Efficacy of neoadjuvant immunochemotherapy in the treatment of stage III non-small-cell lung cancer with cancer driver gene mutations

Introduction

Worldwide, lung cancer remains the most diagnosed non-cutaneous malignancy and the primary cause of cancer-related death (1). Approximately 80–85% of lung cancers are histopathologically classified as non-small cell lung cancer (NSCLC), which includes lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and lung large cell carcinoma (2). At the time of diagnosis, almost 30% of patients with NSCLC present with localized disease, and this is expected to increase with global adaptation of lung cancer screening (3,4). While surgery remains the most effective options for very early stage NSCLC, perioperative chemo-immunotherapy is considered a standard of care strategy for most patients with stages IB–III resectable NSCLC. Recent studies have demonstrated significant long-term benefits, including improved progression-free survival (PFS) and overall survival (OS) rates. This approach involves administering chemotherapy and immunotherapy before and after surgery, which can reduce tumor size, facilitate surgical resection, and enhance the body’s immune response to cancer cells. The integration of immune checkpoint inhibitors with chemotherapy has shown to be effective, making perioperative chemo-immunotherapy a new standard of care for patients with stage IB–IIIA resectable NSCLC (5,6).

Some NSCLCs, especially LUAD, are caused by genetic mutations (7). The epidermal growth factor receptor (EGFR) mutation is the driver gene mutation with the highest incidence in NSCLC, with an incidence of up to 40% to 60% in the Asian population (8). Other common cancer driver gene mutations in LUAD include anaplastic lymphoma kinase (ALK), c-ros proto-oncogene 1, receptor tyrosine kinase (ROS1), rearranged during transfection (RET), mesenchymal-epithelial transition factor (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), human epidermal growth factor receptor 2 (HER2), Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Approximately 15% to 25% of NSCLCs harbor KRAS mutations (9); 4%, BRAF mutations (10); 3–7%, ALK rearrangements (11); 1–6.7%, HER2 mutations (12); 1%, ROS1 rearrangements (13); and 1–2%, RET fusions (14). PI3K mutations are found in 2% to 5% of LUADs and in 8–10% of LUSCs (15). Significant progress has been made in the adjuvant targeted therapy of NSCLC with oncogenic mutations in recent years (4). Furthermore, in the EMERGING-CTONG 1103, NCT01217619, and NEOS trials, neoadjuvant targeted therapy has shown that this strategy is safe, but the pathological response rates in these studies were underwhelming (16-18).

In general, immunotherapy based on programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoint inhibitors are considered effective treatment options for patients with NSCLCs without driver gene mutations (19-22). Studies have shown that the efficacy of immunotherapy is limited in advanced NSCLC harboring specific driver mutations, and neoadjuvant and perioperative immunotherapy trials have excluded patients with NSCLC with driver genetic alterations, particularly EGFR mutations and ALK fusion (23-25). Therefore, there is little data on whether neoadjuvant immunotherapy could be clinically valuable for treating patients with NSCLC harboring cancer driver gene mutations. Zhang et al. demonstrated the potential clinical feasibility and therapeutic effect of neoadjuvant immunotherapy combined with chemotherapy for patients with resectable NSCLC with oncogenic mutations (26). In this study, we examined the feasibility and safety of immunochemotherapy as a first-line treatment for patients with stage III NSCLC and oncogenic mutations. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-60/rc).

Methods

Study design and participants

This retrospective study included 18- to 80-year-old patients with stage IIIA–IIIC NSCLC [according to the eighth edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging (27)], with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and with available results from gene testing. Gene testing was performed in the laboratory of our hospital (the First Affiliated Hospital of the Zhejiang University School of Medicine) by using amplification-refractory mutation polymerase chain reaction (PCR) system. Patients with absence of necessary imaging evaluations (described below as detail), history of previous anticancer therapy, and presence of other concurrent active malignant tumors were excluded. This study was performed at the Department of Thoracic Surgery at the First Affiliated Hospital of the Zhejiang University School of Medicine in accordance with the Declaration of Helsinki (as revised in 2013) and Good Clinical Practice Guidelines and was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of the Zhejiang University School of Medicine [2021 Investigator Initiated Trials (IIT) No. 844]. Individual consent for this retrospective analysis was waived.

Included patients were divided into two groups according to whether there were common cancer driver gene mutations (such as EGFR, ALK, ROS1, RET, MET, KRAS, BRAF, HER2, NRAS, and PIK3CA): a mutation group and a wild-type (WT) group. The flowchart of the study’s inclusion process is presented in Figure 1. All patients received 2–4 cycles of neoadjuvant immunochemotherapy (3 weeks per cycle). The immunotherapy agent was camrelizumab (200 mg), nivolumab (200 mg), sintilimab (200 mg), tislelizumab (200 mg), or pembrolizumab (200 mg). The chemotherapy regimen consisted of platinum [75 mg/m² of cisplatin or carboplatin with an area under the curve (AUC) of the plasma concentration-time curve after a single dose of 5] and 260 mg/m² of albumin-bound paclitaxel.

Figure 1 Flowchart of the study process. ICI, immune checkpoint inhibitor; AUC, area under the curve; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene homolog; ROS1, c-ROS proto-oncogene 1, receptor tyrosine kinase; RET, rearranged during transfection; ALK, anaplastic lymphoma kinase; HER2, human epidermal growth factor receptor 2; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.

Procedures

Before neoadjuvant therapy, systematic imaging evaluations were performed in all enrolled patients as appropriate for each patient, including computed tomography (CT) of the chest and abdomen, positron emission tomography-CT (PET/CT), endobronchial ultrasonography, bone emission CT, brain magnetic resonance imaging, and abdominal ultrasonography, to assess the tumor status and to obtain baseline data.

During the neoadjuvant therapy period, chest CT was conducted every 2 cycles until surgery or until patient’s withdrawal from the treatment. Routine complete blood count and biochemical examinations were performed every week, and myocardial enzyme spectrum, thyroid function, and coagulation function examinations were conducted every 3 weeks as per our institutional standards. Gastrointestinal reactions and skin reactions were evaluated according to patients’ complaints.

After 2 cycles of immunochemotherapy, patients were evaluated by a multidisciplinary clinical team (MDCT) to determine whether there was a possibility for surgery. If the group felt that additional systemic therapy would be beneficial, 1–2 additional cycles were administered before re-evaluation by the MDCT. Patients who were deemed unresectable due to disease progression were offered stage-appropriate therapies. Surgical approaches comprised of open radical surgery or video-assisted thoracoscopic surgery (VATS) with systematic lymph node dissection. After surgery, imaging assessments (CT) were performed every 1–3 months. The patients were followed for at least 1 year after the operation or until the day the treatment was discontinued.

Outcomes

The primary endpoints included objective response rate [ORR; the proportion of patients who achieved complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) (28)], and adverse events [AEs; according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0]. Secondary endpoints were major pathological response (MPR; ≤10% residual viable tumor cells in the postoperative pathologic sample) and pathological complete response (pCR; no residual viable tumor cells in the postoperative pathologic sample) among patients who underwent surgical resection, disease-free survival (DFS; the time from surgical resection to disease progression according to RECIST 1.1 or death), and OS (the time from the initiation of neoadjuvant immunochemotherapy until death from any cause) among patients who underwent surgical resection.

Statistical analysis

Categorical variables are expressed as frequencies (percentages), and the Fisher exact test was used to compare differences between groups. Continuous variables were expressed as the median and interquartile range (IQR), and differences between groups were compared with the Wilcoxon test. The Kaplan-Meier method was used to evaluate DFS and OS, and differences between groups were compared with the stratified log-rank test. Median follow-up time was evaluated using the reverse Kaplan-Meier method. All analyses were performed with R software version 4.1.2 (The R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value of less than 0.05 was considered to be significant.

Results

Characteristics at baseline

From 2020 to 2022, our study included 34 patients with stage III NSCLC, who were categorized into two groups: a mutation group (n=22) and a WT group (n=12). Among the mutation group, 27.3% (6/22) patients had EGFR mutations (L858R mutation: 4, exon 19 deletion: 2), 27.3% (6/22) KRAS mutation (G12D mutation: 3, G12C mutation: 3), 13.6% (3/22) ROS1 fusion, 9.1% (2/22) ALK fusion, 9.1% (2/22) HER2 mutations, 9.1% (2/22) PIK3CA mutations, and 4.5% (1/22) RET fusion (Figure 2). The characteristics of these patients at baseline are shown in Table 1. There were no significant differences between the two groups in terms of age, gender, ECOG performance status, tumor location, clinical stage, pathology, treatment cycle, smoking status, drinking status, or comorbidities.

Figure 2 The percentage change in the maximum diameter of target lesion compared with the baseline tumor size and an overview of clinical response, pathological response, pathological classification, and mutation status. WT, wild-type; SD, stable disease; PR, partial response; pCR, pathologic complete response; MPR, major pathologic response; NA, not available; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene homolog; ROS1, c-ROS proto-oncogene 1, receptor tyrosine kinase; RET, rearranged during transfection; ALK, anaplastic lymphoma kinase; HER2, human epidermal growth factor receptor 2; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.

Response to neoadjuvant therapy

The percentage change in the maximum diameter of target lesion in these patients compared with the baseline tumor size is shown in Figure 2. A significant decrease in maximum diameter was observed after preoperative treatment in both groups (Figure 3A,3B). The difference in the change in the maximum diameter of the target lesion between two groups was also evaluated, but there was no significant difference (Figure 3C). The rate of PR in the WT group was 58.3%, and the rate of PR in the mutation group was 68.2% (P=0.57; Figure 4A). There were no cases of progressive disease (PD) or CR in either group, thus the ORR of both groups was the same as the rate of PR.

Figure 3 The change in the maximum diameter of target lesion. (A) The change in the maximum diameter of target lesion before and after neoadjuvant immunochemotherapy in the mutation group (n=22). (B) The change in the maximum diameter of the target lesion before and after neoadjuvant immunochemotherapy in the WT group (n=12). (C) The comparison of the change in the maximum diameter of the target lesion between the mutation group and WT group. ns, P value >0.05. WT, wild-type.

Figure 4 The distribution of clinical and pathological responses in the mutation group and WT group: (A) PR/SD, (B) MPR, and (C) pCR. Clinical response included PR and SD. Pathological response included MPR and pCR. PR, partial response; SD, stable disease; MPR, major pathological response; pCR, pathologic complete response; WT, wild-type.

Toxicity

There were no AEs that are unexpected in our study (Table 2). No grade 3 or 4 AEs occurred in either group. The incidence of grade 1 and 2 AEs was 72.7% (16/22) in the mutation group and 91.7% (11/12) in the WT group (P=0.38). There were no significant differences in treatment-related AEs between the two groups. All AEs were quickly resolved after symptomatic treatment.

Surgery and pathological response

Eventually, 25 of the 34 patients underwent surgery. These 9 patients [1 patient stable disease (SD), 8 patients PR] were reluctant to undergo surgery and chose to maintain immunotherapy using the previous immunotherapy drugs. After receiving immunotherapy, 4 patients occurred progression disease (PD, at least 20% enlargement in the total diameter of target lesions or the emergence of new lesions) and chose radiotherapy, and the other 5 patients kept SD (neither CR, PR nor PD). The surgical resection rate of the mutation group was 77.3% (17/22), with that in the WT group 66.7% (8/12). The outcomes of surgery and pathological response are summarized in Table 3. All patients who underwent surgery achieved R0 resection. Pneumothorax and pulmonary infection were more common postoperative complication in the WT group than in the mutation group (12.5% vs. 0.0%; P=0.32). The length of hospital stay of the WT group was longer than that of the mutation group (P=0.04), possibly due to the higher incidence of postoperative complications in the WT group. There were no perioperative deaths, and no significant differences were observed in terms of pathological response or other surgical outcomes.

The rate of MPR in the WT group was 75.0% while that of the mutation group was 47.0% (P=0.23; Figure 4B). The rate of pCR in the WT group was 37.5% while that in the mutation group was 23.5% (P=0.64; Figure 4C). In the subgroup analysis (Figure 5), the rates of MPR and pCR in the EGFR mutation group were 50.0% and 0.0%, respectively, which were both lower than those in the WT group (MPR: 57.9%; pCR: 36.8%) (P>0.05). Moreover, the rate of MPR in the KRAS mutation group was 40.0%, which was lower than that in the WT group (60.0%; P=0.62), while the rate of pCR in the KRAS mutation group was 40.0%, which was higher than that in WT group (25.0%; P=0.60).

Figure 5 The distribution of pathological responses in the different mutation and WT groups. The distribution of pathological responses in the EGFR mutation group and EGFR WT group: (A) MPR and (B) pCR. The distribution of pathological response in the KRAS mutation group and KRAS WT group: (C) MPR and (D) pCR. Pathological response included MPR and pCR. MPR, major pathological response; pCR, pathologic complete response; WT, wild-type; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene homolog.

Postoperative survival

At the time of data cutoff (September 2023), the median follow-up time for the WT group was 14.7 months [95% confidence interval (CI): 11.5 to 17.9], while the median follow-up time for the mutation group was 15.5 months (95% CI: 5.9 to 25.1). The median DFS in the two groups was not reached, and the log-rank test showed that there was no significant difference between the two groups (P=0.68), as shown in Figure 6A. The 1-year DFS rate in the WT group was 87.5%, while that in the mutation group was 82.4%. The median OS in the two groups also was also not reached (NR), and the log-rank test showed that there was no significant difference between the two groups (P=0.50), as shown in Figure 6B. The 1-year OS rates in the WT group and the mutation group were both 100.0%. In the subgroup analysis, the median DFS and OS were NR, and the log-rank test showed no significant difference between the EGFR mutation group and the EGFR WT group (P>0.05) (Figure 7A,7B). The 1-year DFS rate in the EGFR mutation group was 100.0%, which was higher than that in the WT group (78.9%). The 1-year OS rates in the WT group and the EGFR mutation group were both 100.0%. The median DFS was NR in the KRAS mutation group and KRAS WT group (P>0.05) (Figure 7C). The median OS was NR in the KRAS WT group and 15.3 months (95% CI: NR to NR) in the KRAS mutation group (P<0.001) (Figure 7D). The 1-year DFS rate in the KRAS mutation group was 80.0%, which was lower than that in the WT group (85.0%). The 1-year OS rates in the WT group and the KRAS mutation group were both 100.0%.

Figure 6 Kaplan-Meier curves of (A) DFS and (B) OS between the mutation group and WT group. DFS, disease-free survival; OS, overall survival; WT, wild-type; Mut, mutation.

Figure 7 Kaplan-Meier curves of the different mutation and WT groups. (A) DFS and (B) OS between the EGFR mutation group and EGFR WT group. Kaplan-Meier curves of (C) DFS and (D) and OS between the KRAS mutation group and KRAS WT group. DFS, disease-free survival; OS, overall survival; WT, wild-type; Mut, mutation; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene homolog.

Discussion

It remains unclear whether patients with locally advanced resectable NSCLC harboring driver genetic alterations should receive neoadjuvant targeted therapy or neoadjuvant immunotherapy. In this study, we aimed to determine the feasibility and safety of immunochemotherapy as a neoadjuvant treatment for stage III NSCLC patients with oncogenic mutations. We found the combination of neoadjuvant immunotherapy and chemotherapy demonstrated certain clinical feasibility and good safety.

In recent years, only a few studies on neoadjuvant immunotherapy for patients with NSCLC patients and oncogenic mutations have been conducted. Zhang et al. reported that neoadjuvant immunotherapy plus chemotherapy in oncogene-mutant NSCLC yielded an ORR of 62.5%, an MPR rate of 37.5%, and a pCR rate of 12.5% (26), which are lower than those in our study, which had ORR, MPR, and pCR rates of 100%, 47.0%, and 23.5%, respectively, in patients with mutated NSCLC after immunochemotherapy. This discrepancy may be due to small sample size and variability in patient populations, oncogene mutations, and treatment regimens. Furthermore, pathologic responses noted in both our study and that reported by Zhang et al. were higher than those noted in neoadjuvant targeted therapy studies. In the EMERGING-CTONG 1103 trial, the rate of MPR and pCR was 9.7% and 0.0%, respectively, in patients with NSCLC and oncogenic mutation after neoadjuvant targeted therapy [first-generations EGFR tyrosine kinase inhibitors (TKIs): erlotinib] (16). In the NEOS trial, the rate of MPR and pCR was 10.7% and 3.6% for these patients after neoadjuvant targeted therapy using third-generation EGFR-TKIs (osimertinib) (18). This suggests that neoadjuvant immunotherapy combined with chemotherapy for patients with stage III NSCLC with oncogenic mutations is feasible and may provide therapeutic effect superior to that of neoadjuvant targeted therapy. However, further larger studies with survival follow-up is necessary to confirm the long-term results of neoadjuvant immunochemotherapy in oncogene-mutant NSCLC. The rate of PD during the neoadjuvant immunochemotherapy in our study was 0%, which highly unusual compared to previous literature. However, we have strictly evaluated tumor treatment response (including CR, PR, SD, and PD) based on the RECIST 1.1. During the neoadjuvant immunochemotherapy, we have indeed not observed any PD. However, in the patients who were reluctant to undergo surgery and chose to maintain immunotherapy using the previous immunotherapy drugs, 4 patients occurred PD after receiving immunotherapy. Therefore, the reason for the 0% PD rate during the neoadjuvant immunochemotherapy might be due to that the group of patients we have selected were all sensitive to neoadjuvant immunochemotherapy. And because of the small sample size and the multiple treatment regimens, patients without PD might be reasonable.

No new or unexpected AEs were observed in our study, and all of the treatment-related AEs were manageable and tolerable. In our study, no grade 3 or 4 AEs occurred, which were different from previous studies (5,18). We observed AEs during neoadjuvant immunochemotherapy until surgery or abandoning treatment. AEs were strictly evaluated by related examinations in our hospital and patients’ complaints. What’s more, AEs were graded according to CTCAE version 5.0 (U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. CTCAE Version 5. Published: November 27, 2017). Therefore, the reasons for the 0% grade 3–4 AEs rate during the neoadjuvant immunochemotherapy might be due to that the group of patients we have selected were all tolerable to the AEs of neoadjuvant immunochemotherapy. And these findings could be influenced by the small sample size and retrospective study design, and the heterogeneity in the patients and treatment regimens. Perhaps by expanding the sample size, we could see grade 3–4 AEs. Because AEs were evaluated by related examinations in our hospital and patients’ complaints, these data might not be recorded in full in this retrospective study. The incidence of AEs was 72.7%, which contrasts with the results of other studies. In the Checkmate-816 trial, after neoadjuvant immunochemotherapy, the incidence of AEs was 92.6% while the incidence of grade 3 and 4 AEs was 40.9% (5). In the EMERGING-CTONG 1103 trial, after neoadjuvant targeted therapy, the incidence of AEs was 70.3% while that of grade 3 and 4 AEs was 0.0% in patients with oncogene-mutant NSCLC (16). In the NEOS trial, the incidence of AEs was 36.8% while that of grade 3 and 4 AEs was 15.8% in patients oncogene-mutant NSCLC after neoadjuvant targeted therapy (18). The low incidence of AEs in our study supports the safety of neoadjuvant immunotherapy for treating patients with oncogene-mutant NSCLC.

Consistent with previously observed reports, the MPR rate, pCR rate, and 1-year DFS were all lower in the mutation group than in the WT group. This indicates that neoadjuvant immunochemotherapy may result in a better therapeutic effect for patients with NSCLC without oncogenic mutations than for those with oncogene mutations. In our subgroup analysis, differences were observed between patients with EGFR mutations and those with KRAS mutations. The MPR and the 1-year DFS rate in the EGFR mutation group were all higher than those in the WT group. However, the MPR rate and the 1-year DFS rate in the KRAS mutation group were all lower than those in the WT group. Whether neoadjuvant immunochemotherapy results in a different therapeutic effect in patients with NSCLC depending on the type of oncogenic mutation is unclear and should be examined in larger-sample investigations.

There are a few limitations to this study which should be addressed. First, we employed a retrospective design and a small sample size, which could have introduced selection bias and limit the statistical power of findings. Second, there was heterogeneity in the patients and treatment regimens in our study. Third, our study was lack of PD-L1 data, which could make effects on the outcomes. Finally, the postoperative follow-up in our study was not extensive, and thus survival outcomes should be interpreted with caution.

Conclusions

The potential of neoadjuvant immunochemotherapy for patients with stage III NSCLC with cancer driver gene mutations is promising. The application prospects of the neoadjuvant immunotherapy combined with chemotherapy in patients with early or locally advanced oncogene-mutated lung cancer are considerable. These findings should be validated in randomized controlled trials with larger sample sizes. Moreover, long-term follow-up should be completed in future studies to confirm whether this neoadjuvant immunotherapy regimen can provide sustained survival benefit in patients with stage III NSCLC with oncogenic mutations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-60/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-60/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-60/prf

Funding: This study was supported by the Key R&D Program of Zhejiang (No. 2023C03172), the National Key Research and Development Program of China (No. 2022YFC2407303), the Zhejiang Province Major Science and Technology Special Program Project (No. 2020C03058), and the Zhejiang Province Lung Tumor Diagnosis and Treatment Technology Research Supported by the Center (No. JBZX-202007).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-60/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 approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of the Zhejiang University School of Medicine (2021 IIT No. 844) and performed in accordance with the Declaration of Helsinki (as revised in 2013) and Good Clinical Practice Guidelines. Individual consent for this retrospective analysis was waived.

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

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(English Language Editor: J. Gray)