EGFR-TKIs with or without stereotactic body radiotherapy to primary lesion in the advanced EGFR-mutated non-small cell lung cancer

Introduction

Lung cancer ranks among the most common forms of malignant tumors worldwide and stands as a leading cause of cancer-related fatalities (1). Non-small cell lung cancer (NSCLC) constitutes the most prevalent subtype of lung cancer, accounting for 85% of all cases (2,3). More than 50% of NSCLC patients are diagnosed at an advanced stage, which presents a daunting challenge in the field of oncology due to its limited treatment options (4). Recent advancements in targeted therapies have revolutionized the landscape of NSCLC treatment (5-9). Currently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib, and osimertinib, represent a key class of targeted therapies. These drugs specifically target aberrant EGFR signals caused by EGFR mutation, which is prevalent in NSCLC patients. EGFR-TKIs have demonstrated substantial clinical benefits, leading to improved outcomes and enhanced quality of life for patients with EGFR-mutated NSCLC and have become the standard treatment for advanced-stage EGFR mutation-positive patients (7-11). However, with the proliferation of TKI-resistant clones in patients, TKI resistance inevitably develops (12) typically within a median of 9 to 13 months for first-generation TKIs (10) and approximately 18 months for third-generation TKIs such as osimertinib (13). Research indicated that the majority of TKI-resistant clones primarily exist within the residual lesions after TKI treatment (14-17). Consequently, most patients experience recurrence after TKI therapy primarily at the sites of the primary tumor or previously existing metastases (18). The growth of these resistant clones within the remaining lesions eventually leads to the failure of TKI therapy.

Stereotactic body radiotherapy (SBRT) has emerged as a pivotal therapeutic modality for early-stage NSCLC, particularly in cases where surgical intervention is not viable due to tumor location or the patient’s overall health condition (19-21). SBRT delivers highly precise and concentrated radiation doses to the tumor site, minimizing exposure to adjacent healthy tissues. This precision enables effective tumor control while reducing the risk of adverse effects, making SBRT an appealing choice, especially for patients’ ineligible for surgery or those who prefer non-invasive treatments.

The synergistic potential of combining EGFR-TKIs with concurrent local treatment, such as SBRT, has garnered significant interest in the oncology community. In recent prospective and retrospective studies, this comprehensive treatment approach has been demonstrated to prolong the time to TKI resistance and improve progression-free survival (PFS) in patients (22-25). The rationale behind this combination lies in the complementary nature of these treatments: EGFR-TKIs tackle systemic disease by inhibiting aberrant EGFR signaling, while SBRT provides localized control, particularly for primary lung lesions and oligometastatic sites.

This retrospective study delves into the comparative efficacy of EGFR-TKI monotherapy versus the combination of EGFR-TKIs and SBRT in the context of advanced NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-635/rc).

Methods

Patients

This single-center retrospective research was approved by the Chongqing University Cancer Hospital Ethics Committee. Between 2018 and 2023, we screened 485 patients who were pathologically diagnosed with NSCLC and received targeted therapy at Chongqing University Cancer Hospital. Inclusion criteria consisted of (I) pathological diagnosis of stage III or metastatic/recurrent NSCLC according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual (26); (II) molecular testing indicating activating EGFR mutations; (III) age 18 years or older; (IV) patients received first-line EGFR-TKI therapy combined with SBRT for the primary tumor before disease progression, or received first-line EGFR-TKI alone without disease progression at the time of the first imaging assessment. In the TKIs plus SBRT group, radiotherapy was administered as part of routine clinical care after patients showed initial tumor shrinkage with EGFR-TKI therapy and achieved stable disease, with persistent residual lesions at the primary site and no evidence of new metastases on serial imaging. The main exclusion criteria included early-stage NSCLC, tumor progression before SBRT, or confirmed disease progression at the first imaging assessment in the TKIs alone group.

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. It was approved by the Ethics Committee of Chongqing University Cancer Hospital (CZLL2025-059-001). Informed consent was waived due to the retrospective nature of the study and the approval by the Ethics Committee.

Treatment and follow-up

All patients received EGFR-TKI treatment, including gefitinib, erlotinib, icotinib, afatinib, or osimertinib. According to the treatment procedure, eligible patients were divided into two groups: the TKIs plus SBRT group (patients were evaluated with stable disease during first-line EGFR-TKI treatment, and subsequently, SBRT to the primary tumor was administered using Varian’s EDGE linear accelerator) and the TKIs alone group (patients received only EGFR-TKIs treatment until disease progression or unacceptable toxicity). The dose-fractionation regimen of SBRT to the primary lung lesions was determined by the treating radiation oncologist based on clinical parameter considerations, including tumor size and location.

Computed tomography (CT) with contrast of the chest and upper abdomen and contrast-enhanced magnetic resonance imaging (MRI) for the brain were performed every 8–12 weeks. The Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) was used to evaluate the response after treatment. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions compared to baseline, with an absolute increase of at least 5 mm, or the appearance of new lesions. The primary endpoint was PFS, defined from the time of initiation of EGFR-TKI treatment to the time of disease progression or death. The secondary endpoints were overall survival (OS), defined from the time of initiation of EGFR-TKI treatment to death from any cause, and safety. The Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) was used to evaluate the grade of adverse events (AEs).

Meta-analysis

A systematic literature review was conducted on PubMed, Cochrane, Embase and other online databases up until January 10, 2025, for randomized clinical trials (RCTs) using the following search terms: (((“Stereotactic body radiation therapy” OR “radiosurgical” OR “gamma knife radiosurgery” OR “cyberknife radiosurgery” OR “Stereotactic radiosurgery” OR “Radiosurgery” OR SBRT) AND “non-small cell lung cancer” OR “NSCLC”)) AND “EGFR tyrosine kinase inhibitor” OR ((EGFR-TKI) OR (Epidermal Growth Factor Receptor tyrosine kinase inhibitor)) AND (“randomized controlled trial” OR “RCT” OR “clinical trial”), with an English language restriction. To ensure the comprehensiveness of the included literature, we also searched relevant abstracts from the American Society of Clinical Oncology (ASCO), American Association for Cancer Research (AACR), World Conference on Lung Cancer (WCLC), and American Society for Radiation Oncology (ASTRO) conferences over the past 10 years. Studies were included based on the following criteria: (I) histologically confirmed NSCLC with EGFR mutation; (II) metastatic or stage IV disease; (III) direct comparison of TKIs combined with SBRT versus TKIs alone; (IV) sufficient data for quantitative meta-analysis [reporting at least one outcome measure (PFS or OS or ≥ grade 3 treatment-related AEs) in terms of odds ratio (OR) or hazard ratio (HR)]. Review Manager 5.4 was used for statistical analysis.

Statistical analysis

Statistical analyses were performed using SPSS 26.0 software (IBM, Armonk, NY, USA). A P value <0.05 was considered statistically significant. Baseline clinicopathologic variables were evaluated by Kruskal-Wallis tests (for continuous variables) or Pearson Chi-squared test (for categorical variables), as appropriate. PFS and OS were calculated by the Kaplan-Meier method, and the Log-rank test was utilized for intergroup comparisons. Univariate and multivariate Cox proportional hazards regression model analyses were used to identify independent prognostic factors associated with PFS. A P value of <0.05 was considered statistically significant.

Results

Patient characteristics

Between September 2018 and September 2023, a total of 485 patients diagnosed with NSCLC and who received targeted therapy were screened. Through the selection process illustrated in Figure 1, a total of 58 patients were included in the study. Among them, 15 patients underwent combined treatment with TKIs and SBRT, while 43 patients received TKI monotherapy. The baseline characteristics of the patients are presented in Table 1. The median age of the patients was 63 years (range, 54–66.3 years), with 30 male patients (51.7%). Nine patients (15.5%) had an Eastern Cooperative Oncology Group (ECOG) performance status score greater than 2. Fifty-one patients (87.9%) were diagnosed with stage IV. Twenty-five (43.1%) patients had a history of smoking. Patients diagnosed with the exon 19 deletion mutation and the exon 21 L858R mutation are both 28 (48.3%). Fifty (86.2%) had histology of adenocarcinoma. Regarding TKI treatments, 39.7% (n=23) of patients underwent gefitinib therapy, 27.6% (n=16) received icotinib, 17.2% (n=10) were treated with erlotinib, 5.2% (n=3) were administered afatinib, and 10.3% (n=6) received osimertinib. In the TKIs plus SBRT group, 15 patients received SBRT to the primary lung lesion with 44–70 Gray (Gy)/5–11 fractions, the median biologically effective dose for an α/β ratio of 10 Gy (BED10) was 100 Gy (range, 100–112.5 Gy). The two groups’ baseline characteristics were generally well-balanced. There were no significant differences between the TKIs plus SBRT group and the TKIs alone group in terms of age, smoking status, sex, ECOG performance status, tumor-node-metastasis (TNM) stage, number of metastatic organs, incidence of brain or bone metastases, and overall AE rates. Among patients with stage IV disease, 7 in the TKIs plus SBRT group and 25 in the TKIs alone group had oligometastatic disease, with no statistically significant difference between the two groups (P=0.53). However, notable differences were observed in EGFR mutation subtypes and the types of EGFR-TKIs administered. Importantly, subsequent multivariate analysis demonstrated that neither EGFR mutation status nor EGFR-TKI type was an independent predictor of PFS, thereby minimizing their potential confounding effect on the study outcomes.

Figure 1 Flow chart of the patient selection process. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; SBRT, stereotactic body radiotherapy; TKI, tyrosine kinase inhibitor.

Survival outcomes

The median follow-up duration was 37.5 months in the SBRT plus TKIs group and 29.3 months in the TKIs alone group. The disease progression was observed in 6 patients in the TKIs plus SBRT group, and all patients in the TKIs alone group experienced disease progression. Compared with the TKIs alone group, the TKIs plus SBRT group showed a significantly longer median progression-free survival (mPFS) [54.9 vs. 10.2 months, HR =0.21, 95% confidence interval (CI): 0.12–0.39, P<0.001, Figure 2]. One patient in the TKIs plus SBRT group died, and the median OS had not yet been reached. In contrast, 20 patients in the TKIs alone group died, with a median OS of 40.5 months (95% CI: 24.4–56.7). In univariate Cox regression analysis, an ECOG score <2 (HR =0.37, 95% CI: 0.17–0.78, P=0.009), the use of SBRT (HR =0.12, 95% CI: 0.05–0.31, P<0.001) and EGFR-TKIs type (HR =0.08, 95% CI: 0.01–0.61, P=0.02) were predictors of longer PFS (Table 2). Further multivariate Cox regression analysis identified SBRT as an independent predictor of prolonged PFS (HR =0.15, 95% CI: 0.05–0.45, P<0.001) (Table 2).

Figure 2 Kaplan-Meier curve compares the PFS between the TKIs plus SBRT group and the TKIs alone group. PFS, progression-free survival; SBRT, stereotactic body radiotherapy; TKI, tyrosine kinase inhibitor.

AEs

AEs are summarized in Table 3. Overall, patients in both groups exhibited good tolerance to the treatments, with no grade 4 or 5 AEs reported. There were no significant differences in the incidence of AEs of any grade between the two groups (46.7% vs. 27.9%, P=0.21). During EGFR-TKI therapy, common AEs such as anemia, fatigue, skin rash, pruritus, diarrhea, and pruritus were observed. One patient experienced grade 3 interstitial pneumonia in the TKIs alone group. The most common AE caused by SBRT is radiation pneumonitis (46.7%). However, the majority of cases were grade 1 or 2, with 2 patients (13.3%) being grade 2 in the TKIs plus SBRT group. The incorporation of SBRT did not result in any cases of severe radiation pneumonitis or esophagitis (≥ grade 3).

Discussion

In this retrospective study, we evaluated the efficacy and safety of combining SBRT with EGFR-TKIs in patients with advanced EGFR-mutated NSCLC. SBRT was administered during TKI treatment, specifically after achieving stable disease. Our findings showed that combining SBRT with EGFR-TKIs significantly prolonged PFS compared to TKI monotherapy. Both groups exhibited expected TKI-related AEs, such as skin rash, neutropenia, and gastrointestinal disturbances. Importantly, this combination did not increase the incidence of grade ≥3 toxicities. The most common SBRT-related AEs—such as radiation pneumonitis, esophagitis, and radiation dermatitis—were predominantly low grade (grade 1–2), indicating favorable tolerability.

However, several limitations of this study should be acknowledged. Firstly, its retrospective design might have led to incomplete or inconsistent data collection, potentially limiting the interpretability and generalizability of the findings. Secondly, the relatively small sample size and incomplete selection of EGFR-TKIs could impact the statistical significance and representation of the results, constraining broader inferences to the entire patient population. Additionally, the short follow-up duration in the combined treatment group, where the median OS has not yet been reached, might not fully capture the comprehensive occurrence of events, potentially influencing the assessment of disease progression and survival outcomes. Lastly, the heterogeneity in radiation dosages due to tumor location might introduce bias into the assessment of treatment effects, leading to less precise or more variable comparative outcomes. To address these limitations and offer more robust conclusions, future prospective studies with larger sample sizes and controlled designs are necessary. Such studies would help mitigate potential biases and provide more reliable evidence to either support or refine the current findings.

EGFR gene mutation is the most common oncogenic mutation in NSCLC, detected in approximately 40% of NSCLC patients (27,28). The development of EGFR-TKI drugs in the past two decades has significantly improved the prognosis for advanced NSCLC patients (5,8,9,29). However, resistance inevitably emerges in patients undergoing TKI treatment. Research assessing the failure patterns of patients under TKI treatment in detail analyzed the disease progression patterns in EGFR mutant NSCLC patients post-TKI treatment. It revealed that the initial progression of NSCLC treated by EGFR-TKIs occurred predominantly in the original disease sites (16,18). Furthermore, a higher risk of primary site failure was associated with larger primary tumors, advocating for the rationality of local treatment for the primary disease site, particularly in patients with primary lung tumors ≥3 cm (18). Similarly, in Li et al.’s study (30) aimed at predicting the progression patterns and failure sites of stage IV lung adenocarcinoma patients under TKI treatment, approximately 40% experienced primary site failure, while 60% showed primary or simultaneous primary and distant failures. Among patients with primary site failure, 51.9% had lung failures, highlighting the significance of treating pulmonary primary lesions during TKI therapy (30). Guo et al.’s study (16) on the residual disease and progression patterns under osimertinib treatment revealed that the majority of patients (92.3%) had residual metastatic sites numbering no more than three at the maximum response. Most residual lesions were located in the lungs (80.8%) and bones. In the subset of patients who did not receive radiation therapy, disease recurrence primarily occurred within residual lesions (50%). The results above indicate that the failure patterns of EGFR-TKI targeted therapy primarily involve progression at the pre-treatment primary and metastatic sites, with the lung being the most common initial site of disease progression. Therefore, local treatment for the pulmonary primary lesion is necessary during TKI therapy.

SBRT is an advanced radiotherapy technique that delivers high doses of radiation to specific target areas, effectively killing cancer cells. It has become a crucial localized treatment modality for cancer (31). Additionally, research has shown that radiation exposure can increase the sensitivity of cell lines with the T790M mutation, which is the most common resistance mutation observed in TKI therapy, to TKI drugs (32). Given these theoretical foundations, the synergistic treatment of TKI and SBRT has sparked significant interest among researchers. We also observed that patients who underwent SBRT targeting the primary lesion exhibited significant PFS extension compared to those who did not. In a prospective study conducted by Peng et al., the median PFS for the TKIs alone group was 9.0 months, whereas the TKI + SBRT group exhibited a significantly extended median PFS of 17.3 months (HR =0.52, 95% CI 0.31–0.89, P=0.02). OS was 23.2 months for the TKIs alone group and 35.2 months for the TKI + SBRT group (HR =0.53, 95% CI: 0.30–0.95, P=0.03) (22). Moreover, treatment-related AEs were generally mild and manageable (22). In an open-label, parallel-group, phase III clinical trial conducted by Wang et al., the median PFS in the TKI combined with the SBRT group increased from 12.5 months to 20.2 months compared to the TKIs alone group (HR =0.22, 95% CI: 0.17–0.46, P<0.001). The median OS also improved from 17.6 to 25.5 months (HR =0.44, 95% CI: 0.28–0.68, P<0.001), and the treatment was well-tolerated (23). Our study is consistent with these two prospective studies, demonstrating favorable outcomes in prolonging both OS and PFS in late-stage EGFR-mutated NSCLC through TKI combined with SBRT treatment. Despite a high rate of radiation pneumonitis observed in the TKIs plus SBRT group, the majority of radiation pneumonitis was mild (grade 1) without obvious symptoms, which was in alignment with the results reported in previous literature. In this study, several factors could contribute to our longer median PFS. Firstly, the difference might arise from variations in patient characteristics and disease profiles among the studied populations, impacting treatment response and disease progression rates. Additionally, differences in treatment protocols, such as SBRT delivery techniques, dosage, or adjunct therapies, could influence PFS outcomes across the studies. Moreover, the criteria for patient inclusion in these two studies were more stringent compared to ours, primarily restricting patients to an ECOG performance score of 0–2, including only stage IV patients, focusing solely on 19 deletions or 21L858R EGFR mutations, and including only first-line 1st generation TKI users. Our broader patient selection is closer to real-world circumstances and may enhance the representativeness of our study results. Nevertheless, the broader patient inclusion inevitably increases heterogeneity among patients; therefore, careful interpretation and application of study results across different patient cohorts are necessary.

To further support our findings, we conducted a meta-analysis by integrating our data with six unique studies (Figure 3), which collectively comprised 715 patients diagnosed with EGFR-mutated NSCLC. Among them, 456 patients received TKI monotherapy, while 259 patients underwent combination treatment with TKI and SBRT. Table 4 presents relevant information about each study (22-25,33,34). First, pooled analyses for PFS and OS were performed on all patients. The HR for PFS in the group receiving combined SBRT treatment was 0.42 (95% CI: 0.28–0.65, P<0.001) (Figure 4A). Due to the high heterogeneity of this subset of results (I²=83%), we conducted a leave-one-out sensitivity analysis to assess the robustness of our findings. The results indicated that the combined effect remained stable regardless of which study was excluded (Table S1). The HR for OS in the combined SBRT group was 0.78 (95% CI: 0.47–1.3, P=0.34), suggesting no significant OS benefit (Figure 4B). While the analysis was restricted to two prospective studies, the HR for OS in the combined SBRT group was 0.47 (95% CI: 0.33–0.67, P<0.001) (Figure 4C). These results align with our retrospective study, indicating a benefit in both PFS and OS with combined SBRT, with lower heterogeneity compared to the inclusion of retrospective analyses (I² values were 0%). However, it is important to note that both of these prospective studies included SBRT to both primary and metastatic lesions. Therefore, the specific clinical benefit of SBRT to the primary tumor in patients with disease stabilization after EGFR-TKI therapy remains to be further validated in large-scale prospective clinical trials.

Figure 3 Flow chart of the article selection process. AACR, American Association for Cancer Research; ASCO, American Society of Clinical Oncology; ASTRO, American Society for Radiation Oncology; WCLC, World Conference on Lung Cancer.

Figure 4 Forest plots show the combined analysis of PFS and OS for patients receiving combined SBRT treatment versus TKI monotherapy. (A) Combined analysis of PFS from 6 dual-arm studies and our data; (B) combined analysis of OS from 5 dual-arm studies; (C) combined analysis of OS from two prospective studies. CI, confidence interval; IV, inverse variance; OS, overall survival; PFS, progression-free survival; SBRT, stereotactic body radiotherapy; SE, standard error; TKI, tyrosine kinase inhibitor.

Two prospective studies and one retrospective study described the grades of AEs. The pooled analysis showed no increased incidence of grade ≥3 AEs in patients who had SBRT (Figure 5). Figure 6 shows the analysis of AEs of all grades (Figure 6A-6L). Although the TKIs plus SBRT group had a higher probability of developing esophagitis (Figure 6D), pneumonitis (Figure 6I), and radiation dermatitis (Figure 6J) compared to the TKIs alone group, all of these events were low grade (grade 1–2), indicating that the addition of SBRT was generally well tolerated. These findings are consistent with the toxicity profile observed in our retrospective cohort.

Figure 5 Forest plot compares the incidence of adverse events of grade ≥3 between the TKIs plus SBRT group and the TKIs alone group. CI, confidence interval; M-H, Mantel-Haenszel; SBRT, stereotactic body radiotherapy; TKI, tyrosine kinase inhibitor.

Figure 6 Comparison of adverse events of all grades between the TKIs plus SBRT group and the TKIs alone group. (A) Anorexia; (B) diarrhea; (C) dry skin; (D) esophagitis; (E) fatigue; (F) mucositis; (G) nausea or vomiting; (H) paronychia; (I) pneumonitis; (J) radiation dermatitis; (K) rash; (L) transaminitis. CI, confidence interval; M-H, Mantel-Haenszel; SBRT, stereotactic body radiotherapy; TKI, tyrosine kinase inhibitor.

Conclusions

In this retrospective study, we investigated the efficacy of combining EGFR-TKI and SBRT in the treatment of advanced NSCLC patients with EGFR mutations. Our findings demonstrated that the addition of local therapy with SBRT significantly prolonged PFS and OS compared to first-line EGFR-TKI therapy alone. Moreover, the adverse effects were mild and overall manageable. These findings contribute valuable insights to the evolving landscape of EGFR-mutated NSCLC treatment, offering hope and optimism for the future management of this challenging disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-635/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-635/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-635/prf

Funding: This study was supported by grants from Basic Scientific Research Project for Central Universities (No. 2023CDJYGRH-YB01 to D.T.), the Chongqing Science and Health Joint Medical Research Project (No. 2023GGXM002 to Y.W.), National Natural Science Foundation Project (No. 82073347 to Y.W.) and Chongqing Talent Plan (No. CQYC20210203119 to Y.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-635/coif). D.T. reports receiving funding support from the Basic Scientific Research Project for Central Universities (No. 2023CDJYGRH-YB01). Y.W. reports receiving funding support from the Chongqing Science and Health Joint Medical Research Project (No. 2023GGXM002), the National Natural Science Foundation Project (No. 82073347), and the Chongqing Talent Plan (No. CQYC20210203119). 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Chongqing University Cancer Hospital (CZLL2025-059-001). Informed consent was waived due to the retrospective nature of the study and the approval by the Ethics Committee.

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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