Immunotherapy in operable non-small cell lung cancer: a systematic review and network meta-analysis of efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy

Introduction

Lung cancer is still the leading cause of cancer-related deaths regardless of the gender according to the new cancer statistics. Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers (1). Surgery is still considered to be the primary measure to achieve clinical cure for patients with early to locally advanced NSCLC with surgical indication (2). However, many patients with operable locally advanced NSCLC relapse or metastasize early after surgery, affecting overall survival (OS). How to improve the long-term survival benefits of patients and reduce recurrence and metastasis is an urgent clinical problem for patients with operable NSCLC. A number of previous clinical trials have shown that it is feasible to add adjuvant or neoadjuvant platinum chemotherapy to the surgical resection of patients with locally advanced NSCLC and which can increase the 5-year OS. Unfortunately, the absolute benefit of this method to OS is only about 5% (3), and the side effects are significant, affecting the therapeutic effect and quality of life of patients. The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of many solid tumors, including NSCLC. The efficacy of these ICIs, especially those targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway, has been validated in large randomized clinical trials of metastatic NSCLC. When combined with platinum-based chemotherapy, the OS of immunochemotherapy was significantly better than that of chemotherapy alone. Therefore, the immunochemotherapy has become the standard treatment for metastatic NSCLC without driving gene mutations. The success of ICI in metastatic NSCLC has increased the confidence of researchers to move the treatment line of ICIs forward. In order to improve the resection rate and improve the prognosis of patients, the researchers have launched a number of randomized clinical trials (4-8) and confirmed that perioperative immunotherapy is expected to improve the long-term benefits of patients, and further answered whether immunochemotherapy has an impact on surgical outcomes.

The positive endpoints of event-free survival (EFS) and pathological complete response (pCR) rates of Checkmate816 provide important data support for immunochemotherapy as the mainstream mode of neoadjuvant therapy for operable NSCLC (4). The double positive results of EFS and OS of KEYNOTE-671 (8) were respectively demonstrated in American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) in 2023, which is the first and only positive OS result in perioperative immunotherapy of operable NSCLC, thus confirming the clinical value of the “sandwich” mode, that is, “neoadjuvant immunochemotherapy-surgery-adjuvant immunotherapy”. Pasqualotto et al. (9) analyzed 7 randomized controlled trials (RCTs) to confirm the benefit of adding immunotherapy as neoadjuvant therapy or adjuvant therapy. They found that immunotherapy plus chemotherapy as neoadjuvant therapy can improve OS, EFS, major pathological response (MPR), and pCR, as well as improve EFS as adjuvant therapy, compared with chemotherapy alone. Similarly, Mei et al. (10) conducted a network meta-analysis (NMA) about perioperative immunotherapy; however, the point of the NMA was to the efficacy and safety of various ICIs. Furthermore, their works confirmed a same result that there was a manageable safety profile of immunotherapy plus chemotherapy as neoadjuvant therapy or adjuvant therapy for resectable NSCLC. However, they didn’t compare the results between neoadjuvant immunochemotherapy and perioperative immunochemotherapy. There are still many problems to be solved in the perioperative immunotherapy in NSCLC. Up to now, clinical research has not been able to determine which treatment strategy is the best solution to improve patient survival and clinical cure rate. For patients with operable NSCLC, which treatment strategy is better: neoadjuvant immunochemotherapy or perioperative immunotherapy (“sandwich mode”)? Which treatment strategy is most suitable for the overall population of operable lung cancer? For specific patients, is adjuvant immunotherapy always necessary?

In order to explore the answers to the above questions, we conducted this meta-analysis. In this study, our aim was to collect and evaluate the efficacy of two current main immunotherapy strategies for operable NSCLC. There is currently no literature that directly compares the two methods. Therefore, meta-analysis was performed through adjusted indirect comparisons on the basis of the Bayesian framework approach. We also compared the results among different subgroups, such as age, gender, histology, and so on. The purpose of this study is to identify the best immunotherapy strategy and offer optimal treatment options for patients with operable NSCLC. We present this article in accordance with the PRISMA-NMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-287/rc) (11).

Methods

This study was registered in PROSPERO to ensure transparency (registration number: CRD42024495955).

Search strategy and selection criteria

A search for the phase II and III RCTs about neoadjuvant immunochemotherapy and perioperative immunotherapy was conducted independently by two authors, with disagreements resolved by the consensus with the intervention of a third reviewer. Language was restricted to English. PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov databases were systematically searched for relevant studies conducted as of December 31, 2023. Online proceedings from annual conferences that took place from 2018 to 2023 were also sourced in order to include the updated outcomes. The American Association for Cancer Research, ASCO, ESMO, Chinese Society of Clinical Oncology, and The World Conference on Lung Cancer were included. The keywords used for the search were “non-small-cell lung cancer, perioperative, neoadjuvant, ICI, pembrolizumab, atezolizumab, nivolumab, ipilimumab, durvalumab, tremelimumab, camrelizumab, tislelizumab, sintilimab, toripalimab”.

Studies had to meet the following criteria: (I) phase II or III studies that enrolled adult patients with operable NSCLC; (II) studies that used immunochemotherapy as neoadjuvant therapy. Exclusion criteria were as follows: (I) treatment with immunotherapy combined with other therapies other than chemotherapy or immunotherapy alone; (II) studies that did not report the EFS; (III) single-arm trials; (IV) letters, reviews, author responses, case reports, editorial comments, duplicate articles and non-English articles. For multiple studies originating from a single trial, only one was assessed. According to the treatment mode, the patients were grouped into three arms: arm A, neoadjuvant chemotherapy alone, defined as patients receiving platinum-doublet chemotherapy alone, including those receiving platinum-doublet chemotherapy plus placebo, before underdoing definitive surgery, followed by follow-up or placebo after surgery, marked as neoadjuvant chemotherapy group. Arm B, neoadjuvant immunotherapy plus chemotherapy, defined as patients receiving immune checkpoint blockades and platinum-doublet chemotherapy before underdoing definitive surgery, followed by follow-up or placebo after surgery, marked as neoadjuvant immunotherapy group. Arm C, neoadjuvant immunotherapy plus chemotherapy before underdoing definitive surgery followed by surgery and adjuvant immunotherapy, patients receiving immune checkpoint blockades and platinum-doublet chemotherapy before underdoing definitive surgery, followed by adjuvant immunotherapy, marked as perioperative immunotherapy group.

Data extraction and quality assessment

Two investigators (Z.H. and Q.Z.) independently read the papers and extracted data from included studies, and any discrepancies were resolved through discussions with the other authors. Two investigators independently extracted data into predesigned tables, recording study ID, treatment regimens, publication year, first author, study arms, design and participant numbers. The following data were collected from each study: (I) characteristics of studies [study ID, National Clinical Trial (NCT) number, first author, publication years, study phase, arm, study design, total number, treatment]; (II) EFS, hazard ratios (HR) with corresponding 95% confidence intervals (95% CIs) for EFS, subgroups including intention-to-treat population, no pCR population, gender: female, gender: male, age <65 years, age ≥65 years, pathology: squamous, pathology: non-squamous, Eastern Cooperative Oncology Group (ECOG) =0, ECOG =1, PD-L1 expression: PD-L1 <1%, PD-L1 expression: PD-L1 ≥1%, PD-L1 expression: PD-L1 1–49%, PD-L1 expression: PD-L1 ≥50%, smoking status: smoker, smoking status: never smoker, baseline stage of disease: stage I–II, baseline stage of disease: stage III. EFS was described as the time from randomization to any disease progression or postsurgical disease recurrence. Not all studies have data for specific subgroups, which we extract based on the specifics of each subgroup. If there is no data in specific subgroup, the number of studies in this subgroup analysis will be reduced according to the actual situation. This work was completed between January 1^st and February 1^st, 2024.

Two investigators (Z.H. and Q.Z.) used the Cochrane Risk of Bias Assessment Tool to evaluate the included RCTs for potential bias sources, such as randomization process, deviations from the intended interventions or measurement, missing data, and the selection of the result and other bias. The risk of bias was categorized as high (red), medium (yellow) or low (green).

Main outcomes and abbreviations

We did this NMA to evaluate the efficacy among neoadjuvant chemotherapy alone, neoadjuvant immunotherapy or perioperative immunotherapy. The primary outcome was EFS, defined as the duration from randomization to either local progression impeding planned surgery, an unresectable tumor, disease progression or recurrence, or death. pCR, defined as 0% residual viable tumor cells in the primary tumor and sampled lymph nodes. MPR, defined as ≤10% residual viable tumor cells in the primary tumor and sampled lymph nodes.

Statistical analysis

Endnote 20.0 was used for literature management and deduplication. Review Manager 5.3 was used for bias judgement. R 4.3.2 software was used for the NMA. The survival outcomes (EFS) were assessed using the HR. Heterogeneity was quantified using the I², I²<25% indicates low heterogeneity, 25–50% medium, as well as I²>50% indicates a high degree of heterogeneity. The Markov chain Monte Carlo (MCMC) method was used via JAGS (v 4.3.0) and getmtc (v 0.8.2) packages in R (v 4.3.2) for consistency models and fixed effects. Four independent Markov chains were used to generate posterior distributions, each running 5,000 burn-in and 20,000 inference iterations/chains. Model convergence was assessed using the Brookse Gelmane Rubin method and trace plots (12). To assess the surface under the cumulative ranking curves (SUCRAs) for each therapeutic regimen, increased SUCRA values indicated higher efficacy and probability of longer EFS (13). The robustness of acquired data was confirmed because of published RCTs in sensitivity analyses.

Results

After searching, a total of 1,799 records from the databases and online conferences were identified. After removing the duplicates and irrelevant articles by screening the abstracts, 72 studies were considered potential eligible for review and 7 studies involving 2,934 patients were finally included in this analysis (4,6,8,14-17) (Figure 1).

Figure 1 Literature search and selection process followed the PRISMA guidelines. PRISMA, Preferred Reporting Items for Systematic review and Meta-analysis.

The risk of bias analysis (Figure 2A,2B) revealed that four trials had a high bias, four trials had an unclear bias. As well as that the remaining had a low risk of bias. Low to moderate heterogeneity in all outcomes in this NMA indicated the justifying by using a fixed-effects model. Meanwhile, consistency and node-splitting analyses were not required because of that there was no closed loop in this NMA.

Figure 2 Risk bias assessment graph using Review Manager 5.3. (A) Risk of bias graph. (B) Risk of bias summary. Studies were classified into one of three categories: low risk, high risk or having “some concerns”.

The characteristics of studies

All studies are randomized clinical trials, of which five of them are phase III studies and the other two are phase II studies. Two of these studies (NCT02998528, NCT04338620) focus on neoadjuvant immunochemotherapy, while the other five studies focus on perioperative immunotherapy (“sandwich mode”, neoadjuvant immunochemotherapy + adjuvant immunotherapy). ICIs involved in these studies include durvalumab, nivolumab, pembrolizumab, toripalimab, and camrelizumab. In these trials, the cycle of neoadjuvant therapy was 3 to 4 cycles. It should be pointed out that, despite there were its own unique features, the NEOTORCH model was divided into neoadjuvant chemotherapy group or perioperative immunotherapy group. Part of detailed characteristics of the included studies are summarized in Table 1. The additional detail characteristics of each trial are summarized in Table S1. The pCR and MPR rates of each trial are presented in Table S2 and network structure diagrams of all subgroups are summarized in Figure S1.

NMA of EFS in the intention-to-treat population

Neoadjuvant immunochemotherapy (HR 0.61, 95% CI: 0.36–0.98) and perioperative immunotherapy (HR 0.56, 95% CI: 0.42–0.71) both significantly improved the EFS of patients with operable NSCLC, comparing to neoadjuvant chemotherapy alone. Compared with neoadjuvant immunochemotherapy, perioperative immunotherapy showed no significant difference in EFS (HR 1.1, 95% CI: 0.62–1.9) (Figure 3, A1).

Figure 3 Network comparisons of EFS among neoadjuvant CT, neoadjuvant I + CT and perioperative I + CT, based on (A) population, (B) gender, (C) age, (D) pathology, (E) ECOG, (F) PD-L1 expression, (G) smoking status, (H) baseline stage of disease. Each cell of the EFS comprises HR and 95% confidence interval; red represents significant results. HR and 95% confidence intervals indicate outcomes for the upper tier of treatment compared with the lower tier. Lung cancer was staged using the eighth version of AJCC TNM staging system. CT, chemotherapy; I + CT, immunotherapy plus chemotherapy; perioperative I + CT, neoadjuvant immunotherapy plus chemotherapy followed by surgery and adjuvant immunotherapy; pCR, pathologic complete response; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; EFS, event-free survival; AJCC TNM staging system, Tumor-Node-Metastasis staging system of American Joint Committee on Cancer; HR, hazard ratio.

Subgroup analysis according to pathological response rate

Because of the lacking of survival data in pCR population, especially in the neoadjuvant chemotherapy arm, we could not analysis the difference of EFS in pCR population. In no pCR population, perioperative immunotherapy significantly improved the EFS compared with the neoadjuvant chemotherapy alone (HR 0.67, 95% CI: 0.44–0.99). There is no significant in EFS between neoadjuvant chemotherapy and neoadjuvant immunochemotherapy (HR 0.84, 95% CI: 0.42–1.7), as well as between neoadjuvant immunochemotherapy and perioperative immunotherapy (HR 0.8, 95% CI: 0.36–1.8) (Figure 3, A2).

Subgroup analysis according to gender

There was no significant difference in EFS was observed among the three groups of female patients. The HR was 0.46 (95% CI: 0.15–1.4) in neoadjuvant immunotherapy and 0.64 (95% CI: 0.38–1.1) in perioperative immunotherapy, respectively, compared with neoadjuvant chemotherapy alone. As well as the HR was 1.4 (95% CI: 0.40–4.9) in neoadjuvant immunotherapy compared with perioperative immunotherapy (Figure 3, B1). In male patients, neoadjuvant immunotherapy is similar to neoadjuvant chemotherapy (HR 0.68, 95% CI: 0.30–1.5) or perioperative immunotherapy (HR 0.79, 95% CI: 0.32–1.9). Perioperative immunotherapy markedly improved the EFS compared with neoadjuvant chemotherapy alone (HR 0.54, 95% CI: 0.35–0.79) (Figure 3, B2).

Subgroup analysis according to age

According to age, patients were divided into groups under 65 years old and those over 65 years old. Among patients under 65 years old, perioperative immunotherapy significantly improved EFS compared with neoadjuvant chemotherapy alone (HR 0.54, 95% CI: 0.37–0.79). There were no significant differences between neoadjuvant chemotherapy and neoadjuvant immunotherapy (HR 0.57, 95% CI: 0.25–1.3), as well as neoadjuvant immunotherapy and perioperative immunotherapy (HR 0.95, 95% CI: 0.39–2.3) (Figure 3, C1). The same results were observed in patients over 65 years old. No significant differences were observed between neoadjuvant chemotherapy and neoadjuvant immunotherapy (HR 0.70, 95% CI: 0.29–1.7), as well as neoadjuvant immunotherapy and perioperative immunotherapy (HR 0.84, 95% CI: 0.30–2.2). As well as perioperative immunotherapy was superior to adjuvant chemotherapy alone (HR 0.59, 95% CI: 0.36–0.88) (Figure 3, C2).

Subgroup analysis according to pathological types

There were two groups were divided according to pathological types, squamous carcinoma and non-squamous carcinoma. Both neoadjuvant immunotherapy (HR 0.50, 95% CI: 0.26–0.97) and perioperative immunotherapy (HR 0.64, 95% CI: 0.46–0.87) notably improved the EFS compared with neoadjuvant alone in non-squamous group. As well as no significant difference between neoadjuvant immunotherapy and perioperative immunotherapy (HR 1.3, 95% CI: 0.61–2.7). However, in patients with squamous disease, only perioperative immunotherapy notably improved EFS compared with neoadjuvant chemotherapy (HR 0.50, 95% CI: 0.29–0.86) (Figure 3, D1,D2).

Subgroup analysis according to ECOG performance status score

In patients with ECOG score 0, perioperative immunotherapy notably improved EFS compared with neoadjuvant chemotherapy (HR 0.57, 95% CI: 0.34–0.90) (Figure 3, E1). There were no significant differences among the three groups in patients with score 1 according to ECOG performance status [neoadjuvant immunotherapy vs. neoadjuvant chemotherapy (HR 0.71, 95% CI: 0.21–2.4), perioperative immunotherapy vs. neoadjuvant chemotherapy (HR 0.56, 95% CI: 0.28–1.1), perioperative immunotherapy vs. neoadjuvant immunotherapy (HR 0.78, 95% CI: 0.19–3.2)] (Figure 3, E2).

Subgroup analysis according to PD-L1 expression

In patients with negative PD-L1 expression, i.e., PD-L1 expression is less than 1%, perioperative immunotherapy significantly prolonged EFS compared with neoadjuvant chemotherapy (HR, 0.72, 95% CI: 0.53–0.97). No significant differences were observed between neoadjuvant immunotherapy and neoadjuvant chemotherapy (HR 0.85, 95% CI: 0.47–1.6), and between neoadjuvant immunotherapy and perioperative immunotherapy (HR 0.85, 95% CI: 0.42–1.7) (Figure 3, F1). The same results were observed in patients with PD-L1 expression over 1% [neoadjuvant immunotherapy vs. neoadjuvant chemotherapy (HR 0.41, 95% CI: 0.12–1.4), perioperative immunotherapy vs. neoadjuvant chemotherapy (HR 0.41, 95% CI: 0.21–0.83), perioperative immunotherapy vs. neoadjuvant immunotherapy (HR 1.0, 95% CI: 0.25–4.2)] (Figure 3, F2). As well as in patients with PD-L1 expression between 1% and 49%, perioperative immunotherapy markedly improved EFS compared with neoadjuvant chemotherapy (HR 0.55, 95% CI: 0.31–0.96). No significant differences were observed in EFS between neoadjuvant immunotherapy and neoadjuvant chemotherapy, or between perioperative immunotherapy and neoadjuvant immunotherapy [neoadjuvant immunotherapy vs. neoadjuvant chemotherapy (HR 0.58, 95% CI: 0.17–2.0), perioperative immunotherapy vs. neoadjuvant immunotherapy (HR 0.95, 95% CI: 0.24–3.6)] (Figure 3, F3). However, in patients with PD-L1 expression higher than 50%, both neoadjuvant immunotherapy (HR 0.24, 95% CI: 0.061–0.96) and perioperative immunotherapy (HR 0.40, 95% CI: 0.21–0.71) markedly improved EFS compared with neoadjuvant chemotherapy. Moreover, perioperative immunotherapy showed no significant difference in EFS compared with neoadjuvant immunotherapy (HR 1.7, 95% CI: 0.35–7.3) (Figure 3, F4).

Subgroup analysis according to smoking status

In current smokers, perioperative immunotherapy markedly improved the EFS compared with neoadjuvant chemotherapy (HR 0.56, 95% CI: 0.34–0.89). Perioperative immunotherapy showed no significant difference in EFS compared with neoadjuvant immunotherapy (HR 0.81, 95% CI: 0.28–2.4), as well as the same result obtained in neoadjuvant immunotherapy compared with neoadjuvant chemotherapy alone (HR 0.68, 95% CI: 0.26–1.8) (Figure 3, G1).There were no significant differences were observed among the three groups in patients never smoking [neoadjuvant immunotherapy vs. neoadjuvant chemotherapy (HR 0.33, 95% CI: 0.087–1.2), perioperative immunotherapy vs. neoadjuvant chemotherapy (HR 0.77, 95% CI: 0.42–1.4), perioperative immunotherapy vs. neoadjuvant immunotherapy (HR 2.3, 95% CI: 0.55–10.0)] (Figure 3, G2).

Subgroup analysis according to baseline stage

In patients with baseline stage I–II disease, no significant differences were observed among the three groups [neoadjuvant immunotherapy vs. neoadjuvant chemotherapy (HR 0.87, 95% CI: 0.42–1.8), perioperative immunotherapy vs. neoadjuvant chemotherapy (HR 0.73, 95% CI: 0.49–1.1), perioperative immunotherapy vs. neoadjuvant immunotherapy (HR 0.84, 95% CI: 0.37–1.9)] (Figure 3, H1). However, in patients with baseline stage III disease, perioperative immunotherapy markedly improved the EFS compared with neoadjuvant chemotherapy (HR 0.54, 95% CI: 0.34–0.85), as well as neoadjuvant immunotherapy compared with neoadjuvant chemotherapy alone (HR 0.50, 95% CI: 0.39–0.63). Moreover, perioperative immunotherapy showed no significant difference in EFS compared with neoadjuvant immunotherapy (HR 0.93, 95% CI: 0.55–1.6) (Figure 3, H2).

Ranking diagram for NMA is shown in Figure 4. Forest maps of all subgroups are summarized in Figure S2.

Figure 4 Ranking diagram for network meta-analysis. The larger the area under the curve, the better EFS the treatment mode. Black bar indicates the probability of being ranked first, gray bar indicates the probability of being ranked second, and light gray bar indicates the probability of being ranked third. The X-axis represents the different therapies, and the Y-axis meaning the probability of ranking. EFS based on specific subgroups. Lung cancer was staged using the eighth version of AJCC TNM staging system. CT, chemotherapy; I + CT, immunotherapy plus chemotherapy; perioperative I + CT, neoadjuvant immunotherapy plus chemotherapy followed by surgery and adjuvant immunotherapy; pCR, pathologic complete response; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; EFS, event-free survival; AJCC TNM staging system, Tumor-Node-Metastasis staging system of American Joint Committee on Cancer.

Heterogeneity was quantified using the I² statistic shown in Figure S3. There is no high degree of heterogeneity. Model convergence in this NMA was confirmed by trace plots (Figure S4). There is no evidence of publication bias.

Discussion

Although surgery is the most important treatment for patients with early NSCLC, patients with NSCLC are prone to relapse and eventually lead to death even after surgery. The 5-year survival rate of patients with stage IB to IIIB decreases from 68% to 26% (18). Therefore, perioperative treatment is of great significance to delay the progression of NSCLC and prolong the survival of patients. Since chemotherapy has no significant effect on the OS of patients with NSCLC, the addition of immunotherapy initiates a new era for NSCLC treatment. As trials mentioned above, in both neoadjuvant therapy and perioperative (neoadjuvant plus adjuvant) therapy, immunotherapy significantly improves the treatment outcome of operable patients with NSCLC. However, there is no final conclusion on the choice of the best strategy of immunotherapy. Most of the NSCLC population receiving neoadjuvant and adjuvant immunotherapy overlapped with each other, and there is also a lack of direct comparison of treatment benefits between neoadjuvant and perioperative immunotherapy. According to the available data, the average pCR rate of patients receiving neoadjuvant immunochemotherapy ranges from 20% to 25%, and it is unknown whether adjuvant therapy is needed in these patients.

To our knowledge, this is the first study to focus on the direct comparison of efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy (“sandwich mode”, including neoadjuvant immunochemotherapy and adjuvant immunotherapy). Our study showed that in the overall population and subgroup analysis, neoadjuvant immunochemotherapy and perioperative immunotherapy had similar benefits in EFS comparing to neoadjuvant chemotherapy alone.

Since CheckMate159 study (19) preliminarily showed the efficacy and safety of neoadjuvant Nivolumab in resectable phase I–IIIA NSCLC, significant advantages of neoadjuvant immunotherapy have been gradually proven: the integrity of tumor and lymphatic system is more conducive to fully activate anti-tumor immune activity, releasing more new tumor antigens, and further activating T cells. Activated T cells travel through the lymphatic stream and the bloodstream to the primary and metastatic sites, playing an anti-tumor role and initiate a series of specific anti-tumor immune responses and providing the earliest treatment opportunity for the removal of micro-metastasis (20). Theoretically, neoadjuvant immunotherapy may be more effective than adjuvant immunotherapy because blood flow and lymphatic between the primary tumors and regional lymph nodes are maintained in neoadjuvant therapy but not in adjuvant therapy (21).

Up to now, whether adjuvant immunotherapy will improve patients’ survival outcomes after neoadjuvant immunochemotherapy plus surgical resection also remains unclear. Some studies have shown that adjuvant immunotherapy can only improve the survival benefits of some patients. The subgroup analysis of IMpower010 research (5) showed that only patients with PD-L1 ≥50% and stage II–IIIA had benefits in disease-free survival (DFS) and OS, suggesting that the beneficiaries’ population of adjuvant immunotherapy may be limited to some extent. Due to the lack of research details, we are unable to further subdivide patients with stage between IB to IIB to analysis the differences. For the overall population of patients with stage between IB to IIB, there are no significant differences in terms of EFS among three groups in our NMA. The possible reasons may be as follows. Firstly, the number of patients with stage III far outnumbers patients with stage between IB to IIB, it is too small to obtain sufficient results. Then, for patients with earlier stages, the predictable EFS after surgery is already long. The follow-up time of these studies could not reach the median progression free survival of these patients. However, for patients with earlier stages, we speculate that adjuvant immunotherapy is unnecessary. We believe that with the maturation of the studies, or more new researches focus on early-stage lung cancer, we may be able to conduct a more in-depth exploration of patients with stage IB to IIB in the future.

In the trials included in our research, as the neoadjuvant therapy in both two treatment strategies are ICI combined with platinum-based doublet chemotherapy, it is reasonable to think that the EFS of the two treatments mainly depends on the postoperative treatment, that is, whether to adopt immunoadjuvant therapy or not. As mentioned above, there was no statistical difference in EFS between the two treatment strategies, either in the overall population or in the subgroup analysis. Patients in the CheckMate816 research (4,22) who achieved a pCR showed remarkable survival, suggesting that adjuvant immunotherapy may not be necessary for these patients. Due to the incomplete data of pCR rate in some included trials, it is hard to make the comparative analysis of EFS with pCR rate as stratification factor, so this current study had not been able to prove whether there is a statistical correlation between the improvement of EFS and the increase of PCR rate. However, our research showed that even for patients who did not reach pCR, there was no significant difference in EFS between neoadjuvant immunochemotherapy and perioperative immunotherapy.

These results may suggest that adjuvant immunotherapy is not absolutely necessary in patients with operable NSCLC who have received neoadjuvant immunochemotherapy plus surgery, at least in some selected patients. As we can obtain from the results, in patients with non-squamous disease, PD-L1 expression more than 50%, or stage III disease, both neoadjuvant immunotherapy and perioperative immunotherapy improved EFS significantly compared to neoadjuvant chemotherapy alone. Meanwhile, there is no statistical difference between these two treatment strategies. Neoadjuvant immunotherapy alone may be tried for these patient groups with discreetly follow-up.

Despite the relevance of our studies, the conclusions should be considered as temporary for its own limitations as follows. Firstly, there is a risk of moderate to high bias in some studies. Secondly, the limited number of RCT included, especially the RCT of neoadjuvant immunochemotherapy, it is significant limitation which may affect the reliability of the results. Thirdly, some data are were separated and calculated from the summary of different meeting, and the lack of complete clinical characteristic information may affect the results of the subgroup analysis. Fourthly, the different ICIs used in each trial also have a certain impact on the results. Lastly, some studies have not yet released complete data, some of the results are of low maturity and need long-term follow-up to further verify, as well as the potential publication bias. We also need further exploration, especially we expect the implement of well-designed head-to-head trials, to verify the conclusions drawn above.

Conclusions

In conclusion, this study serves as the first comparative analysis of efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy. Our findings showed that neoadjuvant immunochemotherapy and perioperative immunotherapy both significantly improved EFS in patients with operable NSCLC. Our findings also support that adjuvant immunotherapy is not absolutely necessary for patients with operable NSCLC who have received neoadjuvant immunochemotherapy plus surgery. Patients with non-squamous disease, PD-L1 expression more than 50%, or stage III disease can try the neoadjuvant immunochemotherapy mode with regular follow-up. Well-designed head-to-head trials are urgently needed to verify, or even expand our findings. The best future treatment strategy values a multi-disciplinary cooperation and evaluation more than ever.

Acknowledgments

Funding: The study was supported by the Youth Project of the Natural Science Foundation of Guangdong Province (No. 2022A1515110399), and the National Key R&D Program of China (No. 2022YFE0133100).

Footnote

Reporting Checklist: The authors have completed the PRISMA-NMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-287/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-287/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-287/coif). All authors report that this study was supported by the Youth Project of the Natural Science Foundation of Guangdong Province (No. 2022A1515110399), and the National Key R&D Program of China (No. 2022YFE0133100). The authors have no other 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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