NSCLC remains the leading cause of cancer-related mortality worldwide, with EGFR mutations being a critical driver in approximately 10-15% of lung adenocarcinomas in Western populations, and up to 40% in Asian cohorts. Although osimertinib has set a new standard as a first-line treatment for EGFR-mutant NSCLC due to its enhanced efficacy and favorable central nervous system penetrance, a significant clinical hurdle emerges in the form of acquired resistance mechanisms. One of the pivotal resistance pathways involves MET gene amplification or aberrant activation, which bypasses EGFR blockade and sustains oncogenic signaling, leading to therapeutic failure.
The FLOWERS trial represents the first randomized assessment aimed explicitly at evaluating whether combining osimertinib with savolitinib could suppress this MET-driven resistance. By enrolling treatment-naïve patients with confirmed EGFR mutations and MET abnormalities — detected through sophisticated genomic profiling techniques — the study systematically compared disease control rates, progression-free survival, and overall safety profiles between the combination regimen and osimertinib monotherapy. Employing stringent inclusion criteria, the investigators ensured the recruitment of a biologically homogeneous patient population, thereby enhancing the interpretability and translational potential of the data.
Intriguingly, the dual inhibition approach demonstrated a profound enhancement in clinical outcomes. Patients receiving the osimertinib-savolitinib combination exhibited significantly extended progression-free survival compared to those on osimertinib alone, underscoring the vital role of MET pathway suppression in overcoming intrinsic resistance. Tumor response rates were also markedly improved, with a higher proportion of patients achieving complete or partial remission. The comprehensive biomarker analyses suggested that concurrent targeting of EGFR and MET could attenuate compensatory pathway activation, which often undermines monotherapy efficacy.
The molecular rationale for combining these agents lies in the complex interplay between EGFR signaling and MET pathway crosstalk. EGFR mutations typically hyperactivate downstream cascades such as the PI3K/AKT and RAS/RAF/MEK/ERK pathways, driving unchecked cell proliferation and survival. However, when MET amplification occurs, cells can bypass the inhibited EGFR route by activating parallel signaling circuits, thus maintaining oncogenic momentum. Savolitinib’s ability to selectively inhibit MET kinase activity disrupts this rescue mechanism, restoring tumor sensitivity to osimertinib and impeding cancer progression.
Furthermore, the trial’s safety data reveal that the combination therapy, while more intensive, maintained a manageable toxicity profile. The adverse events observed were consistent with the known effects of each individual drug and did not lead to a significant increase in treatment discontinuations. Most common side effects included mild to moderate rash, diarrhea, and elevated liver enzymes, which were effectively controlled through dose adjustments and supportive care. This safety reassurance is critical for the adoption of combination regimens in the clinical setting, ensuring patient quality of life alongside therapeutic efficacy.
The FLOWERS trial also incorporated advanced imaging and liquid biopsy methodologies to monitor treatment responses and detect emergent resistance mutations dynamically. These cutting-edge techniques allowed for real-time assessment of tumor burden and molecular landscape, facilitating a more personalized and adaptive treatment strategy. By integrating these diagnostics, clinicians can potentially identify early signs of resistance and modify therapeutic regimens accordingly, optimizing long-term outcomes.
Moreover, this study accentuates the significance of precision oncology and molecular stratification in managing NSCLC. The identification of MET aberrations as actionable targets complements the expanding repertoire of targeted therapies, emphasizing the necessity to tailor treatments based on the tumor’s genetic makeup rather than employing a one-size-fits-all approach. Such stratification not only improves efficacy but also spares patients from unnecessary toxicities associated with ineffective therapies.
Beyond the immediate clinical implications, the FLOWERS trial’s design and outcomes provide invaluable insights for ongoing drug development. The trial methodology sets a precedent for combining targeted agents based on mechanistic synergy and resistance biology, encouraging future studies to investigate similar approaches in diverse oncogenic contexts. This paradigm shift heralds a new era in cancer therapy where combination treatments can preempt resistance and deliver durable responses.
In terms of broader impact, these findings invigorate hopes for improved survival rates in NSCLC patients with dual aberrations, a group historically associated with poor prognosis and limited treatment options. By demonstrating the feasibility and benefit of upfront combination therapy, the trial challenges existing treatment algorithms and prompts regulatory bodies and clinicians to rethink standard care protocols.
It’s also noteworthy that the trial harnessed a global patient cohort, encompassing diverse ethnic backgrounds and healthcare systems, thereby enhancing the generalizability of the results. This inclusivity is crucial in oncology research, ensuring that advances reach and benefit patients across varied demographic and genetic spectra.
Looking ahead, ongoing follow-up studies aim to evaluate overall survival benefits and long-term safety, alongside exploratory analyses into resistance mechanisms that may eventually emerge against the combination regimen. Understanding these dynamics will further refine treatment sequencing and combination strategies, maximizing patient benefit and guiding next-generation inhibitor development.
The FLOWERS trial’s publication arrives at a pivotal moment when artificial intelligence and molecular diagnostics are rapidly reshaping oncology. Integrating multi-omic data with clinical outcomes promises to accelerate discovery and optimize therapeutic decisions, positioning targeted combination therapies such as osimertinib and savolitinib at the forefront of personalized cancer care.
In essence, by delivering compelling evidence for the tandem targeting of EGFR and MET aberrations, this study illuminates a promising pathway to circumvent resistance, enhance patient outcomes, and reshape the therapeutic landscape of EGFR-mutant NSCLC. As researchers and clinicians digest these findings, the stage is set for broader implementation and continued innovation, offering renewed hope for one of the world’s deadliest cancers.
###
References
DOI
10.1038/s41467-025-67950-8
Original Souce URL
https://doi.org/10.1038/s41467-025-67950-8
Funding information
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.].
About Nature Communications
Nature Communications is an open access, multidisciplinary journal dedicated to publishing high-quality research in all areas of the biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences. Papers published by the journal aim to represent important advances of significance to specialists within each field.