活性。治疗时EGFRm循环肿瘤DNA的清除预示着基线ctDNA可检测的患者PFS更长，而对奥西替尼+赛沃替尼的获得性耐药机制是由MET、EGFR或KRAS改变介导的。