The role of immunotherapy in resectable stage II non-small cell lung cancer: a systematic review

Introduction

Lung cancer remains the leading cause of deaths related to cancer surpassing breast and prostate cancers globally. Non-small cell lung cancer (NSCLC) accounts for 80–85% of new cancer cases (1) and surgical complete resection is the mainstay choice of treatment for early-stage NSCLC. However, despite undergoing complete resection, 30% to 55% of NSCLC patients experience recurrence and eventually die from disease relapse (2). These high recurrence rates underscore the urgent need for more effective perioperative treatment strategies in NSCLC.

The immune checkpoint inhibitors (ICIs) have emerged as an important component of the treatment for NSCLC patients in the recent years. Especially programmed cell death 1 (PD-1) and its ligand (PD-L1) transformed the management of advanced and metastatic NSCLC, establishing a new standard of care. These advancements redirected attention to early-stage lung cancer, emphasizing the potential use of ICIs as perioperative treatments to enhance patient outcomes. Despite the potential benefits, concerns remain regarding neoadjuvant immunotherapy, particularly its potential to introduce surgical challenges that may necessitate conversion from minimally invasive surgery to thoracotomy, incomplete resection, delays in planned surgeries, or occurrence of severe adverse events.

While immunotherapy strategies are better established for stage I and III NSCLC, there remains no clear consensus on the optimal approach for resectable stage II disease. In light of this gap, we aimed to review the current evidence on immunotherapy in resectable stage II NSCLC, focusing on its potential to enhance survival and minimize disease relapse. We present this article in accordance with the PRISMA reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-25-46/rc).

Methods

Search strategy

A literature search was conducted on PubMed and Scopus for studies published over the past ten years (2015 to February 2025) to capture the most recent and relevant data (Appendix 1). The following Boolean search strings were used: (immunotherapy) AND (resectable) AND (lung cancer OR non-small cell lung cancer OR NSCLC) for PubMed and (TITLE-ABS-KEY(“non-small cell lung cancer” OR NSCLC OR “lung cancer”)) AND (TITLE-ABS-KEY(resectable)) AND (TITLE-ABS-KEY(immunotherapy)) for Scopus. No language or publication date filters were applied during the initial search. However, non-English publications were excluded during the screening phase. All identified records were imported into Covidence for initial screening. Two independent reviewers assessed titles and abstracts for relevance based on the predefined inclusion and exclusion criteria. Full-text articles were retrieved for studies that passed the initial screening. Additionally, the reference lists of included studies were reviewed to identify any additional eligible articles.

Study inclusion

All study designs, other than case reports, review articles, systematic reviews and meta-analyses, published between 2015 and February 2025 were considered, provided they met our inclusion criteria, which were developed using the Problem, Intervention, Comparison, Outcome, and Study design (PICOS) framework. While case reports were excluded, we included case series that reported outcomes for multiple patients, as they provide valuable information on safety, feasibility, and preliminary efficacy of perioperative immunotherapy in resectable NSCLC.

The study population of interest included patients with resectable or potentially resectable stage II NSCLC. Studies involving unresectable or metastatic disease, small cell lung cancer, or those limited exclusively to stage III disease were excluded.

The interventions of interest were immunotherapy, specifically ICIs, used as perioperative treatment. Studies focused on other perioperative treatments, such as chemotherapy, radiotherapy, or stereotactic radiotherapy, were excluded. However, studies examining combination therapies, such as immunotherapy combined with another modality, were included.

The outcomes of interest included recurrence rates, overall survival (OS), progression-free survival, disease-free survival (DFS), major pathological response (MPR), complete pathological response (pCR), as well as safety and adverse events.

Study quality assessment

For randomized controlled trials (RCTs), we used the Cochrane Risk of Bias tool (RoB 2) (3), which evaluates five domains: the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported results. Each trial was then categorized as having a low risk of bias, some concerns, or a high risk of bias (Figure 1). For non-randomized studies, we used the Methodological Index for Non-Randomized Studies (MINORS) tool (4), which includes 12 methodological criteria (Table 1). Each criterion is scored from 0 to 2 (0= not reported, 1= reported but inadequate, 2= reported and adequate). The global ideal score is 16 for non-comparative studies and 24 for comparative studies. For case series, we used the JBI Critical Appraisal Tool for Case Series (57), which consists of 10 questions. Each item is assessed by the reviewer and rated as “yes”, “no”, “unclear” or “not applicable” (Appendix 2).

Figure 1 Cochrane RoB2 tool for quality assessment of randomized studies.

Data extraction and planned analysis

Data was compiled into a structured form that included the following basic parameters for each study: first author, geographic location of the study, study period, study design, sample size, and intervention (Table 2). Findings were summarized qualitatively, emphasizing trends in pathological response, survival outcomes, and safety. Patterns across studies, including the impact of neoadjuvant versus adjuvant immunotherapy and combination strategies with chemotherapy or radiotherapy, were highlighted.

Where possible, hazard ratios, risk and response rates were collected and presented to allow for comparison across studies. Descriptive synthesis also included evaluation of recurrence patterns and the influence of patient characteristics, tumor histology, and molecular status on outcomes.

This planned analysis approach aimed to provide a comprehensive overview of current evidence for perioperative immunotherapy in resectable NSCLC, with particular attention to data relevant to stage II disease and areas requiring further research.

Results

A total of 676 studies were imported for screening, with 4 duplicates identified manually and an additional 261 duplicates detected by Covidence, leaving 411 studies for title and abstract screening. Following this initial screening, 63 studies were excluded during the title and abstract screening. The studies were excluded for the following reasons: not relevant population (n=18; e.g., non-NSCLC studies, unresectable or metastatic-only cohorts), not relevant intervention (n=21; studies without immunotherapy or using chemotherapy, targeted therapy, or radiation alone), and not relevant study type (n=24; reviews, editorials, commentaries, conference abstracts, guidelines and basic science research). 348 full-text articles were assessed for eligibility. Of these, 286 studies were excluded for the following reasons: 155 were review articles, 22 focused solely on stage III disease, 37 examined the wrong intervention, 35 had an inappropriate study design, 14 were meta-analyses, 9 were study protocols, 6 involved the wrong patient population, 3 assessed the wrong outcomes, 3 were conducted in an unsuitable setting, and 2 were not published in English. Ultimately, 62 studies met the inclusion criteria and were included in the systematic review (Figure 2). The majority of studies were conducted in China, followed by the United States, with a smaller number from European countries. Most of the studies evaluated immunochemotherapy (n=31). Nine studies included immune monotherapy and one included dual immunotherapy. One study included immunochemotherapy in combination with SBRT. Nine studies included immune monotherapy and immunochemotherapy. Two evaluated immunochemotherapy and dual immunotherapy in combination with chemotherapy. One study assessed immune monotherapy and immunotherapy in combination with SBRT. Two studies included immune monotherapy and dual immunotherapy. One included neoadjuvant immunotherapy and adjuvant immune monotherapy with or with our radiation. Three studies investigated neoadjuvant immunochemotherapy and adjuvant immune monotherapy. One study incorporated immune monotherapy, dual immunotherapy and immunochemotherapy. Finally, one study did not specify the type of immunotherapy (Table 3).

Figure 2 Selection process of the studies.

Quality of included studies

All included randomized clinical trials (58-62,64-67) were assessed using the RoB 2 tool and were judged to have a low risk of bias. A total of 52 non-randomized studies were evaluated for methodological quality using the MINORS criteria. One study (56) scored 10 points, 3 studies (10,29,52) scored 11 points, 13 studies (5,8,12,13,15,18,19,26,35,42,49,51,53) scored 12 points, 1 study (16) scored 13 points, 10 studies (14,20,21,30,32-34,38,46,48) scored 14 points, 3 studies (22,24,55) scored 16 points, 2 studies (25,28) scored 18 points, 5 studies (7,9,31,45,47) scored 19 points, 12 studies (6,11,17,27,36,37,39-41,43,44,54) scored 20 points, 1 study (50) scored 21 points and 1 study (23) scored 24 points. Finally, a case series (63) is assessed using JBI Critical Appraisal Tool for Case Series and met the criteria for inclusion in the systematic review, fulfilling all appraisal items except “clear reporting of the presenting site demographic information”.

Pathological and radiological responses

A large number of studies shows an increased rate of pCR and MPR in patients who were treated with immunotherapy (Table 4). Among studies investigating immunochemotherapy, one study investigated the pathological responses of 61 patients with 10 out of 13 patients with stage II disease obtaining an MPR with neoadjuvant pembrolizumab plus chemotherapy (26). Another study reported that MPR rates were 32.1% in the nivolumab plus chemotherapy arm and 50% in the ipilimumab plus nivolumab plus chemotherapy arm. However, the exact number of patients with stage II disease was not given (23). A different single-arm, phase II study investigated atezolizumab in combination with chemotherapy and found that 57% of patients had a MPR in a cohort of 30 patients including 7 with stage II disease (20). A clinical trial investigating neoadjuvant avelumab plus chemotherapy reported four radiologic responses, one complete response and three partial responses out of 15 patients including 5 with stage II disease according to the RECIST 1.1 criteria radiologically, which was lower than minimum six responses needed to continue the study resulting in the termination of the study (22). A phase 1b study with 40 patients reports MPR of 40.5% and pCR of 16.2% with sintilimab as immune monotherapy. In this study, 7 patients out of 40 had stage II disease (32). A study investigating neoadjuvant durvalumab as immune monotherapy for resectable NSCLC in cohort of 46 patients including 40 patients with stage II disease reported that 8 patients achieved MPR with early termination of the study due to 4 postoperative deaths, which were not related to durvalumab-related toxicity (24). Additionally, trials evaluating combined modalities report similar results: A single-arm, phase II trial that investigates stereotactic body radiotherapy (SBRT) combined with tislelizumab and chemotherapy as a neoadjuvant therapy reports an MPR rate of 76% in 46 patients including 8 patients with stage IIB disease (48). In summary, across immunochemotherapy, monotherapy, and multimodal regimens, multiple studies reported measurable pathological responses in cohorts that included stage II patients.

Although most studies deal with oncogene-negative patients, there are also studies that investigate ICIs for resectable oncogene-mutant NSCLC (25,34). A study conducted by Zhang et al. investigating immunochemotherapy reported an MPR rate of 37.5% and pCR rate of 12.5% in a 40 oncogene-mutated NSCLC cohort of 40 patients with 25% of patients having stage II disease (15). Huang et al. reported that an improved MPR was also achieved in the immunochemotherapy combined therapy group compared with the chemotherapy group and the immunotherapy group (53.9% vs. 10.8% vs. 8.7%). Stage II disease was present in 23 of 83 patients in the combined immunochemotherapy group, 9 of 23 in the immunotherapy group, and 49 of 152 in the chemotherapy group (7). Another study reported that compared to chemotherapy or TKI treatment, neoadjuvant therapy combining PD-L1 blockade combined with platinum-based chemotherapy resulted in higher pCR and MPR rates in patients with resectable oncogene-mutant NSCLC; however, these response rates remained lower than those observed in oncogene-negative patients treated with PD-L1 blockade (31). These findings suggest that neoadjuvant immunotherapy may induce meaningful pathological responses in patients with oncogene-mutant NSCLC, including those with stage II disease.

Several studies have focused on specific patient subgroups to better understand variations in treatment response and clinical outcomes. Chang et al. investigated neoadjuvant immune monotherapy and immunochemotherapy in a subgroup of patients consisting of patients with chronic obstructive pulmonary disease (COPD) and they report that the objective response rate (ORR), MPR, and pCR were not significantly different from non-COPD group. 2 patients in COPD group and 4 patients in the non-COPD group had stage II disease (27). A study by Shen et al. investigated squamous cell carcinoma subgroup receiving neoadjuvant pembrolizumab and chemotherapy and reports pCR of 45.9% and an MPR of 64.9% (33). Another study by Lei et al. reported an MPR of 54.2% in immunochemotherapy group in lymphoepithelioma-like carcinoma (36). A study investigated the results of CHECKMATE-816 study in Chinese patients and found consistent findings reporting that nivolumab plus chemotherapy improved event-free survival (EFS) and pCR in comparison to chemotherapy. In this subgroup 31 patients had stage II disease out of 97 patients (61). Pathological responses, including MPR and pCR, were observed across diverse patient subgroups, with stage II patients represented in each cohort.

Another study that investigates the effect of multidisciplinary team-based model consisting of physicians from the departments of thoracic surgery, respiratory and critical care medicine, pathology, radiology, nuclear medicine and radiotherapy reported that multidisciplinary team-based model has satisfactory results in patient selection for radical resection and pathological remission. However, the cohort in this study only includes 2 patients with stage II disease out of 35 patients (29).

OS, EFS and DFS outcomes

Numerous studies have investigated DFS, EFS and OS in patients with resectable lung cancer who received adjuvant or neoadjuvant immunotherapy, aiming to evaluate long-term outcomes and prognostic factors (Table 5). Preoperative immunotherapy has consistently demonstrated promise in the treatment of resectable NSCLC.

Reported rates of DFS and OS vary between studies, reflecting differences in study populations, treatment approaches, and follow-up durations (40,60). The CHECKMATE 816 trial showed an EFS of 31.6 months in the nivolumab plus chemotherapy group while the EFS in the chemotherapy alone group was 20.8 months (60). About 36% of patients were stage II. The RATIONALE-315 study showed that tislelizumab plus neoadjuvant chemotherapy significantly improved EFS in comparison to placebo. This study included 41% with stage II disease in the tislelizumab group and 40% with stage II disease in the placebo group (67). In the NeoR-World retrospective cohort study, Yang et al. reported that DFS was significantly longer in the immunochemotherapy group compared with the chemotherapy group (54). The KEYNOTE-671 randomized trial showed that EFS at 24 months was 62.4% in the pembrolizumab plus chemotherapy group and 40.6% in the placebo plus chemotherapy group (P<0.001), however the estimated 24-month OS was 80.9% in the pembrolizumab group and 77.6% in the placebo group, which was similar. This study included 118 patients with stage II disease out of 397 patients in the pembrolizumab group and 121 patients with stage II disease out of 400 patients in the placebo group (66). Zhao et al. reported that patients in the neoadjuvant immunochemotherapy group had significantly better DFS and OS than those in the neoadjuvant chemotherapy group [(3-year DFS: 75.2% vs. 43.3%) and (3-year OS: 91.5% vs. 58.0%)]. In this study, there were 116 patients per group and stage II disease was observed in 30.2% of patients in the chemotherapy group and 27.6% in the immunochemotherapy group (8). Another phase II study investigating immunochemotherapy by Henick et al. highlighted the median OS was 55.8 months, and the median DFS was 34.5 months with a median follow up of 39.5 months in a cohort consisting of stage I–III disease (19). The AEGEAN trial reported that the duration of EFS was significantly longer with durvalumab than with placebo. In this study the durvalumab group had 28.4% patients with stage II disease and placebo group had 29.4% patients with stage II disease (64). Furthermore, a retrospective cohort study found a statistically significant difference between two groups of neoadjuvant immunochemotherapy and neoadjuvant chemotherapy in DFS (43). The Checkmate-77T trial comparing nivolumab combined with chemotherapy versus chemotherapy combined with placebo, showed that treatment with nivolumab resulted in significantly longer EFS than chemotherapy alone. The nivolumab group included 35.4% patients with stage II disease and the chemotherapy group included 34.9% patients with Stage II disease (65). A five year follow up of neoadjuvant sintilimab as immune monotherapy in NSCLC reported DFS of 65.7% and OS of 80.4% in patients with R0 resection. In this cohort of 40 patients 80% had stage II and III disease; however, the exact numbers of patients with stage II disease were not disclosed (14). Additionally, a single-arm phase II clinical trial reported a 3-year survival rate of 80% with neoadjuvant atezolizumab monotherapy in a group of 181 patients including 71 (39.2%) with stage II disease (21). In summary, immunotherapy-based neoadjuvant regimens may show increased DFS and EFS compared with chemotherapy alone in cohorts that include stage II patients, which comprised roughly 30–40% of patients in these studies.

Moreover, a study has reported that adjuvant immunotherapy does not improve survival in NSCLC patients who achieved major or pCR following induction immunotherapy and surgery (6).

Only a limited number of studies have reported subgroup analyses specifically for stage II disease. In this subgroup, Huang et al. found that patients with stage II disease receiving combined immunochemotherapy had a hazard ratio for DFS of 0.44 [95% confidence interval (CI): 0.16–1.20] compared with those receiving chemotherapy alone (7), while the NeoR-World study reports a hazard ratio of 0.94 (95% CI: 0.49–1.79) (54) for the same comparison. The AEGEAN trial reports a hazard ratio of 0.76 (95% CI: 0.43–1.34) for EFS comparing patients with stage II disease receiving combined immunochemotherapy and chemotherapy alone (64). For the same comparison, The CHECKMATE 77T reports a hazard ratio of 0.81 (95% CI: 0.46–1.43) (65). In the KEYNOTE-671, Wakelee et al. reports a hazard ratio of 0.65 (95% CI: 0.42–1.01) (66) and in the RATIONALE-315, Yue et al. reports a hazard ratio of 0.47 (95% CI: 0.26–0.87) (67) in stage II patients. Out of the studies cited above, only one (RATIONALE-315) showed a statistically significant improvement in DFS or EFS with chemoimmunotherapy as compared to chemotherapy (67), however they were potentially underpowered to detect this. Conversely, the NEOSTAR (23) and the CheckMate 816 (60) studies did not report pathological or survival outcomes separately for patients with stage II disease; instead, results were presented in combination with those for stage IB patients.

Recurrence outcomes

A case-control study involving 23 NSCLC patients who received neoadjuvant ICI-based therapy followed by definitive resection found that two patients experienced mediastinal nodal recurrence (5). This group included 6 patients with stage I, 10 with stage II, and 7 with stage III disease. None of the patients with stage II disease developed mediastinal recurrence after an average follow up of 49 months. Another study by Tegenbosch et al. showed that among patients ineligible for (neo)adjuvant ICI, 21.7 percent experienced recurrence, while twelve of the twenty eligible patients had no recurrence at a 34.1-month median follow-up, indicating they would have been overtreated with ICI (45).

Safety and adverse events

The majority of studies report that adjuvant and neoadjuvant immunotherapy is generally safe and well tolerated in stage II disease (38,42,46,49-53,55,56). A phase I trial demonstrated that neoadjuvant nivolumab as immune monotherapy was not associated with unexpected perioperative morbidity or mortality. However, over half of the video-assisted thoracoscopic surgery (VATS) and robotic procedures required conversion to thoracotomy, primarily due to hilar inflammation and fibrosis. Notably, 10 of the 21 patients included in the study had stage II disease (16). Conversely, a different study reports a higher rate of tissue fibrosis and inflammation in the immune monotherapy group with no difference in operating time nor more conversions or perioperative complications (17). A study by Zhang et al. reported a higher rate of postoperative complications in the group receiving neoadjuvant immunotherapy with sintilimab compared to the upfront surgery and chemotherapy groups. Each group included 37 patients, with 14 stage II patients in the immunotherapy group, 13 in the upfront surgery group, and 11 in the chemotherapy group (9). A study by Seitlinger et al. found that lung cancer patients with endobronchial disease had a higher rate of global complications during neoadjuvant treatment compared to patients without obstruction (37). The available evidence suggests that immunotherapy is feasible, with manageable perioperative complications.

Immune-related adverse events have emerged as a significant concern in patients receiving immunotherapy. A study by Ay et al. reported that there were no adverse events causing death in patients treated with immunochemotherapy. However, blood count abnormalities, diarrhea, and pneumonitis were the most common toxicities leading to treatment discontinuation, while blood count abnormalities, fever, and infections most frequently caused dose interruptions or reductions (35). Conversely, a study by Wu et al. consisting of 42 patients (2 with stage II disease) in pembrolizumab group and 34 patients (3 with stage II disease) in nivolumab group reported that none of the patients had to stop treatment or reduce dose due to adverse events (41). A study by Reuss et al. examining dual immunotherapy, which included 2 stage II patients out of a total of 9, was terminated early due to toxicity. Six patients experienced treatment-related adverse events (TRAEs), and three developed grade ≥3 toxicities (30). There is no consistent pattern regarding immune-related adverse events, with reported toxicities varying across studies and no clear consensus on their frequency or severity in stage II patients.

Additionally, numerous studies have explored the safety of various combination treatment modalities. A case series by Yin et al. investigated sintilimab combined with platinum-based chemotherapy and found the regimen to be both safe and effective. Among 13 patients, including 2 with stage II disease, 9 experienced neoadjuvant TRAEs, with only one patient (7.6%) developing a grade 4 TRAE (63). A RCT that investigates nivolumab with or without relatlimab confirms the safety and feasibility of both arms. In this study, each arm included 30 patients and nivolumab arm has 18 and nivolumab plus relatlimab has 17 patients with stage II disease (62). Similarly, a randomized clinical trial assessing neoadjuvant durvalumab with or without stereotactic body radiotherapy showed that it is safe and feasible and associated with high MPR (58). Combination immunotherapy appears safe and feasible in stage II NSCLC, with mostly manageable adverse events.

Furthermore, a retrospective cohort study by Zhang et al. comparing different approaches of surgery including VATS and thoracotomy confirmed that VATS could achieve similar results as the open thoracotomy, with the advantage of fewer intensive care unit (ICU) stays (39). Mathey-Andrews et al. investigated the feasibility of minimally invasive surgery (MIS) following neoadjuvant immunotherapy in resectable NSCLC and found that there was no difference in rate of MIS lobectomy among patients who received immunotherapy vs. chemotherapy (47).

Moreover, a retrospective cohort study involving 627 patients demonstrated that, based on multivariable regression analysis, the type of neoadjuvant treatment was not a significant determinant of successful minimally invasive surgery for resectable NSCLC (10).

Discussion

Neoadjuvant immunotherapy has emerged as a promising strategy for resectable NSCLC, offering improvements in pathological response and survival outcomes. However, concerns persist regarding its potential to introduce surgical challenges, delay surgery, and cause adverse events. While some studies indicate an increased rate of conversion to thoracotomy due to inflammation and fibrosis (17), others suggest that minimally invasive approaches remain feasible with proper patient selection (10,47,55).

In NSCLC clinical trials, MPR, defined as ≤10% viable tumor cells, and pCR, defined as no viable tumor cells, are increasingly used to evaluate the effectiveness of treatments (68). A retrospective study reported no clinical factor other than PD-L1 expression was predictive of the pathological response (13). Pathological and radiological response rates vary across studies, but overall, neoadjuvant immunotherapy appears to enhance tumor regression, particularly when combined with chemotherapy or other treatment modalities. These responses have been linked to improved survival outcomes, reinforcing the clinical benefit of integrating immunotherapy into the neoadjuvant setting.

Survival analyses further highlight the advantages of immunotherapy in prolonging EFS and OS. While some studies demonstrate a clear survival benefit over chemotherapy alone, others indicate that multimodal approaches, including surgery, may offer superior outcomes. The variability in findings suggests that patient selection, tumor characteristics, and specific immunotherapy regimens play crucial roles in determining treatment efficacy.

Importantly, while immunotherapy has become increasingly integrated into the management of stage III NSCLC, the optimal approach for resectable stage II disease remains less obvious. Although neoadjuvant immunotherapy shows promising improvements in pathological response and survival, recommendations for its use in stage II patients are based on studies combining stage II with stage III disease, with only a single RCT (RATIONALE-315) demonstrating a statistically significant difference in DFS and/or OS in the stage II subgroup. Notably, no studies to date provide stage II-specific data for MPR or pCR, limiting our ability to draw definitive conclusions about the efficacy of these treatments in this population. Consequently, targeted studies are urgently needed to clarify risk stratification, optimal timing and sequencing of immunotherapy, and long-term outcomes, in order to guide evidence-based management and ensure that stage II patients derive similar benefits to those observed in stage III disease.

While current IASLC consensus primarily addresses stage III disease, recent non-consensus expert recommendations suggest that neoadjuvant chemoimmunotherapy followed by surgery may be preferred over upfront surgery for medically operable patients with technically resectable clinical stage II NSCLC, irrespective of PD-L1 expression (69). Complementing this, ESMO guidelines recommend neoadjuvant or perioperative chemoimmunotherapy for resectable stage II–III NSCLC without EGFR or ALK alterations (70). The NCCN guidelines also encourage neoadjuvant immunotherapy approaches in resectable NSCLC (71). This highlights emerging strategies for stage II disease and the need for further studies to establish evidence-based guidance.

Recurrence remains a significant consideration, particularly in patients with advanced disease or mediastinal involvement. Although immunotherapy shows promise in reducing recurrence rates, studies specifically addressing recurrence patterns and long-term relapse outcomes represent only a small subset of the existing literature. Further research is needed to identify predictors of recurrence and optimize postoperative surveillance strategies.

Overall, neoadjuvant immunotherapy continues to redefine the treatment landscape for resectable NSCLC. However, questions remain regarding the optimal regimen, long-term outcomes, and patient selection criteria. Future studies should focus on refining treatment algorithms, addressing safety concerns, and identifying biomarkers to predict response and recurrence risk.

A key limitation of this systematic review is that none of the included studies focused exclusively on stage II NSCLC. All available data came from mixed stage II–III cohorts, with limited separate reporting for stage II patients. This heterogeneity limits true stage-specific interpretation, as treatment response, recurrence risk, and surgical outcomes can differ substantially between stages. Consequently, we included non-randomized and retrospective studies in addition to randomized trials to capture clinically relevant data for this subgroup, which introduces inherent risks of selection bias, confounding, and heterogeneity. As a result, the effectiveness and safety of immunotherapy specifically for stage II disease cannot be reliably determined. The ongoing Impower-030 trial evaluating atezolizumab in neoadjuvant therapy for resectable stage II–III patients, with a planned enrollment of over 450 patients, may provide additional data to guide clinical practice (72). Ideally, however, dedicated studies focusing on stage II patients would provide more accurate guidance for this subgroup. Studies comparing the neoadjuvant versus adjuvant use of immunotherapy in stage II patients may be warranted as well.

Conclusions

Neoadjuvant immunotherapy, particularly when combined with chemotherapy, demonstrates promising improvements in pathological response and survival outcomes in patients with resectable NSCLC. Although several trials are currently ongoing evaluating immunotherapy across different treatment combinations and study populations, the available evidence in the stage II patient population remains limited by the small number of RCTs and heterogeneity across studies. Therefore, further high-quality, stage II-specific randomized trials are needed to confirm these findings and to define optimal treatment strategies in this population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://vats.amegroups.com/article/view/10.21037/vats-25-46/rc

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-25-46/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://vats.amegroups.com/article/view/10.21037/vats-25-46/coif). B.W. serves as an unpaid editorial board member of Video-Assisted Thoracic Surgery from January 2025 to December 2026. The other author has 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.

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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