Adjuvant epidermal growth factor receptor tyrosine kinase inhibitor in resected stage N2 non-small cell lung cancer harboring EGFR mutation

Introduction

Lung cancer has the highest morbidity and mortality worldwide, and in terms of histological type, approximately 80–85% of cases are non-small cell lung cancer (NSCLC) (1,2). Among the patients with NSCLC, around 30% eligible for surgical resection of the lesion (3). For patients with completely resected stage II–IIIA NSCLC, platinum-based adjuvant chemotherapy after surgery is recommended (4). However, the efficacy of adjuvant chemotherapy in reducing the risk of disease recurrence or death is limited to only 16%, which only diminishes the risk of death by 5% at 5 years (4,5).

Epidermal growth factor receptor (EGFR) mutations, including the exon 19 deletions or exon 21 L858R point mutations, are recognized as the predominant oncogenic driver mutations in NSCLC (6,7). EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for patients with advanced NSCLC harboring EGFR mutations (8-10). Numerous clinical studies have demonstrated that adjuvant EGFR-TKI therapy results in superior disease-free survival (DFS) and overall survival (OS) as compared to chemotherapy or placebo in the postoperative adjuvant treatment of completely resected EGFR-mutant NSCLC (11-18).

However, the efficacy of postoperative radiotherapy (PORT) administered with modern techniques following adjuvant EGFR-TKIs for completely resected stage N2 NSCLC remains uncertain. According to published data, patients with postoperative N2 stage NSCLC have a considerably high incidence of local recurrence, ranging from 35% to 60%, and may benefit from PORT (19-22). However, the PORT-C and Lung ART trials demonstrated that PORT does not improve DFS or OS in patients with postoperative stage N2 NSCLC and results in a high incidence of distant metastases, even when combined with adjuvant chemotherapy (23,24). The ADAURA trial confirmed that highly potent TKIs can substantially reduce the risk of distant metastasis, but the local recurrence rate among patients with stage III (N2) NSCLC remains relatively high under this treatment (18). This may be the predominant recurrence pattern in the era of adjuvant targeted therapy. Therefore, the management of adjuvant treatments for patients with EGFR-mutant NSCLC is complex, particularly when mediastinal lymph node metastasis occurs. The efficacy of EGFR-TKI combination therapy (with chemotherapy, radiotherapy, or chemoradiotherapy) as compared to that of EGFR-TKI monotherapy remains unclear. Moreover, further investigation is necessary to ascertain the optimal duration of adjuvant EGFR-TKI therapy and to determine the clinical benefits associated with different generations of EGFR-TKIs.

In this study, we sought to examine the efficacy of adjuvant EGFR-TKI therapy after surgery in patients with stage N2 NSCLC harboring EGFR mutations in terms of DFS and OS. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1305/rc).

Methods

Study design and patient selection

This retrospective study was carried out in accordance with the principles of the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of West China Hospital, Sichuan University (approval No. 2023 [1853]). The requirement for informed consent was waived due to the retrospective nature of the analysis.

Patients with NSCLC who underwent surgical resection between July 31, 2010, and July 31, 2022, at West China Hospital, Sichuan University were consecutively recruited. The sample size was determined by the number of cases in the region during the study period. The inclusion criteria for patients were as follows: (I) age ≥18 years, (II) completion of curative surgery and confirmed mediastinal lymph node (N2) involvement according to pathological diagnosis after surgery [mediastinal lymph node involvement was confirmed by systematic nodal dissection, and pathological staging followed the 8th edition of the tumor-node-metastasis (TNM) staging system], (III) EGFR mutation-positive (exon 19 deletion or exon 21 L858R point mutation, and testing conducted via polymerase chain reaction or next-generation sequencing), and (IV) completion of adjuvant EGFR-TKI combination therapy (chemotherapy, radiotherapy, or chemoradiotherapy prior to EGFR-TKI treatment) or EGFR-TKI monotherapy. Meanwhile, the exclusion criteria were as follows: (I) incomplete resection, (II) stage N0–1 or N3 disease, (III) stage IV disease, (IV) other confirmed malignancies, (V) incomplete clinical data, (VI) duration of EGFR-TKI therapy shorter than 6 months for any reason, and (VII) preoperative neoadjuvant therapy. Given the minimal proportion of missing data (n=8/198, 4.0%, <5%) in this retrospective study, cases with incomplete records were excluded prior to formal analysis, resulting in a final analytic sample of 190 subjects.

Application of adjuvant EGFR-TKI therapy

The treatment options included either EGFR-TKI monotherapy or EGFR-TKI combination therapy after surgery. Patients received oral first-generation EGFR-TKIs (250 mg of gefitinib once a day, 150 mg of erlotinib once a day, or 125 mg icotinib three times a day) or third-generation EGFR-TKIs (80 mg of osimertinib once a day or 110 mg of almonertinib once a day).

Patients continued treatment with EGFR-TKIs until disease recurrence or intolerable toxicity or until instructed to desist at the discretion of the clinicians overseeing the study. Postoperative platinum-based chemotherapy administered via intravenous infusion consisted of 2–6 cycles of pemetrexed + cisplatin/carboplatin (AP), paclitaxel + cisplatin/carboplatin (TP), or gemcitabine + cisplatin/carboplatin (GP). Radiotherapy was administered via megavoltage devices with a photon energy >6 MV, and three-dimensional conformal radiotherapy or intensity-modulated radiotherapy was administered within 3 months after surgery. The prescribed total radiotherapy dose was 50–54 Gy, which was delivered in fractions of 1.8–2 Gy per fraction at five fractions per week, with no more than 10 consecutive treatment-free days.

Follow-up

Patients were followed up every 3 months after surgery for 3 years, twice a year for the next 5 years, and every 12 months for 6–10 years. Follow-up examinations included computed tomography (CT) of the chest and upper/whole abdomen, brain magnetic resonance imaging, and tests for NSCLC biomarkers. Additional diagnostic procedures, such as skeletal scans, positron emission tomography-CT scans, and needle aspiration biopsy, were performed as needed. Locoregional recurrence was defined as disease recurrence within the primary tumor site (bronchial stump and adjacent areas) or regional lymph nodes (ipsilateral hilar, mediastinal, or supraclavicular nodes). Distant metastasis is defined as disease recurrence beyond the locoregional confines, encompassing the contralateral lung lobe(s), distant lymph nodes (e.g., axillary, abdominal), or extrathoracic organs (e.g., brain, bone, liver, adrenal glands). DFS was defined as the time interval from the date of surgery to the date of relapse or the last follow-up without evidence of recurrence. OS was defined as the time interval from surgery to the occurrence of death from any cause or the last follow-up, whichever occurred first. The follow-up period ended on May 31, 2024.

Statistical analysis

All statistical analyses were performed with SPSS version 26.0 (IBM Corp., Armonk, NY, USA). The continuous variables are reported as the mean ± standard deviation (SD), whereas the categorical variables are described in terms of frequencies (percentages). The Mann-Whitney test was used to analyze continuous variables, and the Chi-squared test was used for categorical variables. Univariate analysis included the Kaplan-Meier method for calculation of the DFS and OS, with statistical comparisons being completed via the log-rank test. Cox proportional hazards models were employed for multivariate analyses of DFS and OS, with the proportional hazards assumption of the Cox model assessed via Schoenfeld residuals test. All statistical tests were two-sided, and a P<0.05 was considered statistically significant.

Results

Patients and treatment

A total of 190 patients with stage N2 EGFR-mutated NSCLC who underwent EGFR-TKI therapy after pulmonary resection were included in the study, with patient recruitment spanning from July 31, 2010, to July 31, 2022 (Figure 1). Among the patient cohort (117 females and 73 males), 150 patients had stage IIIA disease, and 40 patients had stage IIIB disease. Postoperative adjuvant therapy consisted of first-generation EGFR-TKIs for 138 patients and third-generation EGFR-TKIs for 52 patients. Among these patients, 127 were administered adjuvant EGFR-TKI monotherapy, while 63 patients received combination therapy with prior administration of EGFR-TKI plus chemotherapy (35 patients), radiotherapy (11 patients), or radiochemotherapy (17 patients). For the chemotherapy regimens, TP was administered in 12 patients, AP in 37 patients, and GP in 3 patients. The detailed demographic and clinical data are presented in Table 1.

Figure 1 Flowchart of patient selection in the study. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Survival analysis

The median follow-up period was 49 months. At the end of the follow-up (May 31, 2024), 109 patients experienced disease progression, the median DFS was 38 months [95% confidence interval (CI): 31.3–44.7], and the 4-year DFS rate was 41.3% (Figure 2A). Moreover, a total of 150 patients were alive and did not reach median OS, with a 4-year OS rate of 80.2% (Figure 2B).

Figure 2 K-M survival curves depicting (A) DFS and (B) OS for the entire study population. CI, confidence interval; DFS, disease-free survival; K-M, Kaplan-Meier; NC, could not be calculated; NR, not reached; OS, overall survival.

The DFS and OS were calculated based on the pathological TNM (pTNM) stage. In the overall patient cohort, a significant association was observed between the pTNM stage and DFS (χ²=6.679; P=0.01; Figure 3A), while no significant association was observed for OS (χ²=0.336; P=0.56) (Figure 3B). The 4-year DFS rate in the stage IIIA subgroup was 48.2% [median survival time (MST): 45 months; 95% CI: 32.9–57.1], while it was only 17.4% in the stage IIIB subgroup (MST: 32 months; 95% CI: 20.4–43.6). The 4-year OS rate was 79.6% in the stage IIIA subgroup (MST not reached), while it was 82.0% in the stage IIIB subgroup (MST: 88 months; 95% CI not measurable).

Figure 3 Subgroup survival analyses for patients. K-M survival curves for (A) DFS and (B) OS according to the disease stage. K-M survival curves for (C) DFS and (D) OS according to the different durations of EGFR-TKI treatment (>3 vs. ≤3 years). K-M survival curves for (E) DFS and (F) OS in patients treated with adjuvant EGFR-TKI monotherapy or combination therapy. CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; HR, hazard ratio; K-M, Kaplan-Meier; NC, could not be calculated; NR, not reached; OS, overall survival; TKI, tyrosine kinase inhibitor.

To examine the influence of treatment duration on DFS and OS, we collected the data on the duration of EGFR-TKI therapy for all enrolled patients. The treatment duration ranged from 6 to 83 months, with a median therapy time of 25 months. Patients were divided into two subgroups based on the duration of EGFR-TKI therapy: >3 and ≤3 years. The results showed a significant positive association between the duration of EGFR-TKI therapy and improved DFS (χ²=46.491; P<0.001) (Figure 3C) and with OS benefit (χ²=20.936; P<0.001) (Figure 3D). In the subgroup with ≤3 years of therapy, the 4-year DFS rate was 22.5% (MST: 29 months; 95% CI: 24.5–33.5), whereas in the subgroup with >3 years of therapy, it was 81.1% (MST: 70 months; 95% CI: 57.6–82.4). Similarly, the 4-year OS rate for patients who received ≤3 years of EGFR-TKI therapy was 69.6% (MST not reached), while that for those who received >3 years was 97.0% (MST not reached). Additionally, to further evaluate the impact of the duration of EGFR-TKI therapy on patient survival, we stratified patients into two subgroups based on therapy duration: >2 and ≤2 years. The results also showed a significant positive association between the duration of EGFR-TKI therapy and improved DFS (χ²=59.217; P<0.001) (Figure S1A) and with OS benefit (χ²=10.259; P=0.001) (Figure S1B). In the subgroup with ≤2 years of therapy, the 4-year DFS rate was 16.4% (MST: 20 months; 95% CI: 16.1–23.9), whereas in the subgroup with >2 years of therapy, it was 60.8% (MST: 58 months; 95% CI: 46.3–69.7). Similarly, the 4-year OS rate for patients who received ≤2 years of EGFR-TKI therapy was 70.2% (MST not reached), while that for those who received >2 years was 87.5% (MST not reached).

To compare adjuvant EGFR-TKI monotherapy and EGFR-TKI combination therapy in terms of DFS and OS, we divided the patients into two subgroups: EGFR-TKI monotherapy and EGFR-TKI combination therapy. No statistically significant differences were observed in terms of DFS (χ²=0.117; P=0.73) (Figure 3E) or OS (χ²=2.246, P=0.13) (Figure 3F). The 4-year DFS rate in the EGFR-TKI monotherapy subgroup was 44.8% (MST: 38 months; 95% CI: 30.2–45.8), while that in the EGFR-TKI combination therapy subgroup was 36.0% (MST: 38 months; 95% CI: 28.4–47.6). The 4-year OS rate was 75.0% in the EGFR-TKI monotherapy subgroup (MST: 86 months; 95% CI not measurable) and 90.3% in the EGFR-TKI combination therapy subgroup (MST not reached).

To examine the association of EGFR-TKI generation with DFS and OS, patients were divided into first- and third-generation EGFR-TKI subgroups. Adjuvant therapy with third-generation EGFR-TKIs was associated with a significantly superior DFS benefit (χ²=16.709; P <0.001) (Figure 4A) as compared to therapy with first-generation EGFR-TKIs, but there was no significant OS benefit (χ²=0.680; P=0.41) (Figure 4B). The 4-year DFS rate was 33.4% in the first-generation EGFR-TKI subgroup (MST: 34 months; 95% CI: 29.8–38.2) and 73.2% in the third-generation EGFR-TKI subgroup (MST not reached). Meanwhile, the 4-year OS rate was 78.6% in the first-generation EGFR-TKI subgroup (MST not reached) and 89.7% in the third-generation EGFR-TKI subgroup (MST: 88 months; 95% CI not measurable).

Figure 4 Subgroup survival analyses for patients. K-M survival curves for DFS (A) and OS (B) in patients who used adjuvant first-generation EGFR-TKIs or third-generation EGFR-TKIs. K-M survival curves for DFS (C) and OS (D) according to the number of PMLNs. K-M survival curves for (E) DFS and (F) OS according to the EGFR mutation status. CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; HR, hazard ratio; K-M, Kaplan-Meier; NC, could not be calculated; No., number; NR, not reached; OS, overall survival; PMLNs, positive mediastinal lymph nodes; TKI, tyrosine kinase inhibitor.

Patients were categorized into two subgroups according to the number of positive mediastinal lymph nodes (PMLNs): <3 and ≥3. The PMLNs <3 subgroup had a significantly better DFS (χ²=5.701; P=0.02) (Figure 4C) and OS (χ²=4.370, P=0.04) (Figure 4D) as compared to the PMLNs ≥3 subgroup. In the PMLNs <3 subgroup, the 4-year DFS rate was 48.2% (MST: 47 months; 95% CI: 35.0–59.0), while it was 31.6% in the PMLNs ≥3 subgroup (MST: 32 months; 95% CI: 22.4–41.6). The 4-year OS rate was 85.3% in the PMLNs <3 subgroup (MST not reached) and 73.0% in the PMLNs ≥3 subgroup (MST: 86 months; 95% CI not measurable).

The overall cohort was also divided into two subgroups based on EGFR mutation status: the EGFR exon 19 deletion subgroup and the EGFR exon 21 L858R point mutation subgroup. There was a significant association of EGFR mutation status with DFS benefit (χ²=4.605; P=0.03) (Figure 4E) and with OS benefit (χ²=6.322; P=0.01) (Figure 4F). The 4-year DFS rate was 50.0% in the EGFR exon 19 deletion subgroup (MST: 52 months; 95% CI: 38.5–65.5) and 33.0% in the EGFR exon 21 L858R point mutation subgroup (MST: 36 months; 95% CI: 29.6–42.4). Meanwhile, the 4-year OS rate was 86.2% in the EGFR exon 19 deletion subgroup (MST not reached) and 74.6% in the EGFR exon 21 L858R point mutation subgroup (MST: 88 months, 95% CI: 49.9–126.1). Forest plots depicting all the subgroup analyses of DFS and OS are shown in Figure 5A and Figure 5B, respectively.

Figure 5 The forest plots depicting subgroup analyses for DFS (A) and OS (B), respectively. CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; HR, hazard ratio; OS, overall survival; PMLN, positive mediastinal lymph node; pTNM, pathological tumor-node-metastasis; TKI, tyrosine kinase inhibitor.

Univariate and multivariate analysis

Univariate analysis for DFS identified several factors that were significantly associated with DFS, including pTNM stage (stage IIIA vs. stage IIIB), duration of EGFR-TKI treatment (>3 vs. ≤3 years), generation of EGFR-TKI (third-generation vs. first-generation), EGFR mutation status (exon 19 deletion vs. exon 21 L858R point mutation), number of PMLNs (<3 vs. ≥3), and metastatic stations of mediastinal lymph nodes (single station vs. multiple stations). In addition, sex, age (≤60 vs. >60 years), smoking history, histology (adenocarcinoma vs. adenosquamous carcinoma), adjuvant treatment regimen (EGFR-TKI monotherapy vs. EGFR-TKI combination therapy), and number of lymph nodes examined [<15 vs. ≥15, the median number of examined lymph nodes was 12 (interquartile range, 10–15)] were also evaluated but did not show a significant association with DFS (Table 2).

Multivariate analysis of DFS was performed for variables including pTNM stage, duration of EGFR-TKI treatment, generation of EGFR-TKI, number of PMLNs, metastatic stations of mediastinal lymph nodes, and EGFR mutation status. The analysis revealed that the pTNM stage, duration of EGFR-TKI treatment, and generation of EGFR-TKI were independent predictors of DFS (Table 2).

In the univariate analysis of OS, the duration of EGFR-TKI treatment, EGFR mutation status, and number of PMLNs were significantly associated with OS (Table 3). The multivariate analysis included the variables of duration of EGFR-TKI treatment, EGFR mutation status, and the number of PMLNs. The results indicated that the duration of EGFR-TKI treatment was an independent prognostic factor for OS (Table 3).

Patterns of recurrence

In the overall cohort, disease progression was observed in 57.4% (109/190) of patients, with distant metastases occurring in 51.6% (98/190) of all enrolled patients and locoregional recurrence in 12.6% (24/190). In the EGFR-TKI monotherapy subgroup, distant metastases occurred in 48.0% (61/127) of all enrolled cases and locoregional recurrence in 11.8% (15/127). In the EGFR-TKI combination therapy subgroup, distant metastases occurred in 58.7% (37/63) of all enrolled patients and locoregional recurrence in 14.3% (9/63) (Figure 6A). Furthermore, we performed a stratified analysis of initial disease progression patterns by EGFR-TKI generation. In the first-generation EGFR-TKI subgroup, the predominant progression sites were brain (26.8%), lung (26.1%), and bone (15.2%) (Figure 6B). In the third-generation EGFR-TKI subgroup, the most frequent progression sites were lung (5.8%), brain (3.8%), and liver (3.8%). In the third-generation EGFR-TKI subgroup, the most frequent progression sites were lung (5.8%), brain (3.8%), and liver (3.8%) (Figure 6C). Among all participants, the most common progression sites were the brain, lungs, and bones (Figure 6).

Figure 6 Bar graphs of recurrence patterns in the overall cohort (A), first-generation EGFR-TKI subgroup (B), and third-generation EGFR-TKI subgroup (C). EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Subsequent treatment and safety

This study recorded the subsequent treatment after patients’ first relapse and/or metastasis. At follow-up, a total of 109 patients experienced disease progression. Of these, 81 (74.3%) patients opted for an alternative EGFR-TKI therapy or continued the original targeted therapy after progression. In addition, after experiencing progression, 28 (25.7%) patients opted for other therapies, such as chemotherapy, radiotherapy, antiangiogenic therapy, and immunotherapy.

Across the entire study population, treatment-related adverse events (TRAEs) of grade 3 occurred in 4.2% (8/190) of patients. No fatal TRAEs were reported. The rate of grade 3 TRAEs was 5.1% (7/138) in the first-generation EGFR-TKI subgroup, compared to 1.9% (1/52) in the third-generation EGFR-TKI subgroup. Rash and liver dysfunction were more frequently observed in the first-generation EGFR-TKI subgroup. Grade 3 rash occurred in 2.9% (4/138) of these patients, while grade 3 liver dysfunction was observed in 2.2% (3/138). Treatment discontinuation due to intolerable grade 3 rash occurred in one patient (receiving gefitinib) following 14 months of adjuvant therapy. In the third-generation EGFR-TKI subgroup, grade 3 rash occurred in one patient (1.9%, 1/52) without resulting in treatment discontinuation.

Discussion

A number of studies demonstrated the efficacy of postoperative adjuvant EGFR-TKI therapy in terms of DFS and OS in patients with NSCLC and EGFR mutations, leading to a shift in the clinical management of this patient population (11-18). However, there remain several unresolved issues, such as the duration of EGFR-TKI adjuvant therapy, the optimal treatment regimen (monotherapy versus combination therapy), and the comparative efficacy of different generations of EGFR-TKIs, which require further investigation and resolution. In patients with postoperative N2 NSCLC, the extent of mediastinal lymph node involvement may also affect the efficacy of EGFR-TKI treatment, complicating the adjuvant administration of EGFR-TKIs. Our study preliminarily addressed several of these issues.

There is no established consensus regarding the optimal duration of adjuvant EGFR-TKI therapy. Related trials, such as ADJUVANT, SELECT, and RADIANT, employed a 2-year treatment period. However, observations from Kaplan-Meier curves for DFS indicate a significant decline after therapy discontinuation (25), suggesting that prolonged exposure to EGFR-TKIs may delay relapse and improve OS. In both the ADAURA and ARTS trials, the designated duration of adjuvant therapy with osimertinib and aumolertinib, respectively, was 3 years (26,27). In the ADAURA trial, the Kaplan-Meier curves continued to diverge between the osimertinib and placebo groups after 3 years, suggesting a potential benefit for patients with prolonged osimertinib treatment (26). The recurrence pattern of NSCLC after surgery involves three distinct peaks, with the third occurring in the fourth year (28,29). Therefore, extending the duration of TKI treatment could provide survival benefits to patients. In this study, patients were categorized into subgroups based on the duration of adjuvant therapy: ≤3 and >3 years. The results indicated that a longer duration of adjuvant therapy was associated with a significant improvement in DFS (P<0.001) and OS (P<0.001). Therefore, if patients can tolerate the side effects of EGFR-TKIs, extending the duration of EGFR-TKI adjuvant therapy is recommended to effectively delay recurrence and metastasis. In addition, dynamic detection of minimum residual disease (MRD) can be performed by detecting circulating tumor DNA (30,31). A positive MRD finding after surgery can serve as a predictive indicator of DFS and assist clinicians in preemptively tailoring adjuvant treatment plans for high-risk patients. Conversely, if MRD remains persistently negative, medical therapy may be temporarily halted to allow for continued monitoring and provide patients the opportunity to recover (30-34). Continuation of EGFR-TKI treatment can be considered if MRD is positive and radiological findings support it (30-34).

The optimal adjuvant EGFR-TKI therapy for patients with mediastinal lymph node involvement in EGFR-mutant NSCLC remains unclear. In patients with advanced NSCLC, combination therapies involving EGFR-TKIs with chemotherapy, radiotherapy, or radiochemotherapy have demonstrated superior survival outcomes as compared to EGFR-TKI monotherapy (35-39). Nonetheless, the definitive superiority of combined EGFR-TKI therapy over monotherapy in the adjuvant treatment paradigm remains to be confirmed. Two meta-analyses suggested that EGFR-TKI combination therapy with chemotherapy has better efficacy than does adjuvant EGFR-TKI monotherapy and that the addition of osimertinib after adjuvant provides improved DFS (40,41). However, there is some evidence indicating that EGFR-TKI monotherapy is comparable to the combination of EGFR-TKI and chemotherapy with respect to DFS and OS in the adjuvant setting (42,43). Li et al. analyzed the ADAURA trial data and found no substantial survival advantage for patients who received adjuvant chemotherapy before osimertinib treatment (44). Furthermore, the latest OS results from the ADAURA included 5-year OS rates of 87% and 88% in the osimertinib groups with and without chemotherapy, respectively, suggesting that there may be no significant OS benefit from adjuvant chemotherapy prior to osimertinib treatment (18).

Currently, the decision to administer adjuvant radiotherapy after surgery for patients with stage N2 NSCLC remains controversial. Several studies in patients with stage N2 NSCLC suggest that PORT may be associated with improved locoregional control and survival (19,45-47). In addition, a comprehensive analysis of the National Cancer Database found that PORT can improve 5-year survival rates by 5–7% in patients with postoperative stage N2 NSCLC (21). Furthermore, two randomized phase III trials reported the efficacy of PORT in reducing local recurrence in patients with stage N2 NSCLC. However, neither study found there to be a substantial improvement in DFS or OS, although a high incidence of distant metastases was observed (23,24). Interestingly, the stratified analysis conducted within the PORT-C trial, which included the number of pathologically detected lymph nodes and positive lymph nodes, revealed statistically significant differences (23). Preclinical studies have attested to the radiosensitizing effects of EGFR-TKIs (48,49), and there is considerable research confirming that the integration of EGFR-TKIs with radiotherapy or radiochemotherapy can significantly prolong DFS and even OS (38,39,50). However, the potential benefits of adjuvant therapies remain unclear. In our study, EGFR-TKI combination therapy, relative to EGFR-TKI monotherapy, provided no statistically significant benefit in DFS (P=0.73) or OS (P=0.13), indicating that the addition of combination therapy does not enhance the survival outcomes for this patient population. Interestingly, the subgroup analysis based on the number of PMLNs (<3 vs. ≥3) revealed a statistically significant difference in DFS (P=0.02) and OS (P=0.04), suggesting that the number of mediastinal lymph nodes involved may influence patients’ survival benefit.

In addition, the efficacy of adjuvant therapy with third-generation EGFR-TKIs as compared to with first-generation EGFR-TKIs remains unclear. The phase III FLAURA trial showed that osimertinib outperformed gefitinib and erlotinib in terms of progression-free survival, OS, and central nervous system efficacy (51). These findings strongly support the incorporation of osimertinib into the standard of care for patients with previously untreated advanced NSCLC with EGFR mutations (51,52). Furthermore, a meta-analysis conducted in an adjuvant setting showed that third-generation EGFR-TKIs as adjuvant therapy tended to have superior efficacy as compared to first-generation EGFR-TKIs (41). In our study, the DFS benefit of adjuvant therapy with third-generation EGFR-TKIs was significantly superior to that of first-generation EGFR-TKIs (P<0.001), although no significant improvement in OS was detected (P=0.41). The lack of OS benefit may be attributed to the impact of follow-up treatment after first recurrence or metastasis, for which aggressive antitumor therapies, such as EGFR-TKI replacement or continuation, radiotherapy, chemotherapy, antiangiogenic therapy, and immunotherapy, were administered.

Furthermore, our study showed that patients harboring the EGFR exon 19 deletion may derive greater benefit from adjuvant EGFR-TKI therapy as compared to those with the EGFR exon 21 L858R point mutation, with significant discrepancies in DFS (P=0.03) and OS (P=0.01). Several studies have reported a greater efficacy and prolonged OS of EGFR-TKIs for patients harboring EGFR exon 19 deletion as compared to those with the exon 21 L858R point mutation (53). A meta-analysis has also supported these findings, suggesting that patients harboring exon 19 deletions may derive greater benefits from adjuvant EGFR-TKI therapy (41). It should be noted that histology (adenocarcinoma vs. adenosquamous carcinoma) was included as a covariate in our univariate analyses of DFS and OS. Our results demonstrated no significant association between histology and DFS (P=0.76) or OS (P=0.87). Currently, the benefit of EGFR-TKIs in EGFR-mutant lung adenosquamous carcinoma remains undefined. Results from several retrospective studies suggest that therapeutic efficacy of EGFR-TKIs in patients with EGFR-mutant adenosquamous carcinoma is comparable to that in lung adenocarcinoma patients (54,55). The notably small adenosquamous carcinoma cohort in our study (n=3) may have compromised statistical power. Prospective randomized controlled trials are warranted for further exploration and validation.

Our study involved certain limitations that should be addressed. Foremost, we employed a single-center, nonrandomized, retrospective design, resulting in potential selection bias and limited generalizability to a broader population. Given the non-randomized treatment allocation in this retrospective study, we are unable to provide definitive clinical rationale for selecting EGFR-TKI monotherapy versus combination therapy (chemotherapy, radiotherapy, or chemoradiotherapy), and it remains unclear whether baseline risk features such as tumor size, nodal burden, performance status, comorbidities, or year of diagnosis influenced regimen choice. Therefore, this also represents a study limitation that may introduce confounding by indication and unmeasured confounders. Concomitantly, the absence of an observed benefit for combination therapy may be influenced by limited statistical power and treatment heterogeneity. Second, the observed association between prolonged EGFR-TKI treatment duration and improved DFS/OS may raise potential concerns about immortal time bias, constituting a study limitation. Third, compared with first-generation EGFR-TKIs, third-generation use in the adjuvant setting is more recent, and shorter median follow-up could inflate apparent DFS or OS effects. Notably, 74.3% of patients received subsequent EGFR-TKI therapy upon disease progression in this retrospective study, potentially confounding OS interpretation. Moving forward, we will maintain ongoing survival surveillance with cohort expansion to better inform clinical practice for this population.

Therefore, the study results should be further confirmed through a randomized clinical trial to accurately determine the efficacy of the treatment strategy. In addition, the OS data obtained in our study are still considered immature, and longer follow-up periods are required for thorough observation and validation of survival outcomes.

Conclusions

Our study found that EGFR-TKI monotherapy and combination therapy demonstrated no significant differences in terms of DFS or OS in patients with completely resected stage N2 EGFR-mutant NSCLC. Adjuvant treatment with third-generation EGFR-TKIs and prolonged treatment duration may offer enhanced survival benefits. However, further prospective trials are necessary to validate these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1305/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1305/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1305/prf

Funding: This work was supported by the Youth Project of Sichuan Natural Science Foundation (Nos. 2023NSFSC1892 and 2024NSFSC1918) and the Postdoctoral Research Project of West China Hospital, Sichuan University (No. 2020HXBH132).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1305/coif). The 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 conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of West China Hospital, Sichuan University (approval No. 2023[1853]). The requirement for informed consent was waived due to the retrospective nature of the analysis.

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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