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

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, safety and tolerability.

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 naïve, advanced NSCLC and offer a meaningful guidance in clinical practice (NCT05163249).