Efficacy and safety of first-line osimertinib in Chinese patients with <i>EGFR</i>-mutated advanced non-small cell lung cancer: a prospective, multicenter, non-interventional study (FLOURISH)

Efficacy and safety of first-line osimertinib in Chinese patients with EGFR-mutated advanced non-small cell lung cancer: a prospective, multicenter, non-interventional study (FLOURISH)

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Lisha Shen¹, Dongqing Lv², Ke-Jing Tang³, Jun Zhao⁴, Dan Zhu⁵, Yanqiu Zhao⁶, Ke Wang⁷, Yan Wang⁸, Zhigang Cai⁹, Ligang Xing¹⁰, Ke Xie¹¹, Jiuwei Cui¹², Lin Mu¹³, Chao Cao¹⁴, Liren Ding¹⁵, Peifeng Chen¹⁶, Jun Liang¹⁷, Yongmin Ding¹⁸, Liqin Lu¹⁹, Jiliang Zhang²⁰, Xinmin Yu²¹, Li Chen²², Jing Zheng¹, Jianya Zhou¹, Jianying Zhou¹

Cancer Biology & Medicine | 2026, 23(8) : 1156 - 1166

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Cancer Biology & Medicine | 2026, 23(8): 1156-1166

• Original Article •

Efficacy and safety of first-line osimertinib in Chinese patients with EGFR-mutated advanced non-small cell lung cancer: a prospective, multicenter, non-interventional study (FLOURISH)

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Affiliations

¹Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China

²Department of Respiratory Disease, Affiliated Taizhou Hospital of Zhejiang Province of Wenzhou Medical University, Taizhou 318000, China

³Department of Respiratory Disease, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China

⁴Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China

⁵Jinhua Municipal Central Hospital, Jinhua 321000, China

⁶The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

⁷West China Hospital of Sichuan University, Chengdu 610041, China

⁸Tumor Hospital Affiliated to Harbin Medical University, Harbin 150081, China

⁹The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China

¹⁰Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan 250014, China

¹¹Sichuan Provincial People’s Hospital, Chengdu 610072, China

¹²The First Hospital of Jilin University, Changchun 130021, China

¹³Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China

¹⁴The First Affiliated Hospital of Ningbo University, Ningbo 315010, China

¹⁵The Second Affiliated Hospital (Binjiang Campus), School of Medicine, Zhejiang University, Hangzhou 310022, China

¹⁶Zhuji People’s Hospital, Zhuji 311800, China

¹⁷Peking University International Hospital, Beijing 102206, China

¹⁸Shengzhou People’s Hospital, Shengzhou 312400, China

¹⁹Zhejiang Provincial People’s Hospital, Hangzhou 310014, China

²⁰Chengdu Seventh People’s Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu 610072, China

²¹Zhejiang Cancer Hospital, Hangzhou 310022, China

²²The First Affiliated Hospital of Nanchang University, Nanchang 330006, China

About Author:

Author contributions

Conceived and designed the analysis: Lisha Shen, Dongqing Lv, Ke-Jing Tang, Jianya Zhou, Jianying Zhou.

Collected the data: Lisha Shen, Dongqing Lv, Ke-Jing Tang, Jun Zhao, Dan Zhu, Yanqiu Zhao, Ke Wang, Yan Wang, Zhigang Cai, Ligang Xing, Ke Xie, Jiuwei Cui, Lin Mu, Chao Cao, Liren Ding, Peifeng Chen, Jun Liang, Yongmin Ding, Liqin Lu, Jiliang Zhang, Xinmin Yu, Li Chen, Jing Zheng, Jianya Zhou.

Contributed data or analysis tools: Lisha Shen, Dongqing Lv, Ke-Jing Tang, Jing Zheng, Jianying Zhou.

Performed the analysis: Lisha Shen, Jing Zheng.

Wrote the article: Lisha Shen, Dongqing Lv, Ke-Jing Tang, Jianya Zhou, Jianying Zhou.

Published: 2026-08-15 doi: 10.20892/j.issn.2095-3941.2025.0566

Outline

Abstract

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Objective:

Osimertinib has demonstrated superior efficacy as a first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) in clinical trials. This study was aimed at providing real-world evidence of osimertinib treatment in Chinese populations.

Methods:

This prospective, multicenter, non-interventional study was conducted from July 27, 2020, to April 27, 2022. Treatment-naïve adults (≥18 years of age) with locally advanced or metastatic EGFR-mutated NSCLC scheduled to receive first-line osimertinib were included. Of 507 patients screened, 481 were eligible in the full analysis set. The primary endpoint was time to treatment discontinuation (TTD). Secondary endpoints included real-world progression-free survival (rwPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.

Results:

Among 481 patients (median age 64.1 years; 62.2% women), the median follow-up was 31.3 months. The mTTD was 24.6 months (95% CI, 22.4–26.7), the median rwPFS was 19.4 months (95% CI, 16.2–20.4), and the mOS was 41.0 months [95% CI, 39.7 to not reached (NR)]. The mOS was 43.1 months (95% CI, 39.7 to NR) in FLAURA-eligible patients vs. 33.5 months (95% CI, 26.8 to NR) in FLAURA-ineligible patients. The mOS was 29.3 months (95% CI: 25.4 to NR) in patients with co-mutations vs. NR (95% CI: 32.9 to NR) in the cohort with EGFR-only mutations. Adverse events occurred in 71.7% of patients, and grade ≥3 events occurred in 11.4%. The safety profiles were similar between FLAURA-eligible and ineligible patients.

Conclusions:

First-line osimertinib demonstrated robust effectiveness and manageable safety in real-world Chinese patients with EGFR-mutated advanced NSCLC, including those ineligible for clinical trials. Patients with co-mutations showed diminished clinical benefit, thus suggesting a potential need for intensified treatment strategies in this population.

Key words

Osimertinib / epidermal growth factor receptor / non-small cell lung cancer / real-world / co-mutations

Cite this Article

Lisha Shen, Dongqing Lv, Ke-Jing Tang, Jun Zhao, Dan Zhu, Yanqiu Zhao, Ke Wang, Yan Wang, Zhigang Cai, Ligang Xing, Ke Xie, Jiuwei Cui, Lin Mu, Chao Cao, Liren Ding, Peifeng Chen, Jun Liang, Yongmin Ding, Liqin Lu, Jiliang Zhang, Xinmin Yu, Li Chen, Jing Zheng, Jianya Zhou, Jianying Zhou. Efficacy and safety of first-line osimertinib in Chinese patients with EGFR-mutated advanced non-small cell lung cancer: a prospective, multicenter, non-interventional study (FLOURISH)[J]. Cancer Biology & Medicine, 2026 , 23 (8) : 1156 -1166 . DOI: 10.20892/j.issn.2095-3941.2025.0566

Full Text

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Introduction

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Lung cancer is the leading cause of cancer-related mortality in China¹. More than 50% of Asian patients with non-small cell lung cancer (NSCLC) exhibit epidermal growth factor receptor (EGFR) mutations^2,3. Osimertinib, a third-generation EGFR-TKI, was approved as a first-line (1L) treatment for patients with EGFRm NSCLC, according to results from the FLAURA study. In that study, osimertinib, compared with erlotinib or gefitinib, significantly prolonged the median progression-free survival (PFS) [18.9 vs. 10.2 months; hazard ratio (HR), 0.46; 95% confidence interval (CI), 0.37–0.57; P < 0.001]⁴. Similarly, in the FLAURA China study enrolling exclusively Chinese patients, osimertinib demonstrated a longer median PFS (mPFS) than first-generation EGFR-TKIs (17.8 vs. 9.8 months; HR, 0.56; 95% CI, 0.37–0.85)⁵.

However, clinical trials differ from real-world practice because the latter often involves older patients or individuals with more comorbidities. For example, in a real-world study in the United States, 55% of patients were classified as FLAURA-ineligible and experienced shorter median osimertinib time to treatment discontinuation (TTD) than FLAURA-eligible populations (12.2 vs. 31.1 months)⁶. Therefore, prospective real-world studies with larger sample sizes are needed to validate the effectiveness and safety of osimertinib among Chinese patients with NSCLC with EGFR mutations in real-world settings.

In recent years, real-world studies have preliminarily confirmed the effectiveness and safety of osimertinib initiated in patients with EGFRm NSCLC^7–10. Although existing real-world investigations have provided preliminary insights, several limitations remain. First, the predominance of retrospective study designs introduced inherent selection bias. Second, the limited sample sizes in the current published prospective real-world evidence have left unresolved questions, particularly regarding clinical efficacy in subgroups such as patients with EGFR co-mutations or those not meeting FLAURA criteria. These gaps further underscore the need for prospective, multicenter investigations.

Materials and methods

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Study design and patients

The FLOURISH study (NCT04391283) was a prospective, multicenter, non-interventional study conducted at 22 sites across China. All participating centers were tertiary care academic hospitals with expertise in thoracic oncology. Eligible patients were ≥18 years of age and had a histological or cytological diagnosis of locally advanced or metastatic NSCLC bearing EGFR mutations. Patients were treatment naïve and were scheduled to receive 1L osimertinib (80 mg once daily). Diagnosis and treatment decisions were made by clinical physicians according to treatment guidelines and clinical practice. Patients participating in other interventional clinical trials aimed at treating locally advanced or metastatic NSCLC and patients with concomitant conditions considered unsuitable for osimertinib by their physicians were excluded. The study protocol was approved by the institutional ethics committee at each participating center. All patients provided written informed consent to participate. Baseline data were obtained from hospital records and were therefore subject to potential missingness; missing data were not imputed, and cases with missing data were not excluded (trial registration No. NCT04391283).

Endpoints

The primary endpoint was TTD, defined as the time from the first dose of osimertinib to the date of osimertinib discontinuation for any reason. Secondary endpoints included real-world progression-free survival (rwPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. rwPFS was defined as the time from the first dose of osimertinib until disease progression recorded in the CRF or death, whichever occurred first. Disease progression was assessed by investigators according to real-world clinical practice, usually on the basis of the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). OS was defined as the time from the first dose of osimertinib to death due to any cause. ORR was defined as the percentage of patients achieving a complete or partial response, as assessed by investigators and recorded in the CRF. DCR was defined as the percentage of patients with non-progression, as assessed by investigators and recorded in the CRF.

Tumor response was evaluated according to RECIST v1.1 criteria by the investigators. Safety and tolerability assessments included adverse events (AEs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, on the basis of clinical practice.

Next-generation sequencing

Tumor tissue samples were collected at baseline. Next-generation sequencing (NGS) was performed on FFPE tissue and plasma-derived cfDNA samples by using panels from Burning Rock Biotech (Guangzhou, China), the central laboratory in this study. Tissue samples were analyzed with the 518-gene OncoScreen™ Plus system at a sequencing depth of 1,000×. Variant detection and annotation were performed with specialized bioinformatics pipelines.

Statistical analysis

Because this study is descriptive in nature and involved no pre-planned hypotheses, no formal calculation of sample size was performed. A total of 500 patients were planned to be enrolled, on the basis of assumptions of an mTTD of 20.8 months and a 95% CI for the median of approximately 18.6–23.3 months. Therefore, the target enrollment of approximately 500 patients was determined to ensure adequate representation of real-world clinical practice and sufficient precision for descriptive analyses of the primary endpoint.

Statistical analyses were performed in SAS version 9.4. Continuous variables are summarized as numbers of patients (n), mean, standard deviation (SD), median, quartiles (Q1, Q3), minimum, and maximum. Categorical variables are summarized as frequency counts and percentages. No imputation of missing data was performed, and all statistical analyses were conducted on non-missing data only. For ORR and DCR, the 95% CIs were calculated with the Clopper–Pearson exact method. For time-to-event endpoints (TTD, rwPFS, and OS), the Kaplan–Meier method was used to estimate the median, and corresponding 95% CIs were calculated with the Brookmeyer–Crowley method. To further explore osimertinib’s efficacy in patients with NSCLC with various disease characteristics, we conducted subgroup analyses. TTD, rwPFS, and OS were analyzed according to EGFRm type (exon 21 L858R vs. exon 19 deletion) and central nervous system (CNS) metastasis (presence vs. absence).

In addition, patients were categorized into FLAURA-eligible and FLAURA-ineligible groups according to the critical inclusion/exclusion criteria from the FLAURA trial (Table S3). On the basis of baseline NGS results, subgroup analyses described outcomes in the EGFR-only mutation group and the EGFR co-mutation group (EGFR mutation combined with additional co-mutations in genes including HER2, KRAS, BRAF, ROS1, ALK, TP53, RB1, or PTEN). Patients were also categorized according to the presence or absence of TP53 co-mutations. TTD, PFS, and OS were calculated for each subgroup. All subgroup analyses were descriptive and were not adjusted for multiplicity, and no formal hypothesis testing was performed for the subgroup analyses.

Results

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From July 27, 2020, to April 27, 2022, a total of 507 patients were screened at 22 sites across China, among whom 481 eligible patients [denoted the full analysis set (FAS)] received at least 1 dose of osimertinib monotherapy as the 1L treatment. At the data cut-off (October 30, 2024), the median follow-up duration was 31.3 months (95% CI: 30.2–32.3).

Patients and treatment

The baseline characteristics of the FAS population are presented in Table 1. The median age was 64.1 years (range: 27.1–88.1). Overall, 62.2% of patients were women, and 76.5% had a performance status (PS) of 0–1. CNS metastases were present in 165 patients (34.3%). The most frequent EGFR-activating mutations were exon 19 deletions (50.9%) and exon 21 L858R mutations (45.9%). De novo T790M mutation was reported in 10 patients (2.1%).

Effectiveness evaluation

Overall effectiveness

At the data cut-off, 426 (88.6%) of 481 patients had tumor response evaluations. ORR and DCR were calculated for both the FAS and the evaluable population. The evaluable population analysis served as a sensitivity analysis to assess the robustness of response outcomes. For the FAS, the ORR was 56.3% (271/481; 95% CI: 51.8–60.8), and the DCR was 84.6% (407/481; 95% CI: 81.1–87.7). Among patients with available tumor response data (n = 426), the ORR was 63.6% (271/426; 95% CI: 58.8–68.2), and the DCR was 95.5% (407/426; 95% CI: 93.1–97.3) (Table S4). After a median follow-up of 31.3 months, 267 patients (55.5%) discontinued osimertinib therapy. The median TTD was 24.6 months (95% CI: 22.4–26.7) (Figure 1). Reasons for discontinuation included disease progression (33.3%), death (35.2%), AEs (7.9%), and other factors (23.6%) (Table S2). Progression events occurred in 274 patients (57.0%), and 169 patients (35.1%) died. The median rwPFS was 19.4 months (95% CI: 16.2–20.4), and the mOS was 41.0 months (95% CI: 39.7 to NR) (Figure 1).

Subgroup analysis of effectiveness

For the 245 patients (50.9%) with exon 19 deletion mutations, the median TTD, rwPFS, and OS were 28.6 months (95% CI: 25.2–32.7), 20.6 months (95% CI: 17.7–22.1), and 41.0 months (95% CI: 39.7 to NR), respectively (Figures 2 and S1). Among the 221 patients (45.9%) with exon 21 L858R mutations, the median TTD was 20.5 months (95% CI: 18.3–23.5), the median rwPFS was 15.4 months (95% CI: 13.2–19.5), and the mOS was 37.2 months (95% CI: 30.0 to NR) (Figures 2 and S1).

At baseline, CNS metastases were present in 165 patients (34.3%). For these patients, the median TTD was 22.2 months (95% CI: 19.6–25.7), the median rwPFS was 15.6 months (95% CI: 14.1–20.3), and the mOS was 40.1 months (95% CI: 39.7 to NR) (Figures 2 and S1). For the 207 patients (43.0%) without CNS metastases, the median TTD, rwPFS, and OS were 25.3 months (95% CI: 22.4–29.3), 19.7 months (95% CI: 15.7–21.4), and 41.0 months (95% CI: 36.8 to NR), respectively (Figures 2 and S1).

Additionally, patients in the FAS were categorized as FLAURA-eligible or FLAURA-ineligible according to the inclusion/exclusion criteria outlined in the FLAURA trial protocol⁴ (Table S3). Of these, 159 patients (33.1%) were classified as FLAURA-ineligible (Table S1), and their median TTD, rwPFS, and OS were 21.4 months (95% CI: 17.7–26.8), 15.1 months (95% CI: 12.3–19.4), and 33.5 months (95% CI: 26.8 to NR), respectively (Figures 2 and S1). In the FLAURA-eligible group (n = 266, 55.3%), the median TTD, rwPFS, and OS were 25.6 months (95% CI: 23.3–28.8), 20.4 months (95% CI: 17.6–21.5), and 43.1 months (95% CI: 39.7 to NR), respectively (Figures 2 and S1). The ORR and DCR of each subgroup are shown in Table S5.

Effects of baseline co-mutations on osimertinib treatment efficacy

Baseline NGS data obtained from 118 patients revealed 2 distinct mutation profiles: 23.7% (28/118) patients had only EGFR mutations, whereas 76.3% (90/118) had additional gene co-mutations (in HER2, KRAS, BRAF, ROS1, ALK, TP53, RB1, or PTEN) (Figure 3). In these subgroups, the median TTD was 32.8 months (95% CI: 21.8 to NR) for patients with EGFR mutations alone and 24.6 months (95% CI: 20.2–26.6) for those with co-mutations (Figure 2). The median rwPFS was 20.8 months (95% CI: 7.4–25.1) in patients with only EGFR mutations, compared with 16.7 months (95% CI: 14.6–20.6) in those with co-mutations. Notably, the mOS was NR (95% CI: 32.9 to NR) in the EGFR-only group but was 29.3 months (95% CI: 25.4 to NR) in the co-mutation group (Figures 2 and S1).

Among the 80 (67.8%) patients bearing TP53 co-mutations, the median TTD, rwPFS, and OS were 23.6 months (95% CI: 19.1–26.4) (Figure 2), 16.7 months (95% CI: 14.6–20.6), and 28.5 months (95% CI: 25.3 to NR), respectively (Figure S1). In contrast, for the 38 (32.2%) patients without TP53 co-mutations, the median TTD, rwPFS, and OS were 32.8 months (95% CI: 24.0 to NR) (Figure 2), 20.8 months (95% CI: 9.6–23.7), and NR (95% CI: 32.9 to NR), respectively (Figures 2 and S1). The ORR and DCR of each subgroup are shown in Table S5.

Safety evaluation

In the FAS, 345 patients (71.7%) experienced at least 1 AE, and 252 (52.4%) experienced at least 1 treatment-related AE. Grade ≥3 AEs were reported in 55 patients (11.4%), and serious AEs occurred in 23 patients (4.8%). AEs leading to dose interruption were reported in 3 patients (0.6%), whereas AEs resulting in treatment discontinuation occurred in 22 patients (4.6%). Three patients (0.6%) experienced fatal AEs (Table 2). Among them, 2 fatal AEs (myocardial infarction, pneumonitis) were considered unrelated to the treatment by the investigators; however, the possibility that one fatal AE (myocardial infarction) was treatment related could not be excluded.

The safety profile of patients in the FLAURA-ineligible subgroup (n = 159) was comparable to that in the overall FAS population. In this subgroup, AEs occurred in 114 patients (71.7%), of whom 91 (57.2%) experienced treatment-related AEs. Grade ≥3 events occurred in 21 patients (13.2%), including 12 (7.5%) treatment-related cases. Among patients with PS ≥2 (n = 36), AEs were reported in 27 patients (75.0%), and grade ≥3 events were reported in 5 patients (13.9%).

Discussion

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This study was the first large-scale, prospective, real-world investigation, to our knowledge, examining the outcomes of 1L osimertinib in Chinese patients with EGFRm NSCLC. Patients with poor PS, various comorbidities, and other exclusion criteria from the FLAURA trial were included, thereby confirming the effectiveness and safety of 1L osimertinib in a broader patient population. Furthermore, our findings suggested that patients with co-mutations might experience diminished clinical benefits from osimertinib monotherapy; therefore, intensified treatment strategies might be necessary in these patients.

Our real-world study indicated a median rwPFS of 19.4 months and an mOS of 41.0 months, values comparable to those in the FLAURA trial (mPFS 18.9 months, OS 38.6 months), despite our cohort’s higher baseline CNS metastasis prevalence (34.3% vs. 20.8%) and higher ECOG ≥2 proportion (7.5% vs. 0%)¹¹. These results aligned with those from previous real-world studies. For example, the prospective Reiwa study⁹, in Japanese patients treated with 1L osimertinib, has reported an mPFS of 20 months and mOS of 41 months. Similarly, the retrospective CAPTRA-Lung study¹², in Chinese patients receiving 1L osimertinib, has reported an mPFS of 19.4 months and an mOS of 40.5 months. The prospective FLOWER study¹³, evaluating osimertinib in Italy, has reported an mPFS of 18.9 months. In addition, our real-world study indicated an ORR of 56.3% (95% CI, 51.8–60.8) and a DCR of 84.6% (95% CI, 81.1–87.7) in the FAS. Notably, a substantial proportion of patients lacked tumor response evaluations, thus potentially influencing our estimates. To enhance interpretability, we also calculated ORR and DCR in the evaluable population. Our findings highlight the importance of systematically capturing tumor response assessments to minimize missingness in future real-world studies.

Exploratory subgroup analyses described variations across different patient groups. In our study, the median rwPFS was 19.7 months in patients without CNS metastases and 15.6 months in those with CNS metastases. Additionally, the median rwPFS was 20.6 months in patients bearing exon 19 deletion mutations and 15.4 months in those with exon 21 L858R mutations. These results were consistent with findings from the FLAURA study⁴ and other real-world evidence¹⁴. Collectively, our findings reinforce osimertinib’s position as a 1L therapy for EGFRm NSCLC.

Notably, inherent differences exist between patients in clinical trials vs. real-world practice. Therefore, our exploration of whether patients not meeting FLAURA criteria might still benefit from osimertinib was essential. In a study by Viray et al.⁶, 55% of patients were classified as FLAURA-ineligible, and the mOS was 16.5 months in the FLAURA-ineligible group and NR in the FLAURA-eligible group. In our study, 55.3% (266/481) of patients were classified as FLAURA-eligible, whereas 33.1% (159/481) were classified as FLAURA-ineligible, predominantly because of comorbidities (71.7%) and ECOG ≥2 (22.6%). In the FLAURA-ineligible group, the median TTD, rwPFS, and OS were 21.4 months, 15.1 months, and 33.5 months, respectively. In the FLAURA-eligible group, these values were 25.6 months, 20.4 months, and 43.1 months, respectively. However, the mOS in our FLAURA-ineligible group was longer than that in the FLAURA-ineligible group reported by Viray et al.⁶ This discrepancy might be due to differences in classification criteria between studies. The FLAURA-ineligible subgroup in the retrospective study by Viray et al.⁶ had more severe clinical characteristics and did not include active infections as a criterion. Our study included more patients with active infections in the FLAURA-ineligible group, who might have met FLAURA criteria after antimicrobial treatment, thus potentially leading to improved outcomes. Nonetheless, our findings were consistent with those of Viray et al.⁶ in indicating that patients classified as FLAURA-ineligible can still benefit from osimertinib, although the benefits are greater in FLAURA-eligible patients.

Although osimertinib has demonstrated superior efficacy, the considerable variation in the duration of responses among populations emphasized the need to identify subsets of patients with poorer outcomes who might benefit from more aggressive treatments. Previous studies on first-generation EGFR-TKIs have shown that concomitant gene mutations significantly compromise therapeutic efficacy in EGFRm NSCLC. The BENEFIT study¹⁵ has demonstrated shorter PFS in patients bearing concurrent driver mutations (HR = 1.78) or tumor suppressor gene alterations (HR = 2.66) than in patients with EGFR mutations alone. Hu et al.¹⁶ have also reported inferior outcomes in patients with EGFRm NSCLC with co-mutations in PIK3CA, ALK, HER2, ROS1, or KRAS (mPFS: 6.0 vs. 10.9 months; mOS: 17.6 vs. 21.0 months).

Although the predictive value of co-mutations has been well characterized for first-generation TKIs, the effects of co-mutation profiles on osimertinib efficacy remain inadequately defined. In a previous prospective study, patients with concurrent TP53 mutations or MET amplification experienced worse clinical outcomes than patients without these co-mutations when treated with 1L osimertinib in a real-world setting¹⁷. However, whether other co-mutations might affect osimertinib monotherapy outcomes has not been explored prospectively in real-world studies. To our knowledge, our study is the first prospective real-world analysis exploring the relationship between osimertinib efficacy and co-mutations involving other driver and tumor suppressor genes. Baseline NGS data from 118 patients revealed that 90 (76.3%) had additional gene co-mutations (in HER2, KRAS, BRAF, ROS1, ALK, TP53, RB1, or PTEN). Patients with these co-mutations had shorter median TTD and OS than patients with EGFR mutations alone (mTTD: 24.6 months vs. 32.8 months; mOS: 29.3 months vs. NR). Furthermore, TP53 mutations, which are frequently observed in NSCLC, were detected in 80 (67.8%) of the patients who had baseline NGS data. Patients with TP53 co-mutations had shorter median TTD and OS than those without TP53 mutations. Collectively, our findings suggested that co-mutations might limit clinical benefit from osimertinib monotherapy.

The variability in treatment effectiveness among subgroups might arise from distinct molecular mechanisms across different co-mutation subtypes. Tumor suppressor genes such as TP53, RB1, and PTEN lose their normal function, thus resulting in inhibition of apoptosis and acceleration of cell cycle progression, and ultimately promoting tumor growth^18–20. In contrast, driver gene co-mutations, such as MET/HER2 amplifications and KRAS/BRAF mutations, enhance tumor invasiveness by activating alternative signaling pathways^21–24. These findings underscore the importance of exploring alternative therapeutic strategies for patients bearing co-mutations.

Recent studies, including FLAURA-2²⁵ and MARIPOSA²⁶, have evaluated combination therapies for advanced EGFRm NSCLC. These studies have demonstrated that osimertinib combined with chemotherapy or lazertinib combined with amivantamab achieves superior outcomes to osimertinib monotherapy, regardless of patients’ co-mutation status. Specifically, the FLAURA-2 study²⁵ analyzed baseline tissue samples from 141 patients, of whom 79 had TP53 mutations. Patients with baseline TP53 co-mutations who received osimertinib plus chemotherapy had longer mPFS than those receiving osimertinib alone (HR = 0.57). Similarly, in the MARIPOSA study²⁶, amivantamab combined with lazertinib, compared with osimertinib alone, significantly prolonged mPFS in patients with TP53 co-mutations (18.2 vs. 12.9 months; HR = 0.65, P = 0.003). However, because of limited sample sizes, larger prospective studies remain necessary. To address this gap, the ongoing TOP study²⁷ is aimed at evaluating the efficacy and safety of osimertinib plus chemotherapy vs. osimertinib alone as a 1L treatment in patients with EGFR-sensitive NSCLC with concurrent TP53 mutations. The results from the TOP study are highly anticipated. Our exploratory analysis highlighted a possible association between co-mutations and diminished osimertinib efficacy, thus underscoring the need for further evaluation through larger prospective trials.

Previous real-world studies have confirmed the safety profile of osimertinib. In the Reiwa study, the incidence of grade ≥3 AEs was 23.3%. In the FLOWER study¹³, 87.3% of patients experienced AEs. Additionally, a real-world study by Kishikawa et al.²⁸ has reported an AE incidence of 89.3%, with grade ≥3 AEs occurring in 26.8% of patients. Our safety results aligned with these prior reports and identified no new safety signals. Additionally, previous studies did not specifically evaluate safety in FLAURA-ineligible populations. To our knowledge, our study is the first to demonstrate the safety and efficacy of osimertinib in this subgroup. Notably, patients with PS ≥2 exhibited an AE incidence comparable to that in the general population, thus supporting continued use of osimertinib in these patients in real-world clinical practice. The safety profile in the FLAURA-ineligible subgroup was similar to that observed in the FAS population, and no additional safety concerns were identified.

This study has several limitations. First, because of the study’s real-world nature, data were primarily derived from medical records and investigator assessments, thus resulting in missing baseline characteristics for some patients. This aspect reflected routine clinical practice, in which comprehensive documentation was not always performed. The potential for selection bias from such missing data should be acknowledged. Second, in this observational study, subgroup analyses were descriptive, and were neither based on pre-specified statistical hypotheses nor adjusted for multiplicity. Furthermore, certain subgroups had relatively small sample sizes. Therefore, our results provide only preliminary signals and directions and should be interpreted with caution. Further validation is warranted.

In conclusion, osimertinib demonstrated robust efficacy and manageable safety profiles in treatment-naïve patients with EGFRm advanced NSCLC in real-world settings. Patients classified as FLAURA-ineligible also benefited clinically and exhibited tolerable safety profiles. Our exploratory analysis indicated inferior real-world clinical outcomes of 1L osimertinib in patients with EGFRm bearing driver and/or tumor suppressor genes co-mutations, thus suggesting a potential need for more aggressive treatment strategies for this population. However, further prospective studies are required to validate this finding.

Funding

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This work was supported by a grant from AstraZeneca China.

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Year 2026 volume 23 Issue 8

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doi: 10.20892/j.issn.2095-3941.2025.0566

Receive Date：2025-10-18
Online Date：2026-11-07
Published：2026-08-15

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History

Received：2025-10-18
Accepted：2026-03-11

Funding

This work was supported by a grant from AstraZeneca China.

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