Flumonertinib after prior third-generation EGFR-tyrosine kinase inhibitor (TKI) therapy in patients with epidermal growth factor receptor-mutated non-small cell lung cancer after resistance to third-generation tyrosine kinase inhibitor treatment: a real-world study

Abstract

Background

Third-generation tyrosine kinase inhibitor (TKI) agents have become the preferred option for the first-line treatment of patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) due to their exceptional efficacy and favorable safety profile. However, resistance to third-generation TKIs is inevitable. Subsequent treatment options are limited and confer only modest survival benefit. This retrospective study examined patients receiving flumonertinib after prior third-generation EGFR-TKI therapy following resistance to third-generation TKIs, with the aim to assess a potential therapeutic approach for this challenging patient population.

Methods

This retrospective study included a cohort of 40 patients who received flumonertinib after prior third-generation EGFR-TKI therapy following resistance to other third-generation TKIs. Kaplan-Meier analysis, Cox proportional hazards regression analysis, and Cox subgroup analysis were employed to examine factors influencing patient survival.

Results

The median progression-free survival (PFS) for the overall cohort was 8.95 months, and the median overall survival (OS) was 18.03 months. Patients who received flumonertinib after prior third-generation EGFR-TKI therapy (80 or 160 mg) as first- to third-line therapy (≤3 prior lines of therapy) demonstrated significantly improved survival outcomes [hazard ratio (HR) =0.43, 95% confidence interval (CI): 0.20–0.89; P=0.02]. Cox subgroup analysis further revealed that patients receiving flumonertinib monotherapy derived a significant survival benefit (HR =0.24, 95% CI: 0.07–0.85, P=0.02; P for interaction =0.04).

Conclusions

For patients with EGFR-mutated NSCLC who develop resistance after treatment with third-generation EGFR TKIs, flumonertinib monotherapy during rechallenge treatment is a viable therapeutic option. Initiating treatment with flumonertinib earlier may lead to better survival outcomes, and thus further investigation of this strategy is warranted.

Highlight box.

Key findings

• For patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who develop resistance after treatment with third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), flumonertinib monotherapy during rechallenge treatment is a viable therapeutic option.

• Patients who received flumonertinib after prior third-generation EGFR-TKI therapy (80 or 160 mg) as first- to third-line therapy (≤3 prior lines of therapy) demonstrated significantly improved survival outcomes (hazard ratio =0.43, 95% confidence interval: 0.20–0.89; P=0.02).

What is known and what is new?

• Third-generation TKI agents provide significantly improved survival outcomes in patients with advanced EGFR-mutant NSCLC; however, therapeutic options become highly constrained once resistance to TKIs develops.

• For patients with EGFR-mutated NSCLC who develop resistance after treatment with third-generation EGFR-TKIs, flumonertinib monotherapy during rechallenge treatment is a viable therapeutic option.

What is the implication, and what should change now?

• This approach offers a potential therapeutic option for patients with advanced EGFR-mutant NSCLC who have developed resistance to third-generation TKIs.

• TKI rechallenge therapy should be implemented in earlier stages of treatment. More extensive research is warranted to establish the feasibility of this approach.

Introduction

Lung cancer is one of the most common types of cancer in the world and has the highest mortality rate among malignancies (1). Approximately 85% of patients have the pathological type of lung cancer, non-small cell lung cancer (NSCLC). A significant driver of NSCLC is the epidermal growth factor receptor (EGFR) mutation, which occurs in approximately 15% of patients worldwide (2,3). This rate is notably higher in Asian populations, reaching around 40%. Certain mutations in the EGFR gene can enhance tyrosine kinase activity, leading to tumor development. The most common mutations of EGFR include exon 19 deletion (ex 19-del) and the L858R mutation in exon 21 (4). Regarding treatment options, particularly for patients with unresectable advanced-stage disease, tyrosine kinase inhibitors (TKIs) are typically selected (5). The advent of TKIs has significantly improved the survival and prognosis of patients with EGFR-mutated NSCLC (6,7). First-generation TKIs, such as gefitinib and erlotinib, have demonstrated substantial therapeutic efficacy (8,9). For instance, a phase III clinical trial comparing gefitinib with platinum-based doublet chemotherapy in chemotherapy-naïve patients found that the gefitinib group had a significantly prolonged median progression-free survival (mPFS) (mPFS: 9.2 vs. 6.3 months; P<0.001). Following this, TKIs became established as the first-line treatment for patients with advanced-stage, EGFR-mutated NSCLC. However, resistance to first-generation TKIs inevitably develops and is often accompanied by acquired genetic mutations such as the EGFR T790M mutation, which renders drugs such as gefitinib ineffective (10). To address this challenge, third-generation TKIs, particularly osimertinib, have entered the therapeutic landscape (11). Representative of this generation, osimertinib demonstrates superior efficacy. For instance, in the AURA3 study involving patients with the T790M mutation who progressed after first-line TKI therapy, osimertinib achieved a mPFS of 10.1 months, superior to the 4.4 months obtained via chemotherapy (12). In the FLAURA study, osimertinib as first-line therapy significantly prolonged both the mPFS and median overall survival (mOS) as compared to previous-generation TKIs (mPFS: 18.9 vs. 10.2 months; mOS: 38.6 vs. 31.8 months; both P values <0.05) (13). Similarly, the AENEAS study reported a higher mPFS (19.3 months) for patients treated with aumolertinib than for those treated with gefitinib (9.9 months) (14). Based on these encouraging trial results, third-generation TKI targeted therapy has become the first-line standard of care, offering significant therapeutic benefits and markedly improving patient survival and prognosis (15). However, the issue of resistance persists. Once the initially used third-generation TKI loses efficacy, subsequent treatment options become severely limited. The relevant guidelines typically recommend second-line therapy with chemotherapy combined with antiangiogenic agents or chemotherapy plus immune checkpoint inhibitors (ICIs) and antiangiogenic agents (16). However, the mPFS for these regimens is generally 4–6 months, and the addition of ICIs does not appear to yield significant benefit. Treatment choices become even more constrained after these regimens are applied (17,18). Moreover, disease progression on third-generation TKIs such as osimertinib may lead to the emergence of new resistance mutations, such as EGFR C797X mutations and MET amplification (19,20). This poses formidable challenges to devising effective subsequent treatment strategies. Due to the established efficacy of TKIs, the strategy of TKI rechallenge has been explored as a potential salvage approach. In 2022, a study comparing osimertinib rechallenge combined with bevacizumab to chemotherapy combined with bevacizumab reported a longer mPFS in the osimertinib rechallenge group (7.0 vs. 4.9 months) (21). Further supporting this concept, a 2023 study investigating afatinib rechallenge following progression after osimertinib administration reported an objective response rate exceeding 30% (22). These findings suggest that rechallenging with a different TKI, potentially a more advanced-generation agent, may yield improved outcomes.

Flumonertinib is a novel third-generation EGFR TKI. It retains the core structural framework characteristic of third-generation TKIs while incorporating unique functional groups that confer strong hydrophobicity, high lipophilicity, and potent electron-withdrawing properties (23). This distinct molecular architecture underpins flumonertinib’s unique pharmacological advantages. In the FURLONG study, flumonertinib demonstrated superior efficacy as first-line therapy (mPFS: 20.8 months) than did gefitinib (mPFS: 10.8 months) (24). Furthermore, flumonertinib maintained favorable therapeutic efficacy in patients who developed T790M mutation-mediated resistance after first-generation TKI treatment. Notably, flumonertinib exhibits significant activity against central nervous system (CNS) metastases in patients with NSCLC and remains effective against disease with uncommon EGFR mutations (25,26). Brain metastases and resistance mutations represent persistent therapeutic challenges, highlighting flumonertinib’s promising clinical potential. Third-generation TKIs, represented by flumonertinib, osimertinib, and aumolertinib, have transformed the treatment paradigm. However, resistance to third-generation TKIs inevitably emerges, substantially diminishing the efficacy of subsequent treatment options. Research has begun exploring the efficacy of rechallenging with prior-generation TKIs after osimertinib resistance (22). Given flumonertinib’s unique molecular structure and established efficacy profile, flumonertinib after prior third-generation EGFR-TKI therapy may yield improved outcomes. Therefore, we conducted a retrospective analysis of patients who received flumonertinib after prior third-generation EGFR-TKI therapy following progression on prior third-generation TKIs (primarily osimertinib or aumolertinib), with those who received initial flumonertinib being excluded. This analysis aimed to identify factors influencing survival outcomes, with the goal of providing a potential therapeutic option for patients with EGFR-mutated NSCLC after progression on third-generation TKIs. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2503/rc).

Methods

Collection of participant data

This retrospective study included 40 patients with prior resistance to third-generation TKIs (excluding flumonertinib) who underwent flumonertinib after prior third-generation EGFR-TKI therapy at Shandong Cancer Hospital and Institute between March 2022 and February 2025; the cutoff date for analysis was March 1, 2025. As this retrospective study was based on existing medical records, no patients were contacted or received additional procedures for the purpose of this research. Follow-up information was obtained from the institutional electronic medical record system, outpatient and inpatient visit records, telephone follow-up, and the provincial mortality registry. The start of follow-up was defined as the date when the patient initiated the study treatment. The end of follow-up was the data cutoff date or the date of death, whichever occurred first. Imaging evaluations were performed according to routine clinical practice, typically every 6–8 weeks during treatment, rather than at strictly fixed intervals. Adverse events were not systematically assessed in this study due to the retrospective design and incomplete availability of safety data during follow-up. The key inclusion criteria included the following: (I) a histopathological diagnosis of NSCLC; (II) EGFR mutations (EGFR ex 19-del, EGFR exon 18 L858R mutation, and other uncommon mutations); and (III) disease progression following prior treatment with third-generation TKIs and treatment with flumonertinib (80 or 160 mg) in later lines of therapy. Patients were excluded if they met any of the following criteria: (I) pathological diagnosis other than NSCLC, including small cell lung cancer or transformed small cell lung cancer; (II) presence of other primary malignancies; (III) absence of EGFR mutation at baseline; and (IV) no third-generation TKIs during treatment. Data on patients’ characteristics were collected including age, histological type, smoking history, Karnofsky Performance Status (KPS) score, tumor stage at baseline, tumor stage upon treatment with the first third-generation TKIs, baseline gene mutation status, gene mutation status before initiation of flumonertinib therapy, TKI sequential treatment mode, and regimen.

Statistical analysis

PFS was defined as the time from flumonertinib treatment to disease progression or death. OS was defined as the time from histopathological diagnosis to censored observation or death. PFS and OS were analyzed via Kaplan-Meier methods. The log-rank test was used to compare survival outcomes between different subgroups, with a P value less than 0.05 being considered statistically significant. For patients missing key outcome data, such as progression-free survival (PFS) and OS, censored data were applied. The proportion of censored data accounted for less than 5% of the total sample. Hazard factors were compared between different cohorts via Cox proportional hazards regression analysis, with variables including line of therapy at initiation of flumonertinib treatment, intracranial progression (IP) status, baseline brain metastasis status, age, smoking history, and radiotherapy history. Cox subgroup analysis was performed to identify factors influencing PFS in patients stratified by line of therapy and included baseline brain metastasis status, IP status, the status of brain metastases before commencing flumonertinib treatment, age, smoking history, history of radiotherapy, disease stage at initiation of the first third-generation TKI, dosage, TKI sequential treatment pattern, therapeutic regimen (monotherapy or combination), and baseline tumor stage. To minimize selection bias, all consecutive patients who met the eligibility criteria during the study period were included. To reduce information bias, a standardized data collection form was used, and medical records were cross-checked by two independent investigators (none of the authors served as an independent investigator in this study). Potential confounding factors were adjusted for using multivariable regression models. Data processing and analysis were performed with R v. 4.5.0 (The R Foundation of Statistical Computing), along with Zstats v. 1.0 (www.zstats.net).

Ethical statement

This study is a retrospective analysis based on medical records. No human subjects were prospectively enrolled, no interventions were performed, and no biological samples were collected for the purposes of this study. The study was reviewed by the Institutional Review Board of Shandong Cancer Hospital and Institute, which determined that ethical approval was not required, and that written informed consent was waived due to the retrospective nature of the research and the use of existing clinical data. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Results

Patient characteristics

We gathered data from 40 patients with NSCLC who experienced disease progression after previous third-generation TKI therapy. Among these patients, 35% were older than 65 years, 55% were female, 97.5% were diagnosed with adenocarcinoma, 17.5% had a history of smoking, 65% had a KPS score less than 90, 65% had stage IVB disease, and 12.5% had stage IIIB disease. They are presented in Table 1. In the total cohort, 85% of patients had stage IV disease upon treatment with the first third-generation TKIs, 12.5% had stage IIIB and other stages (IVA in 2 cases, IIIA in 1 case, IIB in 2 cases, IIA in 1 case, and IA in 3 cases), 57.5% had the EGFR ex 19-del mutation at baseline, 37.5% had the EGFR exon 18 L858R mutation, and the remainder had other EGFR mutations (1 case of EGFR exon 18 mutation and 1 case of EGFR exon 21 L861Q mutation).

Table 1. Clinical characteristics of the patients at baseline (n=40).

Characteristics	N (%)
Age
≥65 years	14 (35.0)
<65 years	26 (65.0)
Gender
Female	22 (55.0)
Male	18 (45.0)
Pathological type
Adenocarcinoma	39 (97.5)
Squamous carcinoma	1 (2.5)
Smoking history
Yes	7 (17.5)
No	33 (82.5)
KPS
≥90	14 (35.0)
<90	26 (65.0)
Tumor stage at baseline
IVB	26 (65.0)
IVA	2 (5.0)
IIIB	5 (12.5)
IIIA	1 (2.5)
IIB	2 (5.0)
IIA	1 (2.5)
IA	3 (7.5)
Tumor stage upon first use of third-generation TKI
IV	34 (85.0)
IIIB	2 (5.0)
Postoperative	3 (7.5)
Postoperative recurrence	1 (2.5)
EGFR mutation at baseline
EGFR exon 19 del	23 (57.5)
EGFR exon 21 l858R	15 (37.5)
EGFR exon 18 mutation	1 (2.5)
EGFR exon 21 L861Q mutation	1 (2.5)
EGFR mutation prior to flumonertinib
No genetic retesting	22 (55.0)
EGFR T790M mutation	12 (30.0)
EGFR exon 19 del	2 (5.0)
EGFR exon 21 l858R mutation	4 (10.0)
TKI sequential treatment mode
Osimertinib > flumonertinib	9 (22.5)
Other TKI > osimertinib > flumonertinib	14 (35.0)
Osimertinib > other TKI > flumonertinib	2 (5.0)
Aumolertinib > flumonertinib	4 (10.0)
Other TKI > aumolertinib > flumonertinib	9 (22.5)
Other TKI > osimertinib > aumolertinib > flumonertinib	1 (2.5)
Osimertinib > aumolertinib > flumonertinib	1 (2.5)
Regimen
Flumonertinib	15 (48.5)
Flumonertinib with other TKIs	2 (6.4)
Flumonertinib plus chemotherapy	3 (9.6)
Flumonertinib plus antiangiogenic drugs	11 (35.5)

Other TKI: first- or second-generation TKI. EGFR, epidermal growth factor receptor; KPS, Karnofsky Performance Status; TKI, tyrosine kinase inhibitor.

Before starting on flumonertinib, 55% had not undergone repeat genetic testing, 30% had the EGFR T790M mutation, 5% had the EGFR ex 19-del mutation, and 10% had the EGFR exon 18 L858R mutation. Regarding treatment, 48.5% were treated with flumonertinib, 35.5% were treated with flumonertinib with antiangiogenic drugs, and the remainder had other treatments. Regarding the patterns of TKI sequencing, 22.5% of patients received flumonertinib after treatment with osimertinib (with or without other anticancer therapies administered in between; the same applies below). A total of 35.0% of patients received other TKIs (first-generation TKI or second-generation TKI) prior to osimertinib, followed by flumonertinib. Additionally, 10.0% of patients received flumonertinib after treatment with aumolertinib, while 22.5% received another TKI prior to aumolertinib, followed by flumonertinib. To assess the potential biases associated with the different variables, univariate and multivariate Cox regression analyses were conducted (Tables S1,S2).

Efficacy of flumonertinib after prior third-generation EGFR-TKI therapy

As of March 1, 2025, 34 patients had experienced disease progression among a total of 40 patients, while 6 patients continued to receive flumonertinib therapy, with a mPFS of 8.95 months. Fifteen patients were alive at the cutoff time, with a mOS of 18.03 months (Figure 1).

Figure 1.

The results of the survival analysis for all patients. (A) PFS for all patients. (B) OS for all patients. mOS, median OS; mPFS, median PFS; OS, overall survival; PFS, progression-free survival.

We subsequently conducted an analysis of PFS across different subgroups: (I) a total of 26 patients were treated with flumonertinib at a dose of 80 mg, among whom 22 experienced progression, representing a progression rate of 84.6%, and 14 patients were treated with flumonertinib at a dose of 160 mg, representing a progression rate of 92.9%; no association was found between dose levels and mPFS, with an of mPFS of 9.55 and 7.50 months for the patients treated with 80 and 160 mg group, respectively [hazard ratio (HR) =1.273, 95% confidence interval (CI): 0.6225–2.605; P=0.18] (Figure 2A). (II) At the time of flumonertinib initiation, 34 patients had CNS metastasis, among whom 30 experienced progression, representing a progression rate of 88.2%; meanwhile, 6 patients did not have CNS metastasis, among whom the progression rate was 83.3%; no association was found between CNS metastasis and mPFS during flumonertinib treatment [non-CNS metastasis group (Not brain M group): 9.55 months; CNS metastasis group (Brain M group): 7.50 months; HR =1.268, 95% CI: 0.5240–3.066; P=0.60] (Figure 2B). In this study, disease progression was defined as overall systemic progression and was not categorized into intracranial or extracranial progression (EP). (III) Seventeen patients received flumonertinib monotherapy, 13 of whom experienced disease progression, representing a progression rate of 76.5%; 11 patients received flumonertinib in combination with antiangiogenic drugs, all of whom experienced disease progression; no association was found between therapeutic regime model and mPFS (flumonertinib monotherapy: 7.00 months; flumonertinib combination with antiangiogenic drugs: 7.50 months; HR =0.5288, 95% CI: 0.2175–1.286; P=0.16) (Figure 2C). (IV) Subsequently, the patients were divided into an IP group and an EP group. The IP group comprised patients who experienced IP after administration of first third-generation TKIs, while the EP group comprised patients who experienced EP after administration of third-generation TKIs. The IP group included 28 patients, and 25 patients experienced progression, representing a progression rate of 89.3%; meanwhile, the EP group included 12 patients, 9 of whom experienced progression, representing a progression rate of 75.0%. No association was found between IP status and mPFS (IP group: 7.00 months; EP group: 7.50 months; HR =1.771, 95% CI: 0.8541–3.671; P=0.12) (Figure 2D).

Figure 2.

Survival analysis (PFS) of different characteristics and treatment strategies. (A) Median PFS of patients treated with different doses (80 or 160 mg). (B) PFS in patients with or without brain metastases. (C) PFS in patients with or without combined vascular-targeting drug therapy. (D) PFS in patients with or without intracranial progression following initiation of first-line third-generation TKI therapy. EP, extracranial progression; IP, intracranial progression; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Subsequently, we performed a Cox regression analysis to evaluate the impact of different variables on PFS in patients receiving flumonertinib after prior third-generation EGFR-TKI therapy treatment (Figure 3A). The horizontal axis is the HR with the 95% confidence CI, and the vertical axis represents the various variables. Patients who received flumonertinib as first- to third-line treatment had a significantly longer PFS than did those who initiated flumonertinib beyond the third line (HR =0.43, 95% CI: 0.20–0.89; P=0.02). In contrast, patients aged 65 years or older had a significantly higher risk of disease progression (HR =2.10, 95% CI: 1.01–4.35; P=0.02). Other factors, including IP, baseline brain metastases, smoking history, and radiotherapy history, did not reach statistical significance, as their P values were greater than 0.05 and their 95% CIs exceeded 1.0. Another Cox proportional hazards model was applied to assess the association of various variables with OS, including IP, baseline brain metastases, smoking history, and lines of flumonertinib treatment, but these did not reach statistical significance (Figure 3B).

Figure 3.

Cox analysis of factors associated with PFS (A) and OS (B) in the overall patient population. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

As the Cox analysis indicated that patients with ≤3 lines of treatment had a longer PFS, we further performed subgroup Cox regression analyses stratified by treatment lines (>3 vs. ≤3 lines) to assess the association of different variables within each group (Figure 4). In the subgroup analysis, no brain metastasis at baseline, brain metastasis prior to flumonertinib therapy, age younger than 65 years, previous radiotherapy history, and an 80-mg dose were factors found to favor early flumonertinib intervention. Flumonertinib after prior third-generation EGFR-TKI therapy conferred survival benefits even in patients who were at stage IV at the time of their first third-generation TKI administration. Notably, the survival benefit remained consistent regardless of IP and baseline tumor stage at the time of flumonertinib initiation. Patients receiving a sequence of first- or second-generation TKIs, followed by third-generation TKIs, and concluding with flumonertinib had a significantly prolonged PFS (HR =0.31, 95% CI: 0.10–0.95; P=0.04). No significant interactions were observed between subgroup factors and treatment line number (P for interaction >0.05).

Figure 4.

Cox subgroup analysis of PFS stratified by line of therapy. 1G, first-generation; 2G, second-generation; 3G, third-generation; Almon, aumolertinib; Beva, bevacizumab; Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; Osi, osimertinib; TKI, tyrosine kinase inhibitor.

Discussion

Third-generation EGFR-TKIs have transformed the treatment landscape for patients with EGFR-mutant NSCLC. Compared to chemotherapy and earlier-generation EGFR-TKIs, they offer superior efficacy and favorable tolerability (11). Consequently, they have been established as the first-line treatment of choice for patients with EGFR mutations. However, the development of drug resistance is inevitable. Following the onset of resistance, therapeutic options become limited. Post-TKI resistance management typically involves platinum-based doublet chemotherapy or chemotherapy combined with ICI therapy (16). The efficacy of treatment regimens at this stage is suboptimal. For instance, in the KEYNOTE-789 study, the addition of pembrolizumab to chemotherapy failed to demonstrate a significant survival benefit compared to chemotherapy plus placebo (mPFS: 5.6 vs. 5.5 months; mOS: 15.9 vs. 14.7 months) (18). Moreover, the mPFS in both groups was markedly shorter than that achieved with first-line regimens. Previous research has indicated that EGFR-mutant NSCLC is generally less responsive to ICIs, underscoring the significant challenges in selecting appropriate subsequent therapeutic strategies (27). Previous studies have examined the efficacy of rechallenge therapy with earlier-generation TKIs following resistance to third-generation TKIs (21,28,29). The mPFS for such rechallenge therapy ranges between 3 and 5 months, with favorable tolerability. In a study investigating 160 mg of flumonertinib for rechallenge after third-generation TKI resistance, the high-dose regimen demonstrated promising efficacy, particularly in patients with intracranial metastases (30). These findings provided the rationale for exploring the clinical outcomes of flumonertinib in real-world patients after failure of other third-generation EGFR-TKIs. In addition, for EGFR non-sensitive mutations, such as exon 18 mutations, exon 20 insertions, and non-L858R exon 21 mutations, furmonertinib has still demonstrated certain antitumor activity. Real-world studies suggest that furmonertinib may be effective against a broader spectrum of non-sensitive EGFR mutation subtypes compared with other third-generation TKIs (25,31-33). Consequently, we enrolled 40 patients who received flumonertinib after developing resistance to a third-generation TKIs to evaluate the efficacy of flumonertinib after prior third-generation EGFR-TKI therapy. In our study, the mPFS reached 8.95 months, and the mOS exceeded 3 years. These results are superior to those reported in previous similar studies (22,28,30). We further sought to identify the factors associated with survival outcomes. In the Cox regression analysis for PFS, patients who had received three or fewer prior lines of therapy exhibited significantly prolonged PFS compared to those who had received more than three lines (HR =0.43, 95% CI: 0.20–0.89; P=0.02). This real-world study included patients with diverse treatment histories and a multitude of variables, which is contrast to the standardized setting of a clinical trial. Nevertheless, an association between the number of prior therapy lines and treatment efficacy was identified. Therefore, we performed a subgroup Cox analysis stratified by the number of prior therapy lines. Significant treatment benefit was observed in nonsmokers, patients without baseline brain metastases, and younger patients. Patients with stage IV disease at the initiation of flumonertinib, those with a history of radiotherapy, and those receiving the 80-mg dose received clear benefit, consistent with conclusions from prior research (24). Phase III clinical trials have demonstrated the efficacy of third-generation TKIs in patients with advanced disease, leading to their approval as first-line treatments. Radiotherapy also confers a survival benefit (24,30,34). A clinical trial comparing different flumonertinib doses found that an 80-mg dose provided favorable efficacy and optimal safety, while 160 mg showed enhanced efficacy against CNS metastases; consequently, 80 mg became the standard dose (34). Furthermore, a prospective study published in 2025 confirmed the efficacy of high-dose flumonertinib against leptomeningeal metastases (35). Clinical studies have confirmed that both flumonertinib and its metabolites efficiently penetrate the blood–brain barrier, eliciting responses in CNS metastases (35,36). Our study also found that patients with brain metastases at treatment initiation could achieve favorable outcomes, highlighting flumonertinib’s potential for advanced disease. Patients treated sequentially with an earlier-generation TKI, followed by a third-generation TKI and then flumonertinib after prior third-generation EGFR-TKI therapy showed significant benefit, aligning with the conclusion regarding the number of therapy lines. Notably, during flumonertinib after prior third-generation EGFR-TKI therapy, monotherapy yielded a significant benefit, and the related subgroup was the only one with a P for interaction of less than 0.05. This finding suggests that even after progression on prior third-generation EGFR-TKIs, certain patients may still derive substantial benefit from flumonertinib monotherapy. Several potential mechanisms could underlie this observation. First, flumonertinib possesses a distinct pharmacokinetic and CNS-penetrating profile (24,26,35), which may offer therapeutic advantages over other third-generation TKIs. Second, patients in the monotherapy group might have had limited resistance mechanisms and more indolent disease biology, allowing flumonertinib to remain effective. Previous clinical studies (13,14,24) have indicated that the greatest benefit from a given TKI is achieved in the first-line setting, with reduced benefit duration in subsequent lines. In this study, over half of the patients received flumonertinib within their first three lines of therapy, contributing to the favorable overall mPFS result.

Based on previous researches (22,28,29), we conducted a retrospective analysis of flumonertinib after prior third-generation EGFR-TKI therapy following resistance to third-generation TKIs. However, our study involved several limitations. First, the sample size was relatively small, meaning that the conclusions drawn from our analysis require further validation. Second, we employed a single-arm design, and the absence of a control group limited our ability to conduct comparative analyses. Third, given that our study was retrospective and reflected real-world practice, the treatments were not standardized as they would be in clinical trials. For example, patients in our cohort received flumonertinib alongside other treatments, such as intrathecal chemotherapy or chemotherapy combined with ICIs, and the dosing of flumonertinib varied across patients. These factors inevitably influenced patient prognostic outcomes. Fourth, not all patients underwent repeat genetic testing (rebiopsy) prior to the flumonertinib after prior third-generation EGFR-TKI therapy. Treatment decisions were based on historical monitoring results, and potential new genetic mutations acquired after previous resistance to third-generation TKIs, which could affect treatment efficacy, might have been overlooked. What’s more, due to the retrospective design and incomplete follow-up data, adverse events were not systematically collected or analyzed. Therefore, the safety profile of flumonertinib in this setting could not be adequately assessed. Future prospective studies with standardized safety monitoring are warranted to better characterize treatment-related adverse events. Finally, retrospective analyses are conducted after events have occurred. This inherent design limitation prevents us from establishing predetermined thresholds for primary endpoints.

Conclusions

For patients with EGFR-mutated NSCLC who develop resistance after treatment with third-generation EGFR TKIs, flumonertinib monotherapy during rechallenge treatment is a viable therapeutic option. Initiating treatment with flumonertinib earlier may lead to better survival outcomes, a strategy which merits further investigation.

Supplementary

The article’s supplementary files as

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. This study is a retrospective analysis based on medical records. No human subjects were prospectively enrolled, no interventions were performed, and no biological samples were collected for the purposes of this study. The study was reviewed by the Institutional Review Board of Shandong Cancer Hospital and Institute, which determined that ethical approval was not required, and that written informed consent was waived due to the retrospective nature of the research and the use of existing clinical data. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Data Sharing Statement

Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2503/dss

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DOI: 10.21037/jtd-2025-1-2503