Osimertinib with or without savolitinib as first-line treatment for MET-aberrant, EGFR-mutant NSCLC: randomized phase 2 trial (FLOWERS)

Domain: neuroscience
Published: 2026-01-13
Editorial outcome: minor_revision

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.

Introduction
The prognosis of patients with advanced non-small cell lung cancer (NSCLC) remains poor, with 5-year overall survival (OS) rates ranging from 12 to 24%1,2. Although successive generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved substantial improvements in efficacy and survival, approximately 20% of patients with EGFR-sensitive mutations receive limited benefit from standard EGFR TKI therapy, with marked inter-patient variability in the duration of clinical response3–5. Evidence suggests that coexisting driver mutations may underlie this variability4. Among these, MET6,7 aberrations are significant co-alterations in EGFR-mutant NSCLC4, with de novo MET amplification and MET overexpression in approximately 2–5% and 11–15% of treatment-naïve EGFR-mutant patients8–11, respectively. Mi12 et al. reported a relatively low prevalence of MET overexpression (2.5%) in a Chinese population.

De novo MET aberrations, including amplification and overexpression, maybe associated with primary resistance to EGFR TKIs13. In EGFR-mutant advanced NSCLC, de novo MET aberrations have been associated with poor responses to first-line EGFR-TKI monotherapy. A subgroup analysis from the BENEFIT trial revealed significant differences in median progression-free survival (PFS) and OS between patients with EGFR mutations only and those with mutations in EGFR and oncogenes, such as MET amplification (5 of 24). When treated with first-line gefitinib, the median PFS was 13.2 months versus 4.7 months (hazard ratio: 2.66, 95% CI: 1.58–4.49, p = 0.0003), and the median OS was 32.0 months versus 21.7 months8,14. Similarly, Lai et al.10 reported that patients with MET amplification (5 [3.2%] of 154) exhibited the shortest time to treatment failure (TTF) to EGFR TKI, with a median TTF of 5 months (range: 1.0–6.4 months). In addition, Yu et al.11 found that patients with MET amplification (4 [2.0%]) had a median progression time of 5 months compared to 11 months in those without amplification (hazard ratio: 3.7, p = 0.019). Notably, patients with coexisting MET amplification undergoing first-line osimertinib treatment experience significantly shorter PFS and OS than those without MET amplification15. Further analysis of the cumulative TTF of EGFR TKI therapy revealed a strong trend suggesting that high MET expression was correlated with a shorter TTF16. A phase 2 study17 compared erlotinib with and without emibetuzumab (a MET monoclonal antibody) as a first-line treatment for patients with EGFR-mutant metastatic NSCLC. The results indicated that patients with EGFR mutation and high MET expression might derive a clinically meaningful difference in PFS and OS from emibetuzumab plus erlotinib.

FLAURA218 and MARIPOSA19,20 studies demonstrated that combination therapy significantly prolonged PFS compared to osimertinib monotherapy. Although first-line combination therapies have demonstrated promising results, several questions remain unanswered in clinical practice. These include a high incidence of grade 3 or higher adverse events (AEs), challenges related to drug convenience, and a lack of publicly available efficacy data on combination therapy in advanced EGFR-mutant NSCLC patients with coexisting de novo MET amplification and/or overexpression. Given the activation of EGFR and MET pathways in patients with concurrent EGFR mutations and MET amplification/overexpression, the efficacy of treatment may be further optimized by the selective administration of dual-target therapy as a first-line approach for this population. Preclinical studies have revealed that combining osimertinib with savolitinib enhances antitumor efficacy compared to monotherapy in lung cancer organoid models with EGFR mutations and MET amplification and/or overexpression21,22. Furthermore, a case series indicated that combining osimertinib with savolitinib as a first-line treatment demonstrated rapid and durable antitumor activity in previously untreated patients with advanced NSCLC with EGFR mutations and MET amplification23.

MET amplification or overexpression is a mechanism of resistance to osimertinib, providing a rationale for evaluating the combination of osimertinib with savolitinib as a first-line treatment to potentially reduce MET-driven resistance. Prospective study on the efficacy of osimertinib monotherapy or osimertinib plus savolitinib in advanced NSCLC patients with coexisting EGFR mutations and de novo MET amplification and/or overexpression was limited.

In this work, we aim to evaluate the efficacy and safety of osimertinib with or without savolitinib as first-line treatment in de novo MET amplification and/or overexpression and EGFR-mutant advanced NSCLC. Osimertinib plus savolitinib shows promising antitumor activity and a manageable safety profile in treatment-naïve advanced NSCLC patients with EGFR mutations and de novo MET aberrations.

Results
Patients and treatment
Patients with MET amplification and/or overexpression who met the definition of study requirement identified by prospective tumor tissue testing (fluorescence in situ hybridization [FISH], next-generation sequencing [NGS], or immunohistochemistry [IHC]) were referred to participate in this study between May 31, 2022, and February 5, 2024. A total of 45 patients with de novo MET amplification and/or overexpression, EGFR-mutant advanced NSCLC were screened for inclusion, and 44 were randomized across 10 research centers, and assigned to either osimertinib monotherapy (cohort 1, 23 patients) or osimertinib plus savolitinib combination therapy (cohort 2, 21 patients) (Supplementary Fig. 1 and Fig. 1). All patients received at least one dose of treatment and were included in the efficacy and safety analyses.

The median age of the patients was 58 years (range: 29–74 years), with 52.3% male. Most patients (42 out of 44, 95.5%) had adenocarcinoma. 13 patients (29.6%) had brain metastasis. In total, 20 patients (45.5%) had an exon 19 deletion, and 19 (43.2%) had the L858R mutation. In addition, 36 patients (81.8%) had MET overexpression, 6 patients (13.6%) had MET amplification, and 2 patients (4.5%) had both MET amplification and overexpression. Baseline demographics and clinical characteristics are summarized in Table 1. The detailed results of MET alteration are presented in Supplementary Table 2. Baseline plasma circulating tumor DNA (ctDNA) mutation analysis was conducted. The top three co-mutations identified by ctDNA analysis in all patients included the following: TP53 (72.7%), PIK3CA (13.6%), and RB1 (13.6%). The baseline ctDNA variants, including EGFR mutations and MET amplification, as well as the common co-mutations, were found to be similar between the two cohorts (Supplementary Fig. 2).

As of the data cutoff date on 28 May 2024, 15 patients (65.2%) in cohort 1 and 15 patients (71.4%) in cohort 2 continued to receive treatment. Two patients in cohort 1 who had disease progression with confirmed MET amplification and/or overexpression were crossed over to cohort 2 (Fig. 1). The median follow-up was 7.8 months (range: 2.8–23.8) in cohort 1 and 8.5 months (range: 3.7–18.7) in cohort 2.

Efficacy
In accordance with the study protocol, the analyses were descriptive only, and no statistical hypothesis testing was undertaken. The confirmed objective response rate (ORR) was 60.9% (95% CI: 38.5–80.3) in cohort 1 and 90.5% (95% CI: 69.6–98.8) in cohort 2 (Table 2 and Fig. 2a). Subgroup analysis indicated that the ORRs across multiple subgroups were consistent with those of overall patients in each cohort (Supplementary Fig. 3). In cohort 1, the best median tumor reduction rate was –42.2% (Fig. 2b). Two patients in cohort 1 with initial progressive disease transitioned to combination therapy after 4 weeks, achieving PR and remaining on combination treatment. In cohort 2, the best median tumor reduction rate was –47.7% (Fig. 2c). The disease control rate (DCR) was 87.0% (95% CI: 66.4–97.2) in cohort 1 and 95.2% (95% CI: 76.2–99.9) in cohort 2. The median duration of response (DoR) was 8.4 months (range: 6.6-NE) in cohort 1 and 18.6 months (95% CI: NR-NE) in cohort 2 (Fig. 2a).

At the time of data cutoff, the investigator-assessed median PFS was 9.3 months (95% CI: 7.4-NE) in cohort 1 and 19.6 months (95% CI: 10.2-NR) in cohort 2, with maturity of 34.8% and 23.8%, respectively (Fig. 3). At 6 months, the PFS rates were 82.1% (95% CI: 66.2–98.0) for cohort 1 and 87.3% (95% CI: 70.2–98.9) for cohort 2. The median OS was not reached, and the data are immature; the results are expected to be released at the final analysis.

Safety
All treated patients experienced at least one treatment-related AEs (TRAEs) (Table 3). The most common TRAEs in cohort 1 included diarrhea (56.5%), rash (52.2%), and pruritus (43.5%), whereas cohort 2 reported rash (52.4%), platelet count decreased (52.4%), diarrhea (42.9%), white blood cell count decreased (42.9%), alanine aminotransferase increase (42.9%), paronychia (42.9%), and peripheral edema (42.9%) (Supplementary Fig. 5, Supplementary Tables 4 and 5). Grade 3 or higher TRAEs were reported in 2 patients (8.7%) in cohort 1 compared to 12 patients (57.1%) in cohort 2 (Supplementary Table 3). Serious TRAEs were reported in 1 patient (4.3%) in cohort 1 and in 4 patients (19.0%) in cohort 2. No fatal TRAEs were recorded in either of the cohorts. In cohort 2, one patient (4.8%) experienced grade 2 interstitial lung disease, leading to permanent discontinuation of both osimertinib and savolitinib; five patients (23.8%) had permanent discontinuation of osimertinib and/or savolitinib (Table 3).

Methods
Study design and patients
This phase 2, open-label, non-comparative, randomized, two-arm, multicenter, interventional study (ClinicalTrials.gov registration: NCT05163249), designated the CTONG2008 (FLOWERS) study30, was conducted in compliance with the Declaration of Helsinki, the Good Clinical Practice guidelines outlined by the International Council for Harmonisation, and all applicable regulatory requirements. The study protocol and amendments were approved by the independent ethics committees or institutional review boards at each participating center (Supplementary Table 6). All patients provided written informed consent. The authors confirm the accuracy and completeness of the data and adherence to the study protocol, which is fully accessible in Supplementary Note 1.

Patients aged 18 years or older with de novo MET amplifications and/or overexpression, EGFR-mutant, histologically or cytologically confirmed locally advanced or metastatic NSCLC who had not received any systemic anti-cancer therapy were enrolled. All patients had measurable disease based on computed tomography (CT) or magnetic resonance imaging (MRI) in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines and an Eastern Cooperative Oncology Group (ECOG) or World Health Organization performance status of 0–1. Adequate liver function was required during screening. MET overexpression was defined as an IHC score of 3+ in at least 75% of tumor cells, based on our previous research. MET amplification was assessed by FISH with a MET GCN of ≥5, or MET/centromere-enriched protein 7 (CEP7) ratio of ≥2, or by NGS of tumor tissue, with ≥20% of tumor cells sequenced at a depth of ≥200× showing a copy number of ≥531,32. The complete eligibility criteria are listed in the Supplementary Note 1. Sex was recorded based on self-report.

Randomisation and masking
Patients were stratified according to the smoking status (yes, no), and EGFR mutation status (19 exon, 21 exon, other mutations) and randomly assigned (1:1) centrally using a computer-generated sequence with a minimization of dynamic randomization method developed by Guangdong Clinical Trial Association to receive either 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 enrollment of patients and assignment to trial cohorts were conducted by the investigators. There was no masking in this open-label study.

Procedures
Patients in cohort 1 who had disease progression with confirmed MET amplification and/or overexpression were allowed to crossover to cohort 2. In cohort 2, if one drug was discontinued due to AEs, the other drug was continued as a monotherapy.

Baseline ctDNA was analyzed using the OncoSonar liquid biopsy test (Genetron Health Co., Ltd, China). Prior to the study treatment, 10 mL of blood samples were collected into Streck Cell-Free DNA Tubes. cfDNA was extracted using the MagMAX Cell-Free DNA Isolation Kit (Life Technologies) on the Kingfisher automated platform, and then quantified with a Qubit 2.0 Fluorometer (dsDNA HS assay, Life Technologies).

ctDNA analysis was performed on plasma ctDNA using the Onco Sonar liquid biopsy assay (Genetron Health Co., Ltd, China, catalog number RSN123), a hybrid capture–based NGS panel covering 172 cancer-related genes. NGS libraries were prepared with UMI barcodes to minimize the occurrence of sequencing artifacts. Then, the sequencing process was performed on the Genetron S2000 platform. The minimum depth across all targeted genes exceeded 20,000×, with depth exceeding 30,000× achieved for known hotspot regions. EGFR exon 19 deletions were further filtered if detected at a variant allele frequency (VAF) of ≥0.5%, supported by a minimum of two independent cfDNA fragments. The assessment of MET amplification was conducted through a read-depth analysis, which was then compared to a panel of normal plasma controls. Amplification was defined as a depth ratio ≥1.15 and a z-score ≥3. In order to systematically characterize the genomic co-mutation landscape, all detected variants were evaluated across the 172-gene panel to identify additional genomic alterations. Finally, co-occurring mutations were summarized at the gene level to determine the prevalence of alterations within the patient cohort. The top three co-mutated genes detected in all these patients were further described in the results section.

Outcomes
The primary endpoint was the confirmed ORR assessed by the investigators. Key secondary endpoints included PFS, DoR, DCR, OS, and safety. Definitions for secondary endpoints are provided in the statistical analysis plan (SAP). Subgroup analyses were conducted across various patient populations based on baseline demographic and clinical characteristics.

Safety was assessed from the time of informed consent to 30 days post-final dose. AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for AEs, version 5.0. TRAEs were determined by investigators. Baseline tumor assessments included CT or MRI scans of the chest and abdomen, covering the liver and adrenal glands. Tumor assessments were performed at week 4 (±7 days) and then every 8 weeks from treatment initiation until objective disease progression per RECIST 1.1 criteria.

Statistical analysis
No hypothesis testing was planned for this study, as all analyses were primarily descriptive. All analyses will be conducted based on the full analysis set (all randomized patients) unless specified otherwise. Based on expected ORRs of 44% for osimertinib monotherapy and 65% for the combination therapy, 22 subjects in each cohort, assuming a 10% dropout rate, will yield the specified precision using Clopper-Pearson’s exact method. Two analyses were planned: The first analysis focused on the primary endpoint of ORR, which was completed after all patients had two efficacy assessments (anticipated 12 weeks post-enrollment of the last patient). The second analysis focused on PFS, with a cutoff of approximately 40-month post-enrollment of the last patient based on a target PFS data maturity of 80%. Detailed analysis plans are described in the SAP.

Baseline demographics and clinical characteristics were summarized by treatment cohort. All variables were analyzed using descriptive statistical methods. Continuous variables were summarized by the number of observations, mean, standard deviation, median, minimum, and maximum values. Categorical variables were summarized as frequencies and percentages for each category. The ORR, DCR, and their 95% CIs were descriptively summarized by cohort with percentages and 95% CIs estimated using the Clopper-Pearson method. The Kaplan-Meier method was used to estimate the median PFS. The number of patients, number of events, median and quartile PFS, PFS rates, and their 95% CIs at predefined landmarks were reported by cohort. AEs were summarized by the MedDRA system organ class and the preferred term. Statistical analysis of clinical data were performed using SAS version 9.4.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "No major comments or revisions.\nPlease check again uniformity of nomenclature (italicized gene names).", "reviewer_2": "The Authors should be acknowledged for their original research manuscript \"Osimertinib with or without savolitinib as first-line treatment for MET-aberrant, EGFR-mutant NSCLC (FLOWERS; CTONG2008): a randomized, multicenter, open-label, non-comparative, phase 2 trial\".\nThis randomized, open-label, non-comparative phase II trial has addressed double oncogene addiction targeting in the first-line setting with very promising results. However, small sample size and trial design, which was descriptive only, with no statistical hypothesis undertaken, overall dampen the strength of the - notable - observed results. This represents an intrinsic feature of the clinical trial which cannot be amended or modified post-hoc.\nNo major comments or revisions.\nPlease check again uniformity of nomenclature (italicized gene names).", "reviewer_3": "This is randomized phase 2 study FLOWERS assessing osimertinib or osimertinib plus Savolitinib for patients with EGFR-mutant lung cancer and de novo MET amplification or overexpression. Primary endpoint was overall response rate with secondary endpoint of PFS and safety. In the monotherapy cohort 1 group the ORR was 60.9%, DCR 87%, mPFS 9.3mo and in the combination cohort 2, the ORR was 90.5%, DCR 95.2% and mPFS 19.6mo. 44 patients total, 23 in cohort 1, 21 in cohort 2.\nThis is an important study since MET signalling drives resistance to EGFR therapy, there is a solid rationale for assessing this combination as 1L treatment. The study was small and did not have a preconceived statistical plan. Further studies are needed to decide on whether this should be standard treatment. For feasibility, it is important to note how many patients were screened to enroll 44 patients.\nComments\n• Introduction can also mention have MET amplification/overexpression is a common mechanisms of resistance to osimertinib so combination treatment upfront can be helpful in preventing MET directed resistance\n• Is there any data as to how many patients with EGFR-mutant lung cancer were screened to identify 45 with de novo MET amp/overexpression? That is an important frequency that is not mentioned in the text.\n• In the text I would specifically state how many patients had MET amplification vs overexpression and the overlap between the two.\n• TP53 and RB1 alterations seem enriched in this population. Is there any association with MET, TP53 and RB1?\n• Data cutoff date was 14 months ago with more than half of patients on treatment still. Can this data be updated? The efficacy data might have changed significantly with these additional possible events. The median follow up was very short. The maturity of the endpoints esp PFS was low.\n• 2 patients had primary progressive disease on osimertinib and subsequent PR when switched to combination therapy- would like to know more about these patients in regards to continued response on osimertinib for how long? Also, any other risk factors that support primary progressive disease? The authors discuss one of the patients with primary progression in the discussion but do not mention the other- both should be discussed in more detail.\n• The authors state that “dual-target therapy… improve convenience and reduces hospital and ambulatory care resources, line 209” The authors likely mean ORAL targeted therapy and so this should be clarified\n• the authors discuss the relevant MET cutoffs for amplification and IHC, but do not relate the discussion to their criteria. Did the criteria change over time? Was it challenging to find patients? Do they have any suggestions for future studies in this space\n• The authors enrolled only 44 patients and I believe the study stopped early due to challenges with enrollments. The discussion does not mention this at all and it is a critical point for the feasibility of this kind of combination treatment. It is clear that this is beneficial for patients with MET overexpression or MET amplification at baseline, but the challenge is these patients are challenging to find. Other methods to identify patients with MET dependence or “other drivers” is needed and the authors should discuss this in more detail in the discussion.\n• Can the authors do a analysis to see if any of the Table 1 characteristics are unbalanced between the arms\n• Figure S4 title is radiographic response in a typical patient in cohort 1; since this is primary progression would note this is an ATYPICAL patient and might just state in title that this is a patient with primary progression on osimertinib with response to the combination\n• Table S2 displays the MET testing results. Can the authors provide how many patients with MET amplification have MET pos IHC and vice versa? Would like to know the overlap between the two biomarkers"}, "author_response": "We would like to thank the editors and the reviewers for their detailed and thoughtful comments on our submission. In our resubmission, we have carefully considered all the points raised and revised the manuscript accordingly. A point-by-point response to all reviewer comments was provided. Specifically, in accordance with your request, we have included the additional ad-hoc follow-up analyses, including the addition of progression-free survival (PFS) and overall survival (OS) with a cutoff date of 11 Aug, 2025, as requested by Reviewer #3 (Comment 5). All changes in the revised manuscript were clearly marked using highlighted text. We appreciate the opportunity to revise and resubmit our work, and we look forward to your further consideration.\nReviewer #1:\n==========\nNo comments.\nResponse:\nWe are grateful to the reviewer for his/her assessment of our work and his/her support in recommending the manuscript without additional revisions.\nReviewer #2:\n==========\nComment 1:\nThe Authors should be acknowledged for their original research manuscript \"Osimertinib with or without savolitinib as first-line treatment for MET-aberrant, EGFR-mutant NSCLC (FLOWERS; CTONG2008): a randomized, multicenter, open-label, non-comparative, phase 2 trial\".\nThis randomized, open-label, non-comparative phase II trial has addressed double oncogene addiction targeting in the first-line setting with very promising results. However, small sample size and trial design, which was descriptive only, with no statistical hypothesis undertaken, overall dampen the strength of the - notable - observed results. This represents an intrinsic feature of the clinical trial which cannot be amended or modified post-hoc.\nNo major comments or revisions.\nPlease check again uniformity of nomenclature (italicized gene names).\nResponse:\nWe sincerely thank the reviewer for their supportive and encouraging comments regarding our study. As suggested, we have carefully reviewed the manuscript to ensure uniformity of nomenclature, and all gene names are now consistently italicized (Lines 3, 7, 47, 67, 78, 83, 85, 122, 147, 148, 218, 221, 272, 280, 292, 521, 523).\nReviewer #3:\n==========\nThis is randomized phase 2 study FLOWERS assessing osimertinib or osimertinib plus Savolitinib for patients with EGFR-mutant lung cancer and de novo MET amplification or overexpression. Primary endpoint was overall response rate with secondary endpoint of PFS and safety. In the monotherapy cohort 1 group the ORR was 60.9%, DCR 87%, mPFS 9.3mo and in the combination cohort 2, the ORR was 90.5%, DCR 95.2% and mPFS 19.6mo. 44 patients total, 23 in cohort 1, 21 in cohort 2.\nThis is an important study since MET signalling drives resistance to EGFR therapy, there is a solid rationale for assessing this combination as 1L treatment. The study was small and did not have a preconceived statistical plan. Further studies are needed to decide on whether this should be standard treatment. For feasibility, it is important to note how many patients were screened to enroll 44 patients.\nComment 1: Introduction can also mention have MET amplification/overexpression is a common mechanisms of resistance to osimertinib so combination treatment upfront can be helpful in preventing MET directed resistance.\nResponse:\nWe thank the reviewer for this suggestion. We have revised the Introduction (see Lines 122-125) to mention that MET amplification or overexpression is a mechanism of resistance to osimertinib, which provides a rationale for evaluating the combination therapy as a first-line treatment.\nRevised text:\nMET amplification or overexpression is a mechanism of resistance to osimertinib, providing a rationale for evaluating the combination of osimertinib with savolitinib as a first-line treatment to potentially reduce MET-driven resistance.\nComment 2: Is there any data as to how many patients with EGFR-mutant lung cancer were screened to identify 45 with de novo MET amp/overexpression? That is an important frequency that is not mentioned in the text.\nResponse:\nThank you for your comment. Patients with MET amplification and/or overexpression who met the definition of study requirement identified by prospective tumor tissue testing (FISH, NGS, IHC) were referred to participate in this study. A corresponding clarification has been included in the Results section (Lines 133-136). However, systematic screening data across all participating centers were not collected in a standardized manner and therefore we cannot provide the precise number of patients screened. We will make efforts to collect the relevant data in subsequent research.\nRevised text:\nPatients with MET amplification and/or overexpression who met the definition of study requirement identified by prospective tumor tissue testing (fluorescence in situ hybridization [FISH], next-generation sequencing [NGS], or immunohistochemistry [IHC]) were referred to participate in this study.\nComment 3: In the text I would specifically state how many patients had MET amplification vs overexpression and the overlap between the two.\nResponse:\nWe thank the reviewer for this helpful suggestion. We have now clarified in the Results section (Lines 146-148) the number of patients with MET amplification, the number with MET overexpression, and the degree of overlap between these two groups. Specifically, 6 patients had MET amplification, 36 patients had MET overexpression, and 2 patients had both alterations.\nRevised text:\nIn addition, 36 patients (81.8%) had MET overexpression, 6 patients (13.6%) had MET amplification, and 2 patients (4.5%) had both MET amplification and overexpression.\nComment 4: TP53 and RB1 alterations seem enriched in this population. Is there any association with MET, TP53 and RB1?\nResponse:\nWe thank the reviewer for this important observation. In our analysis, we reported all detected baseline ctDNA variants, which may appear higher than studies restricted to pathogenic variants only. For comparability, we have re-tabulated pathogenic variants and provided a comparison between FLOWERS with first-line EGFR-mutant trials not enriched for MET-aberrant. As expected by design, FLOWERS was enriched for de novo MET-aberrant, MET amplification occurred in 13.6% in FLOWERS vs 1.2% in FLAURA2 and 0.3% in MARIPOSA.\nTable. Baseline pathogenic variants in FLOWERS vs. other first-line EGFRm NSCLC trials\nVariants, n (%) FLOWERS (n = 44) FLAURA2 (n = 167)1 MARIPOSA (n = 636)2\nMET amplification 10 (22.7) 2 (1.2) 2 (0.3)\nTP53 18 (40.1) 62 (37.1) 293 (46.1)\nRB1 3 (6.8) 6 (3.6) 22 (3.5)\n1. Yang, J.C., et al., MA12.03 FLAURA2: Resistance, and Impact of Baseline TP53 Alterations in Patients Treated With 1L Osimertinib ± Platinum-Pemetrexed. Journal of Thoracic Oncology, 2024. 19(10): p. S101–S102.\n2. Felip, E. et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA. Annals of Oncology 35, 805–816 (2024).\nDespite the MET-aberrant enrichment, the frequencies of TP53 (40.9%) and RB1 (6.8%) in the FLOWERS study were comparable to those reported in first-line EGFR-mutant trials without such enrichment. Specifically, no statistically significant differences (Fisher’s exact test) were observed when compared with FLAURA2 (TP53 37.1%, p = 0.727; RB1 3.6%, p = 0.399) or MARIPOSA (TP53 46.1%, p = 0.535; RB1 3.5%, p = 0.215). These findings indicate that enrichment for MET aberrations in FLOWERS did not lead to concomitant enrichment of TP53 or RB1 alterations.\nComment 5: Data cutoff date was 14 months ago with more than half of patients on treatment still. Can this data be updated? The efficacy data might have changed significantly with these additional possible events. The median follow up was very short. The maturity of the endpoints esp PFS was low.\nResponse:\nWe thank the reviewer for this important suggestion. In our clinical trial protocol, only two analyses were pre-specified: the primary analysis focused on the primary endpoint of ORR, which was completed after all patients had two efficacy assessments, and the second analysis focused on PFS, with a cutoff of approximately 40-month post-enrollment of the last patient based on a target PFS data maturity of 80%. Therefore, additional data updates were not planned in the original study design. Nevertheless, in response to the reviewer’s comment, we have conducted ad-hoc analysis for PFS with a cutoff date of 11 Aug, 2025. The median follow-up time was 22.4 months (95% CI, 19.9–24.9). The updated median PFS was 11.2 (4.0-18.4) months in cohort 1 and 22.6 (13.1-32.1) months in cohort 2, with maturity of 73.9% and 52.4%, respectively. The data maturity for OS was 25%.\nFigure. Kaplan-Meier curves for progression-free survival.\nComment 6: 2 patients had primary progressive disease on osimertinib and subsequent PR when switched to combination therapy- would like to know more about these patients in regards to continued response on osimertinib for how long? Also, any other risk factors that support primary progressive disease? The authors discuss one of the patients with primary progression in the discussion but do not mention the other- both should be discussed in more detail.\nResponse:\nThank you for your valuable comment. We agree that it is necessary to provide further clarification regarding the two patients who experienced primary progressive disease (PD) during osimertinib monotherapy and subsequently achieved partial response (PR) after transitioning to combination therapy. We have added in the Discussion section (Lines 218-230)\nPatient #01023: A 62-year-old male (ECOG PS 1) with stage IVB adenocarcinoma of the right lower lung lobe (cT4N3M1c), with multiple metastases involving the lungs, brain, bones, liver, and eyes. Biomarkers: MET IHC 3+ (95%), PD-L1 80%, EGFR exon 19 deletion (+) and MET CN by NGS (3.4). Randomly assigned to Cohort 1, the patient experienced PD at the first efficacy assessment (week 4). He subsequently crossed over to Cohort 2 and achieved PR, but discontinued after 3 months due to a threefold elevation in grade 3 ALT. On subsequent self-administered dual-targeted therapy, PFS2 was 11.4 months.\nPatient #01019: A 54-year-old male (ECOG PS 1) with stage IVA adenocarcinoma of the right lower lung lobe (cT1cN2M1a, pleural metastasis). Biomarkers: MET IHC 3+ (95%), EGFR exon 19 deletion (+), and PD-L1 20%. Randomly assigned to Cohort 1, the patient achieved SD (−28%) with a PFS of 6.4 months. After progression, he crossed over to cohort 2 and remained PR for more than 1 year at the data cutoff date.\nWe have revised the Discussion sections to include both cases in detail, highlighting their baseline characteristics, initial responses, and outcomes following crossover to combination therapy.\nRevised text:\nNotably, one patient in the osimertinib monotherapy cohort (62-year-old male, ECOG PS 1, stage IVB adenocarcinoma, cT4N3M1c, with extensive metastases; biomarkers: MET IHC 3+ [95%], PD-L1 [80%], EGFR exon 19 deletion [+], MET CN by NGS [3.4]) experienced disease progression within the first four weeks, which was subsequently confirmed as MET overexpression (100% 3+). Following the study protocol, this patient transitioned to combination therapy and achieved PR (Figure S4). The patient discontinued study treatment after 3 months due to a threefold elevation in grade 3 ALT, but on subsequent self-administered dual-targeted therapy, achieved a PFS of 11.4 months. Another patient in the osimertinib monotherapy cohort (54-year-old male, ECOG PS 1, stage IVA adenocarcinoma, cT1cN2M1a, with pleural metastasis; biomarkers: MET IHC 3+ [95%], EGFR exon 19 deletion [+], PD-L1 20%) achieved SD (−28%) with a PFS of 6.4 months. After progression, he crossed over to cohort 2 and remained in PR for more than 1 year at the data cutoff date.\nComment 7: The authors state that “dual-target therapy… improve convenience and reduces hospital and ambulatory care resources, line 209” The authors likely mean ORAL targeted therapy and so this should be clarified.\nResponse:\nWe thank the reviewer for this helpful clarification. Our intention was indeed to emphasize the convenience of oral targeted therapy compared with intravenous regimens. We have revised the text accordingly in the Discussion (Lines 214).\nRevised text:\nAdditionally, oral dual-targeted therapy provides psychological benefits, improves daily life convenience, and reduces the utilization of hospital and ambulatory care resources.\nComment 8: The authors discuss the relevant MET cutoffs for amplification and IHC, but do not relate the discussion to their criteria. Did the criteria change over time? Was it challenging to find patients? Do they have any suggestions for future studies in this space.\nResponse:\nWe appreciate the reviewer’s insightful comment. The eligibility criteria for MET amplification and IHC positivity were predefined in the study protocol and remained unchanged throughout the trial. As the reviewer points out, there is currently no universally accepted standard for defining MET amplification or overexpression. The prevalence of de novo MET amplification and/or MET overexpression in EGFRm treatment-naïve advanced NSCLC patients is low based on previous literature reported, the patient identification is challenging. We have revised the Discussion (Lines 254–261) to clarify how our trial criteria relate to the broader debate on MET cutoffs and to emphasize the need for harmonized definitions in future studies.\nRevised text:\nThese findings highlight the value of precise patient selection and treatment strategies to improve outcomes in advanced NSCLC patients with EGFR mutations and de novo MET amplification and/or overexpression, signifying a potential benefit for this NSCLC subtype. In summary, the establishment of standardized MET testing criteria, coupled with refined biomarker strategies, will be critical for improving patient selection and ensuring the reproducibility and clinical applicability of such combination regimens in subsequent studies.\nComment 9: The authors enrolled only 44 patients and I believe the study stopped early due to challenges with enrollments. The discussion does not mention this at all and it is a critical point for the feasibility of this kind of combination treatment. It is clear that this is beneficial for patients with MET overexpression or MET amplification at baseline, but the challenge is these patients are challenging to find. Other methods to identify patients with MET dependence or “other drivers” is needed and the authors should discuss this in more detail in the discussion.\nResponse:\nWe thank the reviewer for this comment. In our study, enrollment was completed after reaching the target sample size pre-specified in the study protocol (44 patients), rather than being terminated early. We acknowledge these enrollment challenges and emphasize that future studies will require not only harmonized MET testing criteria but also the integration of broader biomarker strategies to more effectively identify patients with MET dependence or alternative oncogenic drivers. We have revised the discussion accordingly to address these important considerations (Lines 258-261).\nComment 10: Can the authors do a analysis to see if any of the Table 1 characteristics are unbalanced between the arms.\nResponse:\nThank you for your insightful comment. We would like to clarify that patients were randomized using a stratified approach based on smoking status and EGFR mutation status. As outlined in the study design, the analyses were descriptive only, and no statistical hypothesis testing was undertaken. Nevertheless, we performed statistical tests to evaluate the distribution of baseline characteristics between the two groups and the results showed that no imbalance was observed between the two groups.\nTable. Baseline demographics and clinical characteristics of the patients.\nCohort 1 Cohort 2 Total P\nCharacteristic\n(n = 23) (n = 21) (n = 44)\nAge, median (range), years 62.0 (40.0–74.0) 56.0 (29.0–72.0) 58.0 (29.0–74.0) 0.249\nSex 0.232\nMale 14 (60.9) 9 (42.9) 23 (52.3)\nFemale 9 (39.1) 12 (57.1) 21 (47.7)\nECOG PS score 0.403\n0 2 (8.7) 4 (19.0) 6 (13.6)\n1 21 (91.3) 17 (81.0) 38 (86.4)\nSmoking history 1.000\nNever Smoked 15 (65.2) 14 (66.7) 29 (65.9)\nFormer Smoker 7 (30.4) 7 (33.3) 14 (31.8)\nCurrently Smoking 1 (4.3) 0 (0.0) 1 (2.3)\nHistological subtype 0.733\nAdenocarcinoma 22 (95.7) 20 (95.2) 42 (95.5)\nAdenosquamous 0 (0.0) 1 (4.8) 1 (2.3)\nCarcinoma\nSquamous Cell 1 (4.3) 0 (0.0) 1 (2.3)\nCarcinoma\nClinical stage 0.222\nIIIB 0 (0.0) 2 (9.5) 2 (4.5)\nIV 23 (100.0) 19 (90.5) 42 (95.5)\nBrain Metastasis 0.222\nNo 15 (65.2) 14 (66.7) 29 (65.9)\nYes 8 (34.8) 5 (23.8) 13 (29.6)\nUnknown 0 (0.0) 2 (9.5) 2 (4.5)\nEGFR mutation 0.898\nL858Ra 10 (43.5) 9 (42.9) 19 (43.2)\nL858R + uncommonb 0 (0.0) 1 (4.8) 1 (2.3)\nOnly uncommonc 2 (8.7) 1 (4.8) 3 (6.9)\nMET aberrant 0.649\nMET OE 20 (87.0) 16 (76.2) 36 (81.8)\nMET Amp 2 (8.7) 4 (19.0) 6 (13.6)\nCohort 1 Cohort 2 Total P\nCharacteristic\n(n = 23) (n = 21) (n = 44)\nMET Amp & OE 1 (4.3) 1 (4.8) 2 (4.5)\nComment 11: Figure S4 title is radiographic response in a typical patient in cohort 1; since this is primary progression would note this is an ATYPICAL patient and might just state in title that this is a patient with primary progression on osimertinib with response to the combination.\nResponse:\nWe thank the reviewer for this helpful suggestion. We have revised the title of Figure S4 to clarify that this patient experienced primary progression on osimertinib and subsequently responded to combination therapy. The updated figure title now reads: “Radiographic response in a patient with primary resistance on osimertinib achieving response to combination therapy.”\nComment 12: Table S2 displays the MET testing results. Can the authors provide how many patients with MET amplification have MET pos IHC and vice versa? Would like to know the overlap between the two biomarkers.\nResponse:\nWe thank the reviewer for this insightful comment. We have now analyzed the overlap between MET amplification and MET positive IHC among the enrolled patients. Specifically, 2 patients with MET amplification also had MET positive IHC. This information has been added to the Results section (Lines 146-148).\nRevised text:\nIn addition, 36 patients (81.8%) had MET overexpression, 6 patients (13.6%) had MET amplification, and 2 patients (4.5%) had both MET amplification and overexpression.\nWe tried our best to improve the manuscript and made some changes in the manuscript.\nWe sincerely appreciate the time and effort that the reviewers have invested in evaluating our manuscript. We are eager to receive any additional feedback or suggestions that may further enhance our work."}, {"round": 2, "reviewer_comments": {"reviewer_3": "The authors have thoroughly address my comments and the manuscript is stronger. I especially appreciate the updated data cut off for PFS."}, "author_response": ""}]

Decision letter