Retrospective real-world associations between EGFR alterations and furmonertinib outcomes in advanced non-small cell lung cancer

Introduction

Epidermal growth factor receptor (EGFR) mutations represent one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with a particularly high prevalence among Asian populations. Over the past two decades, the development and clinical application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment landscape for advanced EGFR-mutant NSCLC, substantially improving patient outcomes (1). Third-generation EGFR-TKIs, including osimertinib, almonertinib, and furmonertinib, have demonstrated superior efficacy, with median progression-free survival (PFS) ranging from 18.9 to 20.8 months. Iterative development of first-, second-, and third-generation inhibitors, therapeutic efficacy and central nervous system (CNS) activity have been progressively enhanced, establishing third-generation TKIs as the preferred first-line treatment option for EGFR-mutant NSCLC (2).

However, clinical practice has revealed that EGFR-mutant NSCLC represents a highly heterogeneous disease entity. Beyond the classic exon 19 deletion (ex19del) and L858R point mutations, a spectrum of uncommon mutations exists, including G719X, S768I, and L861Q. In recent years, these uncommon mutations have been further classified based on their structural and functional characteristics into distinct subgroups (3), including classic-like mutations, T790M-like mutations, exon 20 insertion (ex20ins) mutations, and pocket alpha C-helix compressing (PACC) mutations.

Critically, these distinct mutation subtypes differentially affect the spatial conformation of the EGFR kinase domain, conferring marked variability in sensitivity to different generations of EGFR-TKIs. For example, the TP53 co-mutation has been identified in multiple studies as a negative predictor of EGFR-TKI efficacy (4). Additionally, tumor suppressor gene (TSG) alterations, including NF1, RB1, PTEN, ARID1A, and BRCA1, have been associated with aggressive disease phenotypes and poor outcomes following EGFR-TKI treatment (5). Therefore, further research into whether co-mutations, particularly concurrent TP53 mutations in the context of EGFR mutations, influence survival outcomes and treatment response to EGFR-TKIs across different EGFR mutation subtypes needs to be conducted.

Furmonertinib (AST2818) is a novel third-generation EGFR-TKI that targets both sensitizing EGFR mutations and the Thr790Met mutation while sparing wild-type EGFR (6). In previous phase I/II and phase II clinical studies, furmonertinib demonstrated promising efficacy and good tolerability in patients with locally advanced or metastatic NSCLC harboring ex19del and L858R mutations (7). Additionally, in a phase 1b clinical study that included patients with EGFR ex20ins mutations, high-dose furmonertinib (160 and 240 mg) demonstrated good efficacy. The median PFS was 10.7 months and 7.0 months, respectively, while the disease control rates (DCRs) were 96.6% and 95.5%, respectively, and the safety profile was manageable (8). Data from the FURTHER study showed that first-line treatment with furmonertinib at a dose of 240 mg in patients with EGFR PACC-mutant NSCLC achieved a median PFS of 16.0 months and an objective response rate (ORR) of 68.2%, demonstrating the potential of furmonertinib in treating complex mutation subtypes (9).

This study retrospectively investigated the efficacy of furmonertinib across different EGFR mutation subtypes in terms of treatment response and survival outcomes. Our prespecified primary analyses addressed two core research questions: first, whether survival outcomes differed between patients harboring classical EGFR ex19del vs. L858R mutations receiving first-line furmonertinib; second, which factors, including age, sex, disease stage, and co-mutated genes, were associated with survival outcomes via multivariate Cox regression analysis. Applying these next-generation sequencing (NGS) data to analyze the impact of furmonertinib treatment on the prognosis of patients with different EGFR subtypes and co-mutations can provide a basis for perspective studies. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1103/rc).

Methods

Participants

This study included a total of 154 patients with stage IIIB/C to IV unresectable and untreated EGFR-mutant NSCLC. Participantes were consecutively enrolled from eight cancer centers in China, including Tianjin Medical University Cancer Institute and Hospital (Tianjin), Guangxi Medical University Cancer Hospital (Nanning), Handan Central Hospital (Handan), Nanyang Second General Hospital (Nanyang), Affiliated Hospital of Hebei University (Baoding), Affiliated Hospital of North China University of Science and Technology (Tangshan), Tongliao City Hospital (Tongliao) and First Hospital of Qinhuangdao (Qinhuangdao). A total of 80 mg of standard furmonertinib was administered to each patient as treatment regimen. The enrollment period was from February 4, 2021 to January 3, 2025. The study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (No. E20261028), and conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participating hospitals were informed of and agreed with this study. All participants provided written informed consent.

Demographic, clinical, and molecular characteristics were collected from medical records, including sex, age, tumor stage, histological subtype, smoking history, disease progression, EGFR mutation subtype, and concomitant genetic alterations. Baseline performance status (PS) was assessed using the Eastern Cooperative Oncology Group-PS (ECOG-PS) scale. The status of genes expression, including EGFR ex19del, exon 21 L858R mutations and others 9 genes, were confirmed by NGS. Either tissue or plasma was collected for NGS before initiation of furmonertinib. Sequencing was executed on the DNBSEQ-T7 platform (MGI Tech). All patients had at least one measurable lesion that had not received prior local treatment according to the Response Evaluation Criteria in Solid Tumors version 1.1.

Strict and uniform inclusion and exclusion criteria were applied to minimize selection bias. Patients with missing clinical data or genetic testing results, incomplete follow-up information, unknown treatment details, or concurrent malignancies were excluded from the study. All data were extracted from standardized medical records and NGS reports to reduce information bias. Multivariate Cox regression was used to adjust for potential confounding factors, including age, gender, smoking status, tumor stage, histological subtype, and concomitant genetic alterations.

Efficacy and follow-up

This multicenter, retrospective, real-world study aimed to evaluate the efficacy of furmonertinib in patients with locally advanced, unresectable lung adenocarcinoma (LUAD) and to assess the impact of concomitant genetic alterations on treatment prognosis. Clinical endpoints analyzed included PFS, overall survival (OS), ORR, DCR, and safety outcomes.

PFS was defined as the time from the initiation of furmonertinib treatment to disease progression or death from any cause. OS was defined as the time from the initiation of furmonertinib treatment to death from any cause or the date of the last follow-up. ORR was defined as the proportion of target lesions achieving a complete response (CR) or partial response (PR). DCR was defined as the proportion of target lesions achieving a CR, PR, or stable disease (SD).

Follow-up information was obtained via regular imaging assessments, telephone and WeChat follow-ups, as well as reviews of outpatient, inpatient and treatments medical records. Follow-up visits were scheduled every 8 weeks within the first 6 months of EGFR-TKI treatment initiation, and every 12 weeks thereafter. The last follow-up date was December 1, 2025. Loss to follow-up was defined as no valid clinical or survival data for more than 12 months with unsuccessful contact attempts. No patients were lost to follow-up in the final analysis cohort (n=139).

Statistical analysis

All statistical analyses were performed using R software (version 3.5.2). Categorical variables were expressed as frequencies and compared between groups using Fisher’s exact test. Continuous variables were presented as medians with interquartile ranges and analyzed using the Wilcoxon rank-sum test. Survival analyses were conducted and visualized using the Survival and Survminer packages. PFS and OS curves were estimated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Cox proportional hazards (PHs) models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariable Cox models (PFS and OS) were fitted with complete-case analysis, adjusting for age, disease stage, EGFR mutation subtype, and concomitant mutation status selected from univariate analyses and clinical relevance; PH assumptions were checked via scaled Schoenfeld residuals, and a time-by-covariate interaction term was added to the PFS model as a post-hoc exploratory analysis for the non-PH polygenic mutation status. All statistical tests were two-sided, and P<0.05 was considered statistically significant (*, P<0.05; **, P<0.01).

Results

Baseline clinical and molecular characteristics

Between February 4, 2021 and January 3, 2025, 154 patients with EGFR-mutant NSCLC received furmonertinib, of whom 139 had available efficacy or survival data for analysis, while 8 patients’ efficacy data could not be evaluated (Figure 1). Baseline demographic and clinical characteristics are shown in Table 1. The median age of the included patients was 66 years old. All patients harbored either ex19del or L858R mutations, with only one patient harboring both mutations simultaneously. A total of 90 patients were tested for TP53 status. Among them, 58 cases carried TP53 mutations, 32 patients did not carry TP53 mutations, and 49 patients were unable to undergo TP53 testing due to financial reasons. Nine concomitant driver genes were assessed in 136 patients, including ALK, ROS1, KRAS, NRAS, BRAF, PIK3CA, RET, HER2, and MET. Driver gene profiling was unsuccessful in 3 patients.

Figure 1 Study flow diagram. EGFR, epidermal growth factor receptor; NSCLC, non-small-cell-lung-cancer; OS, overall survival; PFS, progression-free survival.

Efficacy of furmonertinib in advanced EGFR-mutant LUAD

The final follow-up cutoff date was December 1, 2025. Among those harboring EGFR L858R, 66.2% (47/71) of achieved a PR, 29.6% (21/71) had SD, and three had progressive disease (PD). Among those harboring EGFR ex19 del, 72.9% (43/59) achieved a PR, and 27.1% (16/59) had SD. Overall, ORR was 69.5%, and DCR was 97.7% (Figure 2A).

Figure 2 Efficacy of furmonertinib in advanced EGFR-mutant LUAD. (A) Best percentage changes from baseline in target lesion size among patients included in the efficacy analysis population. (B) Duration of furmonertinib treatment and best overall response. (C,D) Kaplan-Meier estimates of PFS and OS in all patients. EGFR, epidermal growth factor receptor; LUAD, lung adenocarcinoma; NE, not evaluable;OS, overall survival; PFS, progression-free survival.

At the last follow-up, 77 patients experienced PD and 22 died. The median duration of furmonertinib treatment was 97 days, and the median duration of response was 406 days (Figure 2B). The median PFS for the entire cohort was 623 days, while the median OS had not been reached (Figure 2C,2D).

Distribution of EGFR mutations and concomitant genetic alterations

Among the 139 patients, the most common EGFR mutation subtype was L858R. A total of 136 patients underwent testing for nine additional genes other than EGFR, and 90 patients underwent testing for TP53. Among the tested patients, the frequencies of concomitant genetic alterations were as follows: TP53 mutations were detected in 64.4% (58/90), EGFR copy number variations in 15.4% (21/136), other non-classical EGFR mutations in 16.2% (22/136), PIK3CA mutations in 8.1% (11/136), ROS1 alterations in 3.7% (5/136), ERBB2 alterations in 3.7% (5/136), ALK fusions in 2.9% (4/136), KRAS mutations or amplifications in 2.9% (4/136), RET fusions in 2.9% (4/136), BRAF mutations or amplifications in 2.2% (3/136), and MET mutations in 0.7% (1/136) (Figure 3). Consistent with previous research, EGFR mutations were largely mutually exclusive with other oncogenic driver alterations except for TP53 alterations (10). Among these alterations, three patients harbored KRAS mutations (all involving codon G12), two patients harbored BRAF alterations (V600E mutation and amplification), and one patient harbored ERBB2 amplification. The clinical significance of the remaining detected variants remains unclear.

Figure 3 Genetic mutation landscape of study patients. CNV, copy number variation; EGFR, epidermal growth factor receptor; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SV, structural variation.

Regression analysis of the impact of genetic alterations status on survival

To investigate the impact of clinical characteristics, disease stage, and genetic alteration status on survival outcomes, univariate and multivariate Cox regression analyses were performed. As of December 2025, 77 PFS events (disease progression or death, 55.4%) and 22 deaths (15.8%) occurred among the 139 patients. Four patients were excluded due to missing covariate data; the multivariable Cox analysis therefore included 135 patients with 75 PFS events and 20 deaths. The results showed that the EGFR L858R mutation (P=0.049) and the presence of multiple genetic alterations (P=0.001) were significantly associated with PFS, while multiple genetic alterations trended toward poorer OS (P=0.059). After adjustment for potential confounding factors, multiple genetic alterations (P<0.001) and the EGFR L858R mutation (P=0.02) were independently associated with inferior PFS (P<0.05) (Table 2).

EGFR mutation subtypes affect the efficacy of furmonertinib

Kaplan-Meier survival analysis showed that among the patients with canonical EGFR mutations, those with ex19del achieved a significantly longer median PFS than those with L858R mutations (median PFS: 750 vs. 516 days, P=0.049). Median OS was not reached in either group. However, patients with L858R mutations exhibited a trend toward worse OS compared with those with ex19del (P=0.13) (Figure 4A,4B). Additionally, a subgroup analysis was performed according to TP53 status. Kaplan-Meier survival analysis showed that regardless of TP53 status, there were no significant differences in PFS or OS among the patients with EGFR-mutant NSCLC receiving first-line furmonertinib treatment (Figure S1).

Figure 4 Subgroup survival analyses of patients. Comparison of PFS (A) and OS (B) between patients with EGFR ex19del and L858R mutations. Comparison of PFS (C) and OS (D) between patients with multiple-gene wild-type and multiple-gene mutant status. Mut, multiple; OS, overall survival; PFS, progression-free survival; WT, wild-type.

Among the 139 patients, 14 (10.1%) harbored clinically significant concomitant genetic alterations other than EGFR and TP53 alterations. These alterations included EGFR amplification, and ALK, MET, RET, ROS1, KRAS, NRAS, BRAF, PIK3CA, and ERBB2 alterations. Compared with the multiple-gene wild-type group, the multiple-gene mutant group had significantly shorter median PFS (187 vs. 642 days, 95% CI: 528–748, P<0.001) (Figure 4C). At the last follow-up, the median OS of both groups had not been reached. However, the survival curves showed that the mortality risk of the group with mutations was significantly higher than that of the wild-type group (Figure 4D).

Discussion

EGFR is the most common oncogenic driver in NSCLC (2). In recent years, targeted therapies against EGFR have significantly improved the survival outcomes of patients with EGFR-mutant NSCLC. With the continuous advancement of NGS technologies, researchers (5) have shown that in addition to EGFR mutations, NSCLC patients often harbor other oncogenic driver gene alterations, such as TP53 co-mutations, which have been associated with a poor prognosis. Moreover, the effects of multiple concomitant genetic alterations on the efficacy of EGFR-TKIs have shown high complexity and heterogeneity (11). Furmonertinib, a novel third-generation EGFR-TKI independently developed in China, has shown encouraging efficacy in rare mutation subtypes such as EGFR PACC mutations (12) and ex20ins (13,14). This study retrospectively analyzed the baseline characteristics and genetic alterations of 139 patients with advanced EGFR-mutant NSCLC to explore the efficacy of furmonertinib across different mutation subtypes, especially in patients with concomitant genetic alterations.

In this study, the majority of patients were female, non-smokers, and had stage IV adenocarcinoma. The predominant EGFR mutation subtype was L858R. Consistent with previous reports, TP53 was the most frequently detected concomitant alteration, occurring in 64.4% (58/90) of the patients. In terms of efficacy, the patients who received first-line treatment with furmonertinib had a median PFS of 20.5 months, an ORR of 69.5%, and a DCR of 97.7%, which were highly consistent with the results reported in the FURLONG study (7). Due to the immature nature of the survival data, longer follow-up is required to further evaluate the effect of furmonertinib on OS. Furthermore, we found that the clinical subtypes and TP53 mutation characteristics were not significantly associated with the treatment response, while patients with concurrent mutation status and the EGFR L858R subtype showed shorter PFS (P<0.05). Age ≥65 years was associated with a trend toward improved PFS (P=0.054) and OS (P=0.058).

Interestingly, there were no statistically significant differences in PFS and OS between the TP53 wild-type group and TP53 mutant group, suggesting that TP53 status alone does not have significant prognostic value. This finding may be related to the EGFR mutation subtypes. A recent study published in Clinical Lung Cancer (15) reported that among patients with EGFR L858R mutations, those with TP53 co-mutations had a significantly shorter median PFS, while TP53 status had no significant impact on PFS in the ex19del subgroup. In our study, patients with ex19del accounted for 50% (29/58) of the TP53 mutant group, which may weaken the negative effects caused by the TP53 mutations. Alternatively, it may be that different types of TP53 mutations have different effects on prognosis. For instance, missense mutations may have a smaller impact on prognosis compared with nonsense or truncating mutations (5). Some studies have reported that TP53 mutations in exons 5–8 may affect the prognosis of patients with NSCLC (16). We grouped the patients according to whether the mutation sites were located in exons 5–8 (45 vs. 13). The results showed that exon 5–8 mutations had no significant impact on prognosis, which may be related to the small sample size and insufficient statistical power to detect significant differences.

It is well known that third-generation EGFR-TKIs, including furmonertinib, can significantly improve the survival of patients with NSCLC. However, as the treatment duration increases, resistance eventually develops. Our study mainly focused on off-target drug resistance mechanisms, including MET amplification, HER2, RET, and ALK alterations, KRAS and BRAF abnormalities, PI3K pathway alterations, and TP53 mutations. The results showed that the presence of multiple genetic alterations was associated with shorter PFS in patients.

Clinically, treatment strategies for patients with high-risk co-mutations or TSG alterations have received significant attention. The ACROSS 2 study (17) first demonstrated that the combination of aumolertinib and platinum-based chemotherapy significantly prolonged median PFS compared with aumolertinib monotherapy (19.78 vs. 16.53 months; HR, 0.58; 95% CI: 0.34–0.97) in patients with EGFR-mutant NSCLC and concomitant TSG mutations. If MET amplification is also present, dual-target therapy combining MET inhibitors with third-generation EGFR-TKIs may be considered (18). Additionally, the ACTIVE study (19) demonstrated that the combination of EGFR-TKIs and anti-angiogenic agents achieved improved therapeutic outcomes. Patients with TP53 mutations, especially those with exon 8 mutations, were more likely to benefit from the dual-target combination therapy.

There are some limitations in this study. First, it was a multicenter, retrospective, non-randomized controlled study; thus, selection bias, recall bias, and the influence of confounding factors on the results cannot be excluded. In addition, although the overall sample size was acceptable, when analyzed by mutation subtypes or concomitant mutations, some subgroups had insufficient cases, which may have resulted in insufficient statistical power and increased the risk of false-positive results. Finally, the NGS platforms, gene panel coverage, and detection depth used by different centers may vary, potentially leading to the omission of some low-frequency co-mutations. Furthermore, data on the functional characteristics of gene mutations (e.g., destructive vs. non-destructive mutations and missense vs. truncating mutations) and TP53 exon positions were not systematically and uniformly collected, limiting more detailed prognostic stratification analyses.

Conclusions

This study explored prognostic associations between EGFR mutation subtypes, co-mutation status and clinical outcomes under furmonertinib therapy. Our real-world data support favorable activity of furmonertinib among patients with advanced EGFR-mutant NSCLC. In this cohort, TP53 mutation status was not significantly associated with survival outcomes, while multiple concurrent non-EGFR genomic alterations exhibited heterogeneous prognostic signals that deserve further investigation. Our observations generate hypotheses that combined evaluation of EGFR subtype and the broader co-mutation landscape may help identify high-risk patient subgroups. However, given the retrospective design and limited sample size of 139 patients, our results cannot directly establish treatment modification strategies for individual mutation profiles. Larger prospective studies are needed to externally validate these genomic-prognostic relationships before they can inform clinical practice.

Acknowledgments

We would like to thank Shaozhang Zhou, Zheng Liu, Qichuan Wang, Liuchun Wang, Yanhong Shang, Jinghao Jia, Hongjiang Yu, Yan Jiang, and Zihui An for their support to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1103/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1103/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1103/prf

Funding: This research was supported by the National Natural Science Foundation of China (No. 82274607), and Tianjin Key Medical Discipline Construction Project (No. TJYXZDXK-3-003A).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1103/coif). Y.J. is from Nanjing Geneseeq Technology Inc., Nanjing, China. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (No. E20261028), and conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participants provided written informed consent. All participating hospitals were informed of and agreed with this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)