Exploring perioperative treatment for non-small cell lung cancer patients harboring EGFR mutation: a real-world multicenter cohort study

Introduction

For early-stage non-small cell lung cancer (NSCLC), which accounts for up to 40% of NSCLC patients at the time of diagnosis (stage I–IIIA), the treatment paradigm has experienced a rapid expansion in the past few years, presenting patients with a greater number of options (1). Also, some cases of stage IIIB NSCLC become potentially resectable and received reasonable neoadjuvant treatment and surgery afterwards under the multidisciplinary thoracic oncology team assessment. Currently, perioperative treatment for resectable and potential resectable NSCLC, encompassing neoadjuvant and adjuvant treatment, comprises a combination of surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. The selection of an appropriate treatment is of crucial significance for these patients.

Driver gene detection is of great importance for all stages of NSCLC, as is the case in resectable NSCLC. For resectable NSCLC patients harboring epidermal growth factor receptor (EGFR)-sensitizing mutations, in adjuvant treatment, the ADAURA study demonstrated that adjuvant osimertinib could extend disease-free survival and overall survival (OS) and has emerged as the standard of care for patients with completely resected stage IB–IIIA EGFR-mutant NSCLC (2). However, the optimal neoadjuvant treatment regimen for EGFR-mutated resectable NSCLC remains a subject of contention. Immune checkpoint inhibitor (ICI) in combination with chemotherapy has exhibited enhanced efficacy and survival benefits in comparison to chemotherapy alone during neoadjuvant and adjuvant treatment, thereby establishing it as an essential component of the perioperative treatment paradigm (3-11). Nevertheless, compared to patients with EGFR-wild type advanced NSCLC, patients with EGFR mutations derive less benefit from ICI treatment in first-line or second-line settings (12-14). Whether EGFR-mutated patients benefit from perioperative immunotherapy remains controversial, and as a result, they have been largely excluded from relevant clinical trials (3,5,7-9). Consequently, neoadjuvant immunochemotherapy is not considered a standard of care for this population. Research concentrating on alternative optimal treatment modalities, such as chemotherapy or tyrosine kinase inhibitors (TKIs), with the aim of further augmenting treatment outcomes for EGFR-mutant resectable NSCLC is ongoing. Recent studies have demonstrated that neoadjuvant TKI treatment has not yielded favorable results, as the pathological response is comparable to that of neoadjuvant chemotherapy (15-19). Research on perioperative immunotherapy is limited, as in former clinical trials very few participants with EGFR mutations were identified, limiting insight in this subgroup of patients (4,6).

Therefore, we initiated this multi-center cohort study to investigate the efficacy and safety of diverse treatment modalities when employed as perioperative treatments in patients with potentially resectable NSCLC harboring EGFR mutations, especially focusing on patients with EGFR mutations receiving immunotherapy neoadjuvant treatment. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-962/rc).

Methods

Study design and patients

This study is a multicenter, retrospective cohort study designed to explore the optional treatment paradigms for neoadjuvant and adjuvant treatments in patients with resectable or potentially resectable NSCLC harboring EGFR mutations. EGFR mutation status detection was performed in the central laboratory of each center by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) or next-generation sequencing (NGS).

Patients eligible for the study were those with pathologically confirmed untreated, stage IIA–IIIB NSCLC [according to 8th edition American Joint Committee on Cancer (AJCC) criteria], who had EGFR mutations (including EGFR exon 19 deletion, 21 L858R mutation and other uncommon EGFR mutations), who were potentially suitable for definitive resection, had an Eastern Cooperative Oncology Group performance status of 0 to 1, and possessed adequate organ function. Exclusion criteria included poor lung function and a history of malignancies. The stage of lymph node (N) was evaluated by pathological detection using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and/or positron emission tomography/computed tomography (PET/CT). All enrolled patients with a clinically positive (PET/CT and/or CT) mediastinum lymph nodes were pathologically confirmed via EBUS-TBNA. Potentially resectable NSCLC was evaluated by a multidisciplinary clinical team (MDT), including oncologists, radiological specialists and thoracic surgeons, and was defined as (I) tumor invading the root of the main vessels, trachea or other unresectable organs which affected indispensable physiological functions and (II) IIIB or more advanced NSCLC not benefiting from surgery alone, for whom definitive chemoradiation is the standard therapeutic regimen. And for potentially resectable NSCLC, MDT after neoadjuvant treatment was required (20).

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital (No. 2025-232), which served as the central institutional review board (IRB) for this study. Given the retrospective nature of the study, which involved no more than minimal risk to participants and used de-identified data, the requirement for individual ethical approval from each participating site was waived by the central IRB, in compliance with national regulations. All patient data were handled in accordance with the ethical standards of the central IRB. Inform consent was waived due to the retrospective nature of this study.

Treatment

Included patients should receive neoadjuvant treatment, including chemoimmunotherapy, chemotherapy or TKI treatment. Neoadjuvant chemoradiotherapy and immunotherapy monotherapy were excluded. Surgery was planned following completing the neoadjuvant treatment, after which the patients could take adjuvant treatment based on physician’s preference.

Outcomes

The primary outcome of the study was pathological response including (I) the pathological complete response (pCR) rate, determined as the absence of any detectable cancer cells in the primary tumor and sampled lymph nodes; (II) the major pathological response (MPR), determined as minimal residual disease in the tumor bed after neoadjuvant therapy, referred to the percentage of viable tumor cells ≤10%, regardless of the presence of residual tumor cells in the lymph nodes. Secondary outcomes included: (I) objective response rate (ORR), which was defined as the percentage of patients with a confirmed complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors criteria version 1.1.; (II) event-free survival (EFS), defined as the time from surgery to the first confirmed disease progression or death from any cause, or data on patients were censored at the last tumor assessment; (III) lymph node downgrade rate defined as the proportion of patients with pathological confirmed lymph nodes downstaging from N3 or N2 to N1 or N0; (IV) safety, recorded and graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Follow-up

Follow up was conducted by outpatient visits or telephone calls. For postoperative patients, physical examinations and chest CT were performed every 3 months for the first year, every 6 months for 2 to 5 years, and annually from then on. The data cut-off date was April 5th, 2024.

Statistical analysis

Continuous variables were presented as mean ± standard deviation or median [interquartile range (IQR)] based on their normality of distribution. Differences between groups were assessed using the t-test or one-way analysis of variance for normally distributed data; otherwise, the Mann-Whitney U test or Kruskal-Wallis H test was employed. Categorical variables were compared using the Chi-squared test or Fisher’s exact test, as appropriate. Survival data were analyzed using the Kaplan-Meier method and log-rank test. All tests were two-sided and P<0.05 was considered statistically significant. The proportion of missing data for key variables was very low (<5%). Accordingly, we performed a complete case analysis, including only observations with data available for all variables in the model. SPSS software (version 26, IBM, Armonk, NY, USA) was used for all the statistical analyses. GraphPad Prism 9 software (GraphPad Software, San Diego, CA, USA) and R (version 4.0, R Foundation for Statistical Computing, Vienna, Austria) were used for visualization.

Results

Patients

Between January 13, 2020 and September 1, 2023, 64 patients with treatment-naïve, resectable NSCLC harboring with EGFR mutation from seven centers across China were screened for eligibility and 41 patients were included in efficacy analysis (Figure 1). For the whole cohort, over half of the patients were male (21/41, 51.2%) and without any smoking history (28/41, 68.3%). A total of 31 (78.1%) patients were adenocarcinoma, 8 (19.5%) with squamous carcinoma and 1 patient was with adenosquamous carcinoma. According to the 8th edition AJCC criteria, there were two patients (4.9%) with stage IIA, 8 patients (19.5%) with stage IIB, 21 patients (51.2%) with stage IIIA and 10 patients (24.4%) with stage IIIB. For EGFR mutation type, 18 patients (43.9%) were harboring with EGFR 19del, 20 patients (48.7%) were with EGFR 21 L858R mutation, 1 patient (3.8%) with EGFR 20ins mutation, 1 patient (3.8%) with EGFR L861Q mutation and 1 patient (3.8%) with EGFR S768I mutation. There were 19 patients (46.3%) without PD-L1 expression data, and 9 patients (22.0%) were PD-L1 negative expression, 9 patients (22.0%) were with 1–49% expression and the rest 3 (7.3%) was with over 50% expression. Most of the gene test was applied using NGS (33/41, 80.5%), and 8 patients (19.5%) were diagnosed using PCR. The detailed baseline demographics and characteristics of different neoadjuvant treatment group were summarized in Table 1.

Figure 1 Diagram of the study enrollment and treatment procedure. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

Neoadjuvant treatment and operative outcomes

Overall, 27 patients received immunochemotherapy and 12 patients took TKI as neoadjuvant treatment. The rest two patients received neoadjuvant chemotherapy. The median number of neoadjuvant treatment cycle was 3 (range, 1–17). The median time interval from last neoadjuvant treatment to surgery was 30 days [interquartile range (IQR), 21–41 days]. Of the 12 patients receiving neoadjuvant TKIs, eight patients received first-generation TKI, including seven of icotinib and one of gefitinib. One took second-generation TKI dacomitinib and the remaining three patients took third-generation TKI osimertinib. Assessment of radiographic response included all 41 patients who initiated neoadjuvant therapy, irrespective of subsequent surgery. For the 41 patients who received neoadjuvant treatment, based on RECIST 1.1, one patient (2.4%) achieved CR, 23 patients (56.1%) achieved PR, and 14 (34.2%) achieved stable disease (SD). The ORR was 58.5% [95% confidence interval (CI): 42.1–73.7%]. Regarding different neoadjuvant treatment groups, the ORRs of the immunochemotherapy group, TKI group and chemotherapy group were 63.0% (42.4–80.6%), 41.7% (15.2–72.3%) and 100% (15.8–100%), respectively (P=0.30) (Figure 2). Two patients in immunochemotherapy group and one patient in the TKI group (7.3%) experienced progressive disease (PD) during neoadjuvant treatment. Among them, one patient in the immunochemotherapy group experienced distant metastasis and did not receive surgery (Table 2).

Figure 2 Tumor response and survival outcomes of the entire cohort. (A) Best percentage change in target lesion size from baseline. The upper dashed line at +20% represents the threshold for PD and the lower dashed line at −30% represents the boundary for PR per RECIST 1.1 criteria. *, one patient with adenosquamous carcinoma; **, one patient with EGFR 20 exon insertion, one patient with EGFR L861Q mutation and one patient with EGFR S768I mutation. (B) Kaplan-Meier plots for EFS of whole cohort. EFS, events-free survival; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MPR, major pathological response; pCR, pathological complete response; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

A total of 40 patients (97.5%) underwent definitive surgery. Regarding the surgical approach, 39 patients (97.5%) received minimally invasive surgery and one patient (2.5%) required conversion from minimally invasive surgery to thoracotomy. Moreover, 30 (75.0%) patients received lobectomy, 10 (25.0%) patients received bi-lobectomy and no pneumonectomies were performed. All 40 patients achieved R0 resection. For postoperative pathological lymph node evaluation, among the 40 patients, 20 (50.0%) patients were classified as N0, 8 (20.0%) as N1, 12 (30.0%) as N2 and no patient as N3. Of the 34 patients with N3, N2 or N1 before neoadjuvant treatment and surgery, 19 patients (55.9%) achieved pathological lymph node downgrade. Of the 40 patients, 28 (70.0%) patients achieved pathological downstage. There were no significant differences among different neoadjuvant treatment groups in surgical approach, type of resection, R0 resection rate, lymph node downgrade rate, and pathological downstage rate.

Regarding pathological response, of all 40 patients, 10 patients achieved MPR and the MPR rate was 25.0% (95% CI: 12.7–41.2%). Four patients achieved pCR and the pCR rate was 10.0% (95% CI: 2.8–23.7%) (Table 2). For the immunochemotherapy group, the MPR rate was 30.8% (14.3–51.8%) and for TKI group, the MPR rate was 8.3% (2–38.5%) (P=0.08). The pCR rates of the immunochemotherapy group and TKI group were 15.4% (4.4–34.9%) and 0% (0–26.5%), respectively (P=0.18). Furthermore, the pathological response was explored in 36 patients with EGFR sensitive mutation receiving neoadjuvant TKI therapy or immunochemotherapy. For 17 patients with EGFR 19del, the MPR rate was 23.5% (6.8–49.9%) and the pCR rate was 5.9% (0.1–28.7%). For 19 patients with EGFR 21L858R, the MPR rate was 26.3% (9.1–51.2%) and the pCR rate was 15.8% (3.4–39.6%). Between patients harboring different EGFR mutation, the MPR and pCR rates showed no significant differences (P=0.56 and 0.35, respectively). There were no significant differences in MPR or pCR rates between different neoadjuvant treatment groups for patient with EGFR 19del or 21L858R mutation. For three patients receiving osimertinib as neoadjuvant treatment, one patient achieved MPR while no patient achieved pCR. The MPR was 33.3% (95% CI: 0.8–90.6%) and pCR was 0%. For nine patients receiving first- or second-generation TKI, no patient achieved MPR or pCR. The MPR rate differed significantly between these groups (P=0.004) (Table S1).

Of note, there were three patients with PD-L1 expression over 50% in this study. These three patients with high PD-L1 expression received chemotherapy, immunochemotherapy and targeted therapy as neoadjuvant treatment, respectively, and all received definitive surgery. Only one patient who received immunochemotherapy as neoadjuvant treatment achieved both pCR and MPR, while the rest two patients did not achieve MPR or pCR.

Adjuvant treatment and survival outcomes

At the cut-off date of September 25th, 2024, the median duration of follow-up for all participants was 24.0 months (range, 5.0–62.0 months). Overall, 35 of 40 (87.5%) patients took adjuvant treatment. Of the 35 patients, 18 patients (51.4%) took EGFR-TKI and 14 patients (40.0%) received adjuvant immunotherapy. The rest three patients (8.6%) received adjuvant chemotherapy. Of the 18 patients receiving adjuvant EGFR-TKI, eight patients took third-generation TKI osimertinib and the rest 10 patients took icotinib.

During the follow-up period, a total of 10 patients experienced disease relapse. Five patients developed pulmonary metastases; two patients were with extracranial distant metastasis and the other three developed brain metastases. The median EFS for the whole cohort were not reached and the 12-month EFS rate was 94.2% (95% CI: 86.9–100%), the 24-month EFS rate was 75.8% (95% CI: 61.3–93.7%) and the estimated 36-month EFS rate was 48.5% (95% CI: 27.2–86.4%). Median OS was not reached.

For different neoadjuvant treatment groups, there was no significant differences in EFS among immunochemotherapy group, TKI group or chemotherapy group (P=0.33) (Figure 3A). In subgroup analysis, there was no difference in EFS between patients achieved MPR and those not (P=0.57) (Figure 3B). Patients achieved pCR tended to have prolonged EFS than those not, though there was no significant difference (P=0.14) (Figure 3C). For patients taking different adjuvant treatment, there was no difference in EFS among those taking EGFR-TKI, immunotherapy or chemotherapy (P=0.31) (Figure 3D). Considering the limited number of patients in chemotherapy group, the neoadjuvant immunochemotherapy group and TKI group were compared separately. There was no significant difference in EFS between these two groups (P=0.68) (Figure S1).

Figure 3 Kaplan-Meier plots for EFS of (A) patients receiving different neoadjuvant treatment; (B) patients with or without MPR; (C) patients with or without pCR; (D) patients receiving different adjuvant treatment. EFS, events-free survival; EGFR, epidermal growth factor receptor; MPR, major pathological response; pCR, pathological complete response; TKI, tyrosine kinase inhibitor.

Furthermore, the relationship of different perioperative treatment and EFS was explored. Patients received TKI or immunotherapy as adjuvant treatment (n=32) were divided into three groups according to the neoadjuvant treatment: immunochemotherapy + immunochemotherapy (I+I) group, TKI +TKI (T+T) group and immunochemotherapy + TKI (I+T) group. Results indicated that EFS of three groups showed no significant differences (P=0.66) (Figure S2). To explore the optional adjuvant treatment for those who received neoadjuvant treatment while did not achieve MPR or pCR, we compared the EFS of different adjuvant treatment group. For those 12 patients who received TKI as neoadjuvant treatment, 10 patients still took TKI as adjuvant treatment and two patients did not take adjuvant treatment. For those 26 patients who received neoadjuvant immunochemotherapy and surgery, eight patients who did not achieved pCR nor MPR changed to adjuvant TKI treatment (I+T). Of the 18 patients who did not achieve pCR in immunochemotherapy group, the median EFS of the I+I group was 18.0 (95% CI: 10.0–25.9) months, while the median EFS of the I+T group was not reached (P=0.48) (Figure S3). Similarly, of the 14 patients who did not achieve MPR in the immunochemotherapy group, the median EFS of the I+I group was numerically lower than the I+T group, with the median EFS of 18.0 (95% CI: 9.6–26.6) months, while the median EFS of the I+T group was not reached (P=0.65) (Figure S4).

Safety

Treatment-related adverse events (TRAEs) were listed in Table 3. A total of 26 patients (63.4%) experienced TRAEs, and no grade 5 TRAEs were observed. Grade 3 or 4 TRAEs occurred in eight patients (19.5%), of whom three were with grade 3 neutrophilopenia, two were with grade 3 leukopenia and one with grade 3 transaminase elevated. Discontinuation of neoadjuvant treatment was occurred in one patient (3.8%) with grade 3 anemia and lung infection. The most common TRAEs during neoadjuvant were fatigue (17.1%), neutrophilopenia (19.5%), leukopenia (12.2%) and transaminase elevated (12.2%).

Immune-related adverse events (irAEs) occurred in two patients (4.9%). All irAEs were limited to grade 1 and occurred during neoadjuvant therapy, including one case of hyperthyroidism that persisted throughout adjuvant treatment and one of hypothyroidism that resolved during adjuvant treatment, with neither requiring treatment discontinuation. No surgery-related complications were reported and no surgery-related death occurred within 90 days postoperatively. Of note, considering that the application of EGFR-TKI may lead to increased toxicity if administered in close proximity to immunotherapy, the AEs of this group were further explored. Among the eight patients who received neoadjuvant immunotherapy followed by adjuvant TKI, four experienced AEs after a median follow-up of 6.5 months (range, 5.0–44.0 months). The spectrum of AEs was predominantly grade 1–2. One patient experienced grade 3 neutropenia, and one case of grade 1 hypothyroidism happened during neoadjuvant treatment was attributed to an irAE. No cases of interstitial pneumonia occurred (Table S2). For the other 19 patients receiving neoadjuvant immunochemotherapy, 14 patients took adjuvant immunotherapy and the other five patients did not receive adjuvant treatment. For patients receiving neoadjuvant immunochemotherapy and adjuvant immunotherapy, most occurred AE was fatigue and one case with grade 1 hyperthyroidism was considered as irAE. Detailed profile was summarized in Table S3. For patients receiving neoadjuvant TKI, 10 of the 12 patients still took TKIs as adjuvant treatment and one patient received adjuvant chemotherapy. The rest one patient did not take adjuvant treatment. No patients received adjuvant immunotherapy and there was no irAE recorded.

Discussion

In our study, we provide real-world evidence regarding the application of different perioperative therapies for EGFR-mutant resectable NSCLC patients. Results indicated that neoadjuvant immunochemotherapy yielded superior pathological response, as both the pCR and MPR showing numerically higher in the immunochemotherapy group compared to the TKI group.

The perioperative treatment landscape for resectable NSCLC has evolved rapidly in recent years. In the neoadjuvant setting, for resectable NSCLC, the current optional treatment modalities include immunochemotherapy, which, however, primarily focuses on the driver-gene negative NSCLC. In the adjuvant setting, studies have shown that the application of EGFR-TKIs can prolong survival in EGFR-mutated resectable NSCLC patients (21-24). Nevertheless, whether adjuvant immunotherapy can confer survival benefits for these patients remains unknown. Consequently, the optimal therapeutic strategy during the perioperative period for driver gene-positive resectable NSCLC remains an area of ongoing exploration. Regarding perioperative immunochemotherapy, key clinical trials including the AEGEAN study and the Keynote-671 study have reported analysis results for the EGFR mutation subgroups (6,11). In the subgroup analysis of the AEGEAN study, for EGFR-mutant patients, the median EFS was 30.8 months in the durvalumab group and 19.6 months for the placebo group [hazard ratio (HR) =0.86, 95% CI: 0.35–2.19]. The pCR rates were 3.8% and 0% respectively (95% CI: −10.0% to 19.1%), and the MPR rates were 7.7% and 4.0% respectively (95% CI: −13.2% to 21.0%). Although the subgroup analysis results suggested that compared to placebo, durvalumab showed numerical improvements in EFS, pCR, and MPR for EGFR-mutant patients, better EFS, pCR, and MPR data were observed for durvalumab in the population without EGFR mutations. In the subgroup analysis of the Keynote-671 study, in the population of patients with EGFR mutations, pembrolizumab also demonstrated a significant improvement in EFS compared to placebo (HR =0.09, 95% CI: 0.01–0.74). Another retrospective data analysis exploring the efficacy of neoadjuvant therapy in driver gene-positive populations showed an ORR of 62.5%, an MPR rate of 37.5%, and a pCR rate of 12.5% for driver gene-positive NSCLC (25). In our study, the MPR rate was 30.8% and the pCR rate was 15.4%, which was comparable to the above-mentioned studies. This indicates the potential benefit of immunochemotherapy as neoadjuvant treatment for EGFR-mutated patients. However, caution must be exercised when interpreting the data due to the small sample size and the lack of further analysis on PD-L1 expression, EGFR mutation subtypes, and other factors. Further exploration through prospective large-scale studies is warranted.

Previous investigations of EGFR-TKIs as neoadjuvant therapy demonstrate modest efficacy. The CTONG 1103 study compared erlotinib with gemcitabine plus cisplatin in stage IIIA–N2 EGFR-mutant NSCLC, and found an ORR of 54.1% for erlotinib versus 34.3% for chemotherapy (P=0.09), with no pCR in either group (15,26). Three patients (9.7%) in the erlotinib group achieved an MPR, while none did in the chemotherapy group. Another study with 70 patients compared first-generation EGFR-TKI with chemotherapy versus EGFR-TKI monotherapy, and showed an ORR of 50.0% for the combination and 40.5% for monotherapy (P=0.50), with MPR rates of 20.0% and 10.5% respectively (P=0.36) (27). The monotherapy group had a 7.89% pCR rate, while none in the combination group. A single-arm phase 2b study of neoadjuvant osimertinib showed a 71.1% ORR, with no reported pathological response. In stage IB–IIIA EGFR-mutant NSCLC, neoadjuvant osimertinib yielded a 48% PR rate, 15% MPR, and no pCR (28). In the NORA study, MPR and PCR rates were 24% (n=6) and 0%, respectively following neoadjuvant osimertinib (29). In our study, the TKI group had an MPR rate of 8.3% and no patient in the TKI group achieved pCR. Also, both previous studies and our study indicated that the MPR rate were not different between the EGFR mutations (EGFR 19del and 21L858R) (29). These collective data suggest suboptimal pathological responses with neoadjuvant EGFR-TKIs, particularly regarding pCR achievement. However, result of NeoADAURA trial showed promising pathological response for neoadjuvant osimertinib (30). In this phase III clinical study, patients with stage II–IIIB, resectable, EGFR-mutant NSCLC were randomized to neoadjuvant osimertinib (plus chemotherapy or as monotherapy) or chemotherapy alone. The osimertinib-based arms demonstrated significantly superior MPR rates [26%/25% vs. 2%; odds ratio (OR) =19.8/19.3, P<0.0001] and enhanced tumor downstaging in N2 disease (53% vs. 21%; OR =4.8/4.2) versus chemotherapy, alongside a trend for EFS benefit. This study establishes the efficacy of perioperative osimertinib and paves the way for further research to refine its application.

The different pathological responses of neoadjuvant immunochemotherapy and TKI might contribute to the different mechanisms of EGFR-TKIs and immunotherapy in the neoadjuvant setting. While EGFR-TKIs primarily target specific molecular pathways involved in cancer cell proliferation and normalize the process, immunotherapy engages the entire immune system to mount an anti-tumor response. Additionally, the tumor immune microenvironment of early stage and advanced stage NSCLC might be different. Chen et al. indicated that the distribution of two B cell subtypes (naive B cells and plasma cells) in different stages of NSCLC shows differences. The naive B cells in stage III are significantly lower than in stage I. Moreover, the higher the infiltration level of naive B cells, the higher the survival rate and recurrence-free rate (31). Li et al. showed that advanced NSCLC with brain metastases exhibited stronger systemic immunosuppression. Compared to patients without early metastasis, there is a significant increase in PD-L1 expression, myeloid-derived suppressor cell (MDSC) abundance, and Treg percentage in peripheral blood mononuclear cells (32). The different tumor immune microenvironment of early-stage NSCLC compared to advanced NSCLC and the different mechanism of EGFR-TKIs might result in difficulties in achieving a rapid pathological response during the neoadjuvant setting for resectable NSCLC compared to the rapid response of EGFR-TKI in treating advanced stage NSCLC. Neoadjuvant ICIs enable tumor conditioning and the expansion of tumor-specific memory T cells early in the course of the disease. Therefore, the combination of immunotherapy and chemotherapy as neoadjuvant treatment could generate a better pathological response (33-35). This possible mechanism difference highlights the significance of understanding the underlying biology of each treatment approach and tailoring therapeutic strategies accordingly. A previous study indicated that EGFR-TKIs could not only directly inhibit tumor cell viability but also indirectly enhance antitumor immunity through the downregulation of PD-L1 (36). In the neoadjuvant setting of EGFR-mutant NSCLC, many other combination therapies in including EGFR-TKI with chemotherapy are still under exploration (NCT04351555, NCT05011487, NCT05430802 and NCT05132985). More studies are needed to determine the best treatment strategy and apply it in clinical practice for these patients.

Though neoadjuvant immunotherapy showed pathological efficacy in EGFR-mutant patients, concerns of hyperprogressive disease (HPD) still exist. Biological mechanisms of HPD are currently being elucidated and some previous studies indicated that EGFR aberrations had significantly increased rate of tumor growth after ICI treatment and might resulted in HPD in these patients (37,38). However, results of our study showed that most patients in neoadjuvant immunotherapy group achieved disease remission. Though there were two patients with disease progression after neoadjuvant immunotherapy, the progression pattern of these two patients was not HPD which was defined by most studies as a >50% increase in tumor burden with a <2-month time to treatment failure (37,39,40).

In our study, among the 35 patients receiving adjuvant treatment, 18 patients took EGFR-TKI and 14 patients received adjuvant immunotherapy. Neoadjuvant immunotherapy provides a unique opportunity to assess and identify patients who benefit from the paradigm of immunotherapy paradigm. Thus, in the adjuvant setting, those who did not benefit from immunotherapy could switch to adjuvant EGFR-TKIs as previous studies have demonstrated the survival benefit of adjuvant EGFR-TKI (2). In our study, for those who did not achieve a pathological response in the neoadjuvant immunochemotherapy group, different adjuvant treatments were chosen. The median EFS was numerically higher for those switched to TKI compared to those who continued immunotherapy. Our study indicated that for those who did not achieve pathological remission after neoadjuvant immunochemotherapy, adjuvant TKI might prolong survival. No significant difference was found mainly due to the small cohort. Therefore, larger scale cohort study is still warranted.

There are some limitations in this study. Firstly, this is a retrospective cohort study focusing on real-world data. Non-randomized treatment allocation introduces the potential for selection bias. To reduce the selection bias, we collected data from seven centers in China to ensure the representativeness of the patients. Secondly, the study is limited by a small sample size. The number of patients in chemotherapy group was limited. The predominant use of earlier-generation TKIs complicates the comparison of outcomes with immunochemotherapy. Thirdly, data on EFS or OS were immature due to a short follow-up time. Despite these limitations, we believe our study provides valuable real-world data on the activity and safety of neoadjuvant chemoimmunotherapy in a patient group typically excluded from trials. Further large scale of prospective, biomarker-strategic clinical trials to guide treatment selection are warranted.

Conclusions

In conclusion, perioperative immunotherapy combined with chemotherapy shows potential as a treatment strategy for EGFR-mutant resectable NSCLC due to comparable efficacy, manageable safety, and a high pathologic response rate. Further prospective clinical trials are needed to determine the optimal perioperative treatment for these patients.

Acknowledgments

The authors thank all the patients and their families.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-962/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-962/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-962/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82172864), Hunan Provincial Natural Science Foundation of China (No. 2024JJ9137), Project of Health and Health Commission of Hunan Province (No. 20201566), Hunan Cancer Hospital Climb Plan (Nos. ZX2020005-5 and YF2020005), Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, Beijing Xisike Clinical Oncology Research Foundation (No. Y-XD202001-0215), and the science and technology innovation Program of Hunan Province (No. 2023SK4024).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-962/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital (No. 2025-232), which served as the central IRB for this study. Given the retrospective nature of the study, which involved no more than minimal risk to participants and used de-identified data, the requirement for individual ethical approval from each participating site was waived by the central IRB, in compliance with national regulations. All patient data were handled in accordance with the ethical standards of the central IRB. Inform consent was waived due to the retrospective nature of this study.

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

References

1. Lu T, Yang X, Huang Y, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res 2019;11:943-53. [Crossref] [PubMed]
2. Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:1711-23. [Crossref] [PubMed]
3. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
4. Cascone T, Leung CH, Weissferdt A, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med 2023;29:593-604. [Crossref] [PubMed]
5. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21:1413-22. [Crossref] [PubMed]
6. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
7. Lu S, Zhang W, Wu L, et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 2024;331:201-11. [Crossref] [PubMed]
8. Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol 2020;15:816-26. [Crossref] [PubMed]
9. Cascone T, Awad MM, Spicer JD, et al. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med 2024;390:1756-69. [Crossref] [PubMed]
10. Yue D, Wang W, Liu H, et al. Perioperative tislelizumab plus neoadjuvant chemotherapy for patients with resectable non-small-cell lung cancer (RATIONALE-315): an interim analysis of a randomised clinical trial. Lancet Respir Med 2025;13:119-29. [Crossref] [PubMed]
11. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
12. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8. [Crossref] [PubMed]
13. Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol 2017;12:403-7. [Crossref] [PubMed]
14. Lisberg A, Cummings A, Goldman JW, et al. A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC. J Thorac Oncol 2018;13:1138-45. [Crossref] [PubMed]
15. Zhong WZ, Chen KN, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol 2019;37:2235-45. [Crossref] [PubMed]
16. Xiong L, Li R, Sun J, et al. Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study. Oncologist 2019;24:157-e64. [Crossref] [PubMed]
17. Zhang Y, Fu F, Hu H, et al. Gefitinib as neoadjuvant therapy for resectable stage II-IIIA non-small cell lung cancer: A phase II study. J Thorac Cardiovasc Surg 2021;161:434-442.e2. [Crossref] [PubMed]
18. Lv C, Fang W, Wu N, et al. Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial. Lung Cancer 2023;178:151-6. [Crossref] [PubMed]
19. Blakely CM, Urisman A, Gubens MA, et al. Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study. J Clin Oncol 2024;42:3105-14. [Crossref] [PubMed]
20. Zhu X, Sun L, Song N, et al. Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial. BMC Med 2022;20:493. [Crossref] [PubMed]
21. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial. J Clin Oncol 2021;39:713-22. [Crossref] [PubMed]
22. Yue D, Xu S, Wang Q, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018;6:863-73. [Crossref] [PubMed]
23. He J, Su C, Liang W, et al. Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial. Lancet Respir Med 2021;9:1021-9. [Crossref] [PubMed]
24. Herbst RS, Wu YL, John T, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol 2023;41:1830-40. [Crossref] [PubMed]
25. Zhang C, Chen HF, Yan S, et al. Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis. NPJ Precis Oncol 2022;6:66. [Crossref] [PubMed]
26. Zhong WZ, Yan HH, Chen KN, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial. Signal Transduct Target Ther 2023;8:76. [Crossref] [PubMed]
27. Xu Y, Ji H, Zhang Y, et al. Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer. Oncologist 2024;29:e932-40. [Crossref] [PubMed]
28. Aredo JV, Urisman A, Gubens MA, et al. Phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutated non-small cell lung cancer. J Clin Oncol 2023;41:8508.
29. Lee JB, Choi SJ, Shim HS, et al. Neoadjuvant and Adjuvant Osimertinib in Stage IA to IIIA, EGFR-Mutant NSCLC (NORA). J Thorac Oncol 2025;20:641-50. [Crossref] [PubMed]
30. He J, Tsuboi M, Weder W, et al. Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer. J Clin Oncol 2025;43:2875-87. [Crossref] [PubMed]
31. Chen J, Tan Y, Sun F, et al. Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer. Genome Biol 2020;21:152. [Crossref] [PubMed]
32. Li YD, Lamano JB, Lamano JB, et al. Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. Cancer Immunol Immunother 2019;68:1501-13. [Crossref] [PubMed]
33. Liu J, Blake SJ, Yong MC, et al. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer Discov 2016;6:1382-99. [Crossref] [PubMed]
34. Zhang C, Yin K, Liu SY, et al. Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy. J Immunother Cancer 2021;9:e002312. [Crossref] [PubMed]
35. Friedman J, Moore EC, Zolkind P, et al. Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells. Clin Cancer Res 2020;26:679-89. [Crossref] [PubMed]
36. Chen N, Fang W, Zhan J, et al. Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation. J Thorac Oncol 2015;10:910-23. [Crossref] [PubMed]
37. Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res 2017;23:4242-50. [Crossref] [PubMed]
38. Forschner A, Hilke FJ, Bonzheim I, et al. MDM2, MDM4 and EGFR Amplifications and Hyperprogression in Metastatic Acral and Mucosal Melanoma. Cancers (Basel) 2020;12:540. [Crossref] [PubMed]
39. Champiat S, Dercle L, Ammari S, et al. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1. Clin Cancer Res 2017;23:1920-8. [Crossref] [PubMed]
40. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy. JAMA Oncol 2018;4:1543-52. [Crossref] [PubMed]