Abstract
To investigate the efficacy and safety of osimertinib plus savolitinib for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and de novo MET aberrations, we conducted a randomized, multicenter, open-label, phase 2 study (ClinicalTrials.gov identifier: NCT05163249). Treatment-naïve patients with locally advanced or metastatic NSCLC harboring de novo MET amplification or overexpression and EGFR mutations were randomized to receive osimertinib monotherapy (cohort 1, 80 mg orally once daily) or combination therapy (cohort 2, osimertinib 80 mg orally once daily and savolitinib 300 mg orally twice daily). The primary endpoint was the confirmed objective response rate (ORR). A total of 44 patients were randomized to either cohort 1 (n = 23) or cohort 2 (n = 21). The pre-specified study endpoint was achieved. The confirmed ORR was 60.9% (95% confidence interval [CI]: 38.5–80.3) in cohort 1 and 90.5% (95% CI: 69.6–98.8) in cohort 2, with disease control rates of 87% (95% CI: 66.4–97.2) and 95.2% (95% CI: 76.2–99.9). Treatment-related adverse events of grade 3 or higher occurred in 2 patients (8.7%) in cohort 1 and 12 patients (57.1%) in cohort 2. Osimertinib plus savolitinib showed promising antitumor activity and manageable safety.
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The deidentified patient data are not publicly available due to restrictions imposed by the institutional review board. Reasonable requests will be reviewed by the Guangdong Provincial People’s Hospital. Access is restricted to qualified researchers for non-commercial academic use and will be shared in a deidentified format for 10 years after publication. Individual patient-level raw data containing identifiable patient information cannot be shared. Source data are provided with this paper. The ctDNA data generated in this study have been deposited in the Genome Sequence Archive, an approved public repository, under accession code HRA014210 and are publicly available. The remaining data are available within the Article, Supplementary Information or Source Data file. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81972164 [J.-J.Y.] and 82003273 [A.L.]), the High-level Hospital Construction Project of Guangdong Provincial People’s Hospital (Grant No. DFJH201809 [J.-J.Y.]), the Natural Science Foundation of Guangdong Province (Grant No. 2019A1515010931 [J.-J.Y.]), the Guangdong Association of Clinical Trials Guangdong Association of Clinical Trials (GACT) /Chinese Thoracic Oncology Group (CTONG) (Grant No. CTONG-YC20220106 [J.-J.Y.]), Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer (2017B030314120 [Y.L.W.]), the Chinese Society of Clinical Oncology pilot MET aberrant Solid Tumor Research Project (Grant Nos. Y-2022METAZZD-0110 [J.-J.Y.] and Y-2022METAZQN-0122 [A.L.]), and AstraZeneca China [J.-J.Y.]. We extend our gratitude to the patients and their families who participated in the FLOWERS trial. We thank Xiaolong Cao from the Affiliated Panyu Central Hospital of Guangzhou Medical University for his efforts in carrying out this study. A professional medical writer funded by the sponsor, assisted in drafting this manuscript.
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J.-J.Y. and A.L. contributed to the conceptualization, writing—original draft, and funding acquisition. J.-J.Y., A.L., W.N.F., J.L., B.F.X., J.Z., Y.J., K.J.T., Y.S.L., C.Z.Z., Y.F., C.R.X., Y.L.S., and H.J.C. recruited and treated patients and gathered clinical data on efficacy and safety. J-JY and HHY contributed to formal analysis of the data. Z.K.S. performed the bioinformatics analysis. AstraZeneca contributed to resources for the study. All authors had access to all the data in the study, and participated in reviewing, editing, and approving the final paper. All authors had final responsibility for the decision to submit the manuscript for publication. J-JY and AL have accessed and verifed the data.
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J.J.Y. received grants or contracts outside the submitted work and consulting fees from AstraZeneca. The remaining authors declare no competing interests.
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Li, A., Feng, WN., Li, J. et al. Osimertinib with or without savolitinib as first-line treatment for MET-aberrant, EGFR-mutant NSCLC: randomized phase 2 trial (FLOWERS). Nat Commun (2026). https://doi.org/10.1038/s41467-025-67950-8
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DOI: https://doi.org/10.1038/s41467-025-67950-8
