Design and Rationale for a Phase II, Randomized, Open-Label, Two-Cohort Multicenter Interventional Study of Osimertinib with or Without Savolitinib in De Novo MET Aberrant, EGFR-Mutant Patients with Advanced Non-Small-Cell Lung Cancer: The FLOWERS Trial
Design and Rationale for a Phase II, Randomized, Open-Label, Two-Cohort Multicenter Interventional Study of Osimertinib with or Without Savolitinib in De Novo MET Aberrant, EGFR-Mutant Patients with Advanced Non-Small-Cell Lung Cancer: The FLOWERS Trial
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DOI：
10.1016/j.cllc.2022.09.009
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发表时间：
2022-01-01
影响因子：
3.6
通讯作者：
Yang, Jin-Ji
中科院分区：
文献类型：
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作者：
Li, Anna;Chen, Hua-Jun;Yang, Jin-Ji
前言：表皮生长因子受体(EGFR)突变是晚期非小细胞肺癌(NSCLC)中众所周知的基因改变，与EGFR酪氨酸激酶抑制剂(EGFR-TKI)一线治疗带来的显著生存益处有关。然而，大约30%的患者对EGFR-TKIs治疗表现出原始抵抗。同时存在MET扩增/过度表达的患者在EGFR-TKI单一治疗中进展时间较短。Osimertinib(Tagrisso，AZD9291)已被推荐作为EGFR突变的晚期NSCLC患者的一线治疗药物。Savolitinib(AZD6094，HMPL-504)是一种高度选择性的MET-TKI，已在多种MET改变的癌症中显示出抗肿瘤活性。方法：这项FLOWS试验是一项II期、随机、开放标签、2个队列的多中心试验，旨在评价奥西美替尼联合或不联合萨伏利替尼作为一线治疗De-nevo MET扩增/过度表达、EGFR突变阳性、局部晚期或转移性非小细胞肺癌患者的疗效和安全性。大约44名患者将随机接受奥西美替尼(每天一次80毫克)单一治疗或奥西美替尼(每天一次80毫克)和萨伏利替尼(每天两次300毫克)联合治疗；在奥西美替尼单一治疗队列中，病情进展后被证实为MET阳性(MET扩增/过度表达)的患者将有机会接受交叉联合治疗作为二线治疗。主要终点将是客观应答率。关键的次要终点将是无进展生存期、应答持续时间、疾病控制率、总生存期、安全性和耐受性。结论：该研究结果将为EGFR-TKI联合MET-TKI联合疗法(Osimertinib+savolitinib)治疗新发MET扩增/过度表达、EGFR突变阳性、治疗初治、晚期NSCLC的疗效和安全性提供更好的前景，并为临床实践提供有意义的指导。
Introduction: Epidermal growth factor receptor (EGFR) mutations are well-known genetic alterations in advanced non -small cell lung cancer (NSCLC) which are associated with remarkable survival benefits from first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, around 30% of patients exhibit primary resistance to EGFR-TKIs therapy. Co-existing MET amplification/over-expression has showed shorter time to progression on EGFR-TKI monotherapy. Osimertinib (TAGRISSO, AZD9291) has been recommended in EGFR-mutant advanced NSCLC patients as first-line treatment. Savolitinib (AZD6094, HMPL-504) is a highly selective MET-TKI which has demonstrated anti-tumor activity in various cancers with MET alterations. Methods: This FLOWERS study, a phase II, randomized, open -label, 2-cohort multicenter trial aimed to evaluate the efficacy and safety of osimertinib with or without savolitinib as first-line therapy in patients with de novo MET amplified/over-expressed, EGFR-mutant positive, locally advanced or metastatic NSCLC. Approximately 44 patients will be randomized to receive osimertinib (80 mg once daily) monotherapy or osimertinib (80 mg once daily) and savolitinib (300 mg twice daily) combination therapy; patients in osimertinib monotherapy cohort confirmed as MET positive ( MET-amplified/over-expressed) after disease progression will have the opportunity to receive the cross-over combination therapy as second-line treatment. Primary endpoint will be objective response rate. Key secondary endpoints will be progression-free survival, duration of response, disease control rate, overall survival, safet y and tolerabilit y. Conclusion: The results of the study will provide better perspectives on the efficacy and safety of EGFR-TKI plus MET-TKI combination therapy (osimertinib plus savolitinib) in patients with de novo MET-amplified/over-expressed, EGFR-mutant positive, treatment naive, advanced NSCLC and offer a meaningful guidance in clinical practice (NCT05163249).