Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON.
Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON.
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DOI：
10.1158/2159-8290.cd-22-0586
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发表时间：
2023-01-09
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影响因子：
28.2
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Savolitinib+奥希替尼联合治疗在既往接受EGFR酪氨酸激酶抑制剂治疗后发生疾病进展的MET扩增、EGFR突变晚期NSCLC患者中具有可接受的安全性特征，并显示出抗肿瘤活性。MET抑制剂和EGFR酪氨酸激酶抑制剂（EGFR-TKI）联合治疗可克服获得性MET介导的奥希替尼耐药。我们提供了最终Ib期TATTON（NCT 02143466）分析（B部分，n = 138/D部分，n = 42），评估口服savolitinib 600 mg/300 mg每日一次（q.d.）+ 奥希替尼80 mg q.d. MET扩增、EGFR突变（EGFRm）晚期非小细胞肺癌（NSCLC）和既往EGFR-TKI治疗进展的患者。观察到可接受的安全性特征。在部分B和D中，客观缓解率分别为33%-67%和62%，中位无进展生存期（PFS）为5.5 - 11.1个月和9.0个月。MET拷贝数≥10时，抗肿瘤活性可能会增加。在基线ctDNA可检测的患者中，治疗期间EGFRm循环肿瘤DNA清除预测PFS较长，而对奥希替尼+ savolitinib的获得性耐药机制由MET、EGFR或KRAS改变介导。savolitinib + osimertinib联合治疗代表了MET扩增/过表达、EGFRm晚期NSCLC且既往接受EGFR-TKI治疗后疾病进展的患者的一种有前景的治疗方法。对该组合的获得性耐药机制包括通过MET、EGFR和KRAS的耐药机制。治疗中的ctDNA动力学可以预测临床结果，并可能提供一个机会，为早期决策提供信息。 这篇文章在本期专题中突出显示，第1页
Savolitinib plus osimertinib combination therapy has an acceptable safety profile and demonstrated antitumor activity in patients with MET-amplified, EGFR-mutated advanced NSCLC who experienced disease progression on prior EGFR tyrosine kinase inhibitor therapy. MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n = 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. 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% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months 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. The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making. This article is highlighted in the In This Issue feature, p. 1