Efficacy and safety of concurrent immune checkpoint inhibitors combined with radiotherapy or chemoradiotherapy for advanced non-small cell lung cancer: A systematic review and single-arm meta-analysis

Background The recent usage of immunotherapy combined with chemoradiotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) patients. However, determining the most effective therapy combination remains a topic of debate. Research suggests immune checkpoint inhibitors (ICIs) post-chemoradiotherapy enhance survival, but the impact of concurrent ICIs during chemoradiotherapy on rapid disease progression is unclear. This meta-analysis aims to assess the effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced non-small cell lung cancer. Methods We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant studies, extracting data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results The analysis included ten studies with 490 participants. Stage III NSCLC ORR was 81.8%, while Stage IV ORR was 39.9%. One-year PFS and OS for Stage III were 68.2% and 82.6%, compared to 27.9% and 72.2% for Stage IV. Common adverse events included anemia (46.6%), nausea (47.6%), rash (36.4%), and radiation pneumonitis (36.3%). Conclusions Our meta-analysis shows concurrent ICIs with chemoradiotherapy are effective and safe in advanced NSCLC, particularly in stage III patients at risk of progression before starting ICIs after chemoradiotherapy. The findings support further phase III trials. The review protocol was registered on PROSPERO (CRD42023493685) and is detailed on the NIHR HTA programme website.


Introduction
Lung cancer constitutes the primary cause of cancer-related mortality globally [1].Non-small cell lung cancer (NSCLC) accounts for roughly 80% to 85% of all lung cancer cases, with advanced NSCLC comprising over 20% of cases at initial diagnosis [2,3].In patients with inoperable and advanced NSCLC, definitive concurrent chemoradiation therapy (cCRT) traditionally represented the standard of care (SoC).However, the long-term results of cCRT were unsatisfactory, exhibiting a 5-year survival rate of only 15% to 30% [4].ICIs for NSCLC, particularly advanced NSCLC, have emerged as an effective treatment approach, as numerous clinical trials have substantiated their clinical advantages [5][6][7].The integration of ICIs with radiotherapy or chemotherapy has been vigorously pursued, consistently yielding positive outcomes since the pivotal findings of the PACIFIC trial in 2017 [8][9][10][11].Presently, the consolidative use of ICIs is globally sanctioned by health authorities and embraced in guidelines as the SoC [12].
The role of radiation therapy in modulating the immune system, thereby creating an environment conducive to anti-tumor immunity, is increasingly recognized [13,14].Radiation therapy is noted for its diverse immunomodulatory effects, including enhanced antigen presentation, chemokine secretion, effector T-cell recruitment to the tumor site, and promoting immunogenic cell death driven by lymphocytes [15].Additionally, post-radiation activation of inhibitory T-cell regulatory pathways, such as the PD-1/PD-L1 axis, has been observed, contributing to these immunological results [16].Importantly, radiation therapy can induce an increase in PD-1 and PD-L1 expression on both immune and tumor cells, highlighting the strategic value of combining it with PD-1/PD-L1 inhibitors [17].However, recent evidence indicates that the treatment schedule, particularly the timing and sequence of radiotherapy-immunotherapy combinations, is crucial for efficacy.The ideal timing for integrating ICIs with radiotherapy or chemoradiotherapy to achieve synergistic effects requires additional research [18].The PACIFIC trial recommended initiating durvalumab within 1 to 42 days after radiotherapy.In contrast, current NCCN guidelines recommend starting durvalumab after completing both radiotherapy and chemotherapy, without specifying an exact start time following radiotherapy.Furthermore, recent studies have explored the feasibility of concurrent ICIs with radiotherapy or chemoradiotherapy, reporting outcomes that suggest significant therapeutic potential.The simultaneous use of ICIs with radiotherapy or chemoradiotherapy has shown promising results, underscoring the need for more in-depth examination of this combined approach.The concurrent therapeutic strategies involving ICIs and radiotherapy not only demand further investigation but also refinement to optimize clinical effectiveness.
Moreover, the adverse events associated with combining ICIs with radiotherapy or chemoradiotherapy are a concern, as balancing efficacy and safety is vital.The concurrent use of ICIs with radiotherapy or chemoradiotherapy may lead to systemic effects, particularly an increased risk of immune-related pneumonitis, the most severe of all reported adverse outcomes.This meta-analysis is designed to evaluate the efficacy and safety of combining ICIs with radiotherapy or chemoradiotherapy in treating advanced non-small cell lung cancer.The expected findings of this study could expand the spectrum of clinical management options available.

Search strategy
Four databases-PubMed, Embase, the Cochrane Library, and Web of Science-were thoroughly searched for pertinent studies.The final search date was 4 January 2024.The search strategy incorporated both MeSH terms and free-text words: "concurrent radiotherapy" OR "concurrent radiation therapy" OR "concurrent chemoradiotherapy" OR "concurrent radiotherapy AND immunotherapy" OR "concurrent chemoradiotherapy AND immunotherapy" AND ("immune checkpoint inhibitors" OR "PD-1 inhibitors" OR "PD-L1 inhibitors" OR "CTLA-4 inhibitors" OR "immune modulation" OR "immunotherapy") AND "advanced NSCLC" OR "advanced non-small cell lung cancer".Searches were restricted to English language publications.Additionally, the references of the included articles were reviewed to identify further relevant studies.

Selection criteria
Studies were included in this meta-analysis if they met the following inclusion criteria: 1) population: patients diagnosed with advanced non-small cell lung cancer (NSCLC); and 2) intervention: patients treated with concurrent immune checkpoint inhibitors (ICIs) combined with radiotherapy/chemoradiotherapy.Study Type: Prospective interventional research, retrospective analyses, or randomized controlled trials (RCTs).3) Outcomes: Clinical tumor outcomes of interest, including objective response rate (ORR), one-year progression-free survival (PFS), one-year overall survival (OS), and adverse events (AEs), were reported.4) Tumor responses were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) [19], version 1.1.Toxic effects were assessed for incidence and severity using the Common Terminology Criteria for Adverse Events (CTCAE).The exclusion criteria were as follows: Animal-related studies, cell studies, reviews, meta-analyses, duplicates, case reports, or letters.
Two investigators independently screened the articles for eligibility using the inclusion and exclusion criteria.Any disagreements regarding study selection were resolved by discussion between the two investigators or with the involvement of a third investigator.

Data extraction and quality assessment
Two investigators independently extracted data from all included studies and also performed a quality assessment of the studies.The extracted data included author name, publication year, study type, sample size, intervention, tumor stage, median follow-up time, EGFR mutation status, and reported endpoints.Clinical and safety outcomes were evaluated based on the overall response rate (ORR), one-year overall survival (OS), one-year progression-free survival (PFS), incidence of any adverse events (AEs), and incidence of grade 3 or higher AEs.
Furthermore, the quality of the included randomized controlled trials (RCTs) was assessed using the Jadad scale, while the retrospective studies were evaluated using the Joanna Briggs Institute Critical Appraisal Checklist for Patient Series.The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included noncontrolled trials.

Statistical analysis
This meta-analysis was conducted using STATA 17 software (StataCorp LP, College Station, TX, United States) to analyze the data.Heterogeneity among studies was assessed with the chisquare test and I 2 statistic, with p values less than 0.1 denoting significant differences.In cases where there was significant variability (p < 0.1 and I 2 > 50%), the analysis utilized a random effects approach.On the other hand, for scenarios with lower variability, a fixed-effects approach was chosen.Furthermore, sensitivity analyses were performed to evaluate the robustness and reliability of the findings.The possibility of publication bias was assessed using Begg's and Egger's tests.

Ethics approval and consent to participate
This meta-analysis was conducted in accordance with the Declaration of Helsinki.Informed consent was obtained from the participants of all included studies, and the study was approved by their respective institutional ethics committees.As this study is a meta-analysis of previously published data, no additional informed consent was needed.

Study selection
The initial search across four databases-PubMed (n = 37), Embase (n = 93), Cochrane Library (n = 10), and Web of Science (n = 49)-resulted in 189 relevant published studies.After removing duplicate articles and reviewing titles and abstracts, 20 studies remained.Further scrutiny of the full-text articles led to the exclusion of 10 studies due to the lack of available full text, insufficient sample sizes, or the investigation of nonchemotherapeutic drugs.Ultimately, ten studies, including 490 patients satisfied the inclusion criteria and were included in this meta-analysis.The selection process is depicted in Fig 1 , and the specifics of each study are detailed in Table 1.The median age of participants ranged from 62 to 72 years across the studies.Male patients (n = 288) outnumbered female patients (n = 202).Adenocarcinoma (n = 238) and squamous cell carcinoma (n = 149) were the predominant histological types.Various radiotherapy techniques were employed, including 3D-CRT, VMAT, SBRT, SCRT, and proton therapy, with total radiation doses ranging from 45Gy to 66Gy.PD-L1 expression levels were reported in 7 studies, with more patients having TPS�1% (n = 133) than TPS<1% (n = 69).Chemotherapy regimens mainly consisted of platinum-based drugs such as cisplatin or carboplatin combined with paclitaxel, pemetrexed, etoposide, or vinorelbine.The immune checkpoint inhibitors used included durvalumab, pembrolizumab, nivolumab, ipilimumab, sintilimab, and gefitinib.In most studies, ICIs were administered concurrently with chemoradiotherapy, starting on the same day.Further details of each study, including patient characteristics, treatment modalities, and sequences, are provided in Table 2.

Quality assessment
The evaluation of the six non-randomized studies was conducted using the Newcastle-Ottawa Scale (NOS), which analyzes studies across three domains: selection of the study groups, comparability of the groups, and ascertainment of the outcome for cohort studies or the exposure for case-control studies, through eight specific criteria.Two retrospective studies were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Series, focusing on methodological quality across ten areas, including case selection, description of the condition or health issue, and clarity in presenting case details.The three included Randomized Controlled Trials (RCTs) were appraised using the Jadad Scale, which concentrates on three essential elements: the description of randomization, blinding, and accounting for lost-to-follow-up participants.Details of these quality assessments are provided in Table 3.

Newcastle-Ottawa Scale (NOS) for non-randomized studies
The numbers Q1-Q18 in the heading signs were as follows: I, representative of the exposed cohort; II, representative of the nonexposed cohort; III, representative of the exposed cohort; Akamatsu et al. [21] Bestvina et al. [ Liu et al. [23] Welsh et al. [24] Tachihara et al. [ Jabbour et al.

JADAD scale for reporting randomized controlled trials
Numbers Q1-Q4 in heading signified: Q1: Was the study described as randomized?Q2: Was the method of randomization appropriate (e.g., computer-generated random numbers)?Q3: Was the study described as double-blind?Q4: Was there a description of withdrawals and dropouts?

JBI critical appraisal checklist for patient series for included retrospective studies
Numbers Q1-Q10 indicated the following inquiries: Q1, were criteria for inclusion in the case series clearly defined?Q2, was the condition assessed in a consistent, reliable manner for all participants in the case series?Q3, were reliable methods utilized for identifying the condition in all case series participants?Q4, did the case series include participants consecutively?Q5, was participant inclusion in the case series complete?Q6, were participant demographics in the study reported with clarity?Q7, was clinical information of the participants clearly reported?Q8, were case outcomes or follow-up findings clearly documented?Q9, was demographic information of the presenting site(s)/clinic(s) clearly documented?Q10, was the statistical analysis conducted appropriately?

Tumor response
All studies included in this analysis evaluated the effectiveness of concurrent immune checkpoint inhibitors (ICIs) combined with radiotherapy or chemoradiotherapy in treating advanced non-small cell lung cancer (NSCLC).The overall response rates (ORRs) observed in these studies varied widely, with a range from 30% to 90.9%.Owing to significant heterogeneity among the studies (I 2 = 92.1%,p < 0.01), a random-effects model was utilized for the meta- analysis.The analysis revealed a combined ORR of 69.9% (95% CI: 57.1%-82.8%).When further stratifying the results by disease stage, it was found that for patients with stage III NSCLC treated with ICIs alongside radiotherapy, the ORR was 81.8% (95% CI: 74.7%-88.9%).Conversely, for patients with stage IV NSCLC, the ORR was 39.9% (95% CI: 27.4%-52.3%).These outcomes are graphically represented in Fig 2 .Heterogeneity analysis indicated that the primary data originated from the study conducted by Jabbour et al.

Survival
Although some studies in the meta-analysis did not meet the predetermined endpoint, all provided data on one-year overall survival (OS) and progression-free survival (PFS) for patients receiving concurrent treatment with immune checkpoint inhibitors (ICIs) and radiotherapy or chemoradiotherapy.Employing a random-effects model (I

Subgroup analysis comparing different radiotherapy modalities
In this subgroup analysis, we explored how various radiotherapy modalities affect important efficacy measures, such as overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) who received a combination of radiotherapy and immune checkpoint inhibitors.The meta-analysis of ORR (Fig 4 ) showed that in the 3D-CRT subgroup, individual study effect sizes ranged from 0.734 to 0.914, with a pooled estimate of 0.821 (95% CI: 0.747, 0.895), indicating a significant tumor reduction in 82.1% of patients.However, moderate subgroup heterogeneity (I 2 = 59.9%, p = 0.041) suggests potential variability in ORR outcomes, possibly due to differences in study design, patient characteristics, or treatment protocols.In contrast, the SCRT subgroup demonstrated individual study effect sizes of 0.800 and 0.905, with a pooled estimate of 0.850 (95% CI: 0.747, 0.952), implying an average response rate of 85.0%.The subgroup exhibited low heterogeneity (I 2 = 30.2%,p = 0.231), indicating a higher level of consistency among the included studies.There was no statistically significant overall heterogeneity between the subgroups (p = 0.655), and the combined ORR for both subgroups was 0.828 (95% CI: 0.771, 0.886), demonstrating substantial efficacy for both modalities, albeit with a slight advantage for SCRT.

Sensitivity analysis
The study conducted a sensitivity analysis by systematically excluding one study at a time to assess its impact on the combined results.The results of this analysis demonstrated that the pooled results, along with their 95% confidence intervals, remained relatively unchanged regardless of which study was excluded.This reaffirms the overall reliability of the meta-analysis results.Supplementary Figure provides a visual representation of the outcomes of the sensitivity analysis (please refer to the Supplementary material for more details).

Publication bias
To ensure the robustness of the meta-analysis findings, Egger's and Begg's tests were employed to assess potential publication bias.The test results were largely consistent with the overall results.However, it is worth noting that there were indications of publication bias for diarrhea in terms of safety considerations (please refer to the Supplementary material for more details).

Discussion
The efficacy of durvalumab following chemoradiotherapy in the treatment of [specific condition, e.g., non-small cell lung cancer] has been strongly supported by the PACIFIC trial, demonstrating both substantial and sustained benefits in OS and lasting improvements in PFS.At the five-year milestone, patients treated with durvalumab exhibited OS rates of 42.9% (95% confidence interval [CI]: 38.2%-47.4%),while the placebo group registered 33.4% (95% CI: 27.3%-39.6%).Similarly, the PFS rates for the durvalumab cohort reached 33.1% (95% CI: 28.0%-38.2%),significantly exceeding the 19.0%(95% CI: 13.6%-25.2%)observed in the placebo group.Furthermore, the stratified hazard ratio (HR) for OS was 0.72 (95% CI: 0.59%-0.89%),with a median OS of 47.5 months for the durvalumab group compared to 29.1 months for the placebo group.The stratified HR for PFS was equally noteworthy at 0.55 (95% CI: 0.45%-0.68%),and the median PFS was notably prolonged among durvalumab-treated patients at 16.9 months, in contrast to 5.6 months in the placebo cohort.These findings underscore durvalumab's potential as a significant therapeutic advancement post-chemoradiotherapy.Subsequently, several authors have reported real-life data on the treatment of advanced NSCLC with ICIs after CRT, highlighting the combination of ICIs with radiotherapy or chemoradiotherapy as one of the most effective therapy strategies for advanced NSCLC [30][31][32].
A comprehensive meta-analysis conducted by Zhang et al., comprising 23 studies, including a cumulative patient cohort exceeding 4,400 individuals, has been published.Drawing from real-world data, this meta-analysis demonstrates that the short-term efficacy and safety profile of durvalumab align with the findings reported in the PACIFIC trial.The consistency of these results reinforces durvalumab's application as a means to enhance clinical outcomes for patients with unresectable stage III NSCLC [10].However, it is crucial to note that these investigations explicitly excluded patients experiencing disease progression before commencing ICIs following radiotherapy and chemotherapy.Notably, this subgroup constitutes approximately 20% to 30% of the clinical population.Addressing the management of this significant and underserved patient demographic is pressing, as it presents a critical gap in current therapeutic protocols.Elucidating optimal treatment strategies for these patients is essential for advancing the standard of care and improving outcomes for all patients affected by this condition.Recent research efforts have focused on exploring the efficacy and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced NSCLC, potentially improving the survival rate for those who missed the opportunity to receive ICIs after cCRT [33][34][35].Here, our study provides a systematic review and meta-analysis of available data concerning the efficacy and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced NSCLC.
Our comprehensive systematic review and meta-analysis contribute significantly to the body of knowledge regarding the concurrent use of ICIs with radiotherapy or chemoradiotherapy for advanced non-small cell lung cancer (NSCLC).A notable aspect of our study is the incorporation of a critical yet frequently overlooked patient subset, comprising 20% to 30% of the clinical population, who undergo disease progression following radiotherapy and chemotherapy.By including this subgroup in our analysis, we provide a more comprehensive evaluation of therapeutic effectiveness and safety; thus, furnishing a robust evidentiary foundation to guide and enhance clinical decision-making within the broader NSCLC treatment context.
This meta-analysis elucidates the efficacy outcomes of concurrent ICIs with radiotherapy or chemoradiotherapy as a compelling treatment strategy, as reflected in the ORR, one-year OS rate, and one-year PFS rate.These findings address a gap in prior research, which had not definitively determined the complete potential of this approach.Specifically, the efficacy of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced NSCLC demonstrated a wide range, with ORR spanning from 30% to 90.9%, including both stage III and IV NSCLC.
The findings indicate that concurrent use of immune checkpoint inhibitors (ICIs) with radiotherapy or chemoradiotherapy may offer benefits similar to the traditionally studied sequential approach.This combination strategy holds promise, especially for patients at risk of disease progression during or after radiotherapy and chemotherapy.However, concerns persist regarding increased side effects with the combined use of radiotherapy and immunotherapy, given its relatively recent introduction as a treatment strategy [37].Balancing efficacy and safety is crucial when combining ICIs with radiotherapy or chemoradiotherapy.Concurrent use of these therapies may lead to systemic effects, particularly an elevated risk of immunerelated pneumonitis, which is the most severe reported adverse outcome.Our meta-analysis underscores the safety profile of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced NSCLC.Although the incidence of grade 1-2 adverse events increased, the occurrence of grade 3 or higher serious adverse events did not surpass that reported in the PACIFIC trial, with mortality attributable to grade 5 or above events standing at 3% and 4.4%, respectively.These findings suggest that concurrent ICIs with radiotherapy or chemoradiotherapy result in manageable adverse events without worsening the severity of immune-related adverse events (irAEs).
Pneumonitis and radiation pneumonitis are common adverse events associated with the administration of ICIs and concurrent chemoradiotherapy.The combined use of these treatments may lead to increased pulmonary toxicity compared to each treatment alone.However, the occurrence of grade 3 or higher pneumonitis was reported to be below 10%.It is noteworthy that the primary contribution to grade 3 or higher pneumonitis among all studies included in this meta-analysis originated from KEYNOTE-799 [29], which reported an incidence rate of 4.0% for grade 3 or higher pneumonitis, slightly higher than the 3.4% reported in the PACIFIC trial.This variance may be attributed to several factors inherent to the KEYNOTE-799 study design, such as the concurrent administration of pembrolizumab with chemoradiotherapy, contrasting with the sequential use of durvalumab after chemoradiotherapy in the PACIFIC trial.Additionally, differences in patient characteristics, treatment regimens, and follow-up duration could contribute to the observed disparities in pneumonitis incidence.Furthermore, the occurrence of grade 3 or higher pneumonitis observed in this study aligns with established toxicity profiles of concurrent chemoradiotherapy for stage III NSCLC, and the overall safety profile is consistent with the adverse events observed with ICIs followed by radiotherapy/chemoradiotherapy in first-line advanced NSCLC (Table 5).
These findings emphasize the critical need for vigilant monitoring and proactive management of irAEs when utilizing concurrent ICIs with radiotherapy or chemoradiotherapy.Future research efforts should prioritize the identification of predictive biomarkers and prognostic factors to stratify patients according to their susceptibility to developing severe adverse events, notably immune-related pneumonitis [38].Through refined patient selection and optimized treatment approaches, the risk of life-threatening complications can be mitigated, leading to potential improvements in overall treatment outcomes.
Innovative approaches to reduce the occurrence and severity of immune-related pneumonitis should be investigated.Possible strategies could involve dose adjustments, altering the timing of ICIs and radiotherapy, or implementing prophylactic medications.By proactively addressing safety concerns linked to concurrent therapy, we can maximize the benefits of this promising treatment approach while safeguarding patient well-being.
Our meta-analysis sought to investigate the effect of concurrent immune checkpoint inhibitors combined with radiotherapy or chemoradiotherapy in advanced NSCLC.While the subgroup analysis comparing different radiotherapy modalities did not reveal statistically significant differences in this study, it is crucial to acknowledge the potential impact of radiotherapy dose, target volume, techniques, and immunotherapy approaches based on evidence from prior research.
The optimal radiotherapy dose and fractionation for maximizing synergistic effects with immunotherapy remain subjects of ongoing investigation.Preclinical studies suggest that hypofractionated radiotherapy, such as stereotactic body radiation therapy (SBRT), may augment immunomodulatory effects compared to conventional fractionation [42,43].Radiotherapy has the potential to trigger more potent anti-tumor immune responses by enhancing tumor antigen release, facilitating dendritic cell activation, and promoting cytotoxic T-cell infiltration [44].Nevertheless, clinical evidence comparing different radiotherapy doses and fractionation alongside ICIs is limited.Additional prospective trials are warranted to ascertain the optimal radiotherapy regimen that optimizes systemic anti-tumor immunity.
The irradiated target volume is another critical factor that could impact the effectiveness of combining radiotherapy with ICIs.Although our study did not specifically investigate target volumes, emerging evidence suggests that irradiating larger tumor volumes or multiple metastatic sites might result in improved outcomes by enhancing the diversity of tumor-associated antigens and facilitating a more robust abscopal effect [45].However, it is essential to carefully weigh the potential toxicity risks associated with larger irradiation volumes against the immunomodulatory advantages.
Furthermore, advancements in radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), and proton beam therapy (PBT), have facilitated more accurate tumor targeting while minimizing radiation exposure to normal tissues.These modern radiotherapy methods hold potential in reducing the incidence of radiation-induced toxicities when combined with ICIs, particularly in lowering the occurrence of radiation pneumonitis.Although our study did not pinpoint an optimal radiotherapy approach through subgroup analysis due to restricted sample sizes and the utilization of multiple radiotherapy techniques in some included trials, we anticipate that forthcoming prospective studies comparing advanced radiotherapy modalities with ICIs will illuminate the most effective radiotherapy strategy to optimize treatment outcomes.By carefully balancing efficacy and toxicity profiles, we envision that the ideal combination of radiotherapy and ICI will not only enhance treatment efficacy but also minimize adverse events, offering patients with advanced NSCLC safer and more efficient radiotherapy-immunotherapy options.
The selection of specific ICI agents and their sequencing with radiotherapy could also influence treatment outcomes.Our analysis encompassed studies employing various ICIs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (durvalumab, atezolizumab), and CTLA-4 inhibitors (ipilimumab).Although all these agents enhance Tcell-mediated anti-tumor immunity, they target different pathways and may interact with radiotherapy differently [46,47].However, the optimal sequencing strategy remains contentious and necessitates further clinical validation.
When incorporating ICIs with radiotherapy or chemoradiotherapy, identifying predictive biomarkers is essential for optimizing patient selection and cost-effectiveness.For patients at low risk of progression, ICIs may offer marginal benefits at a high cost.Conversely, for highrisk patients, the potential survival benefits may outweigh the costs.Developing biomarkerbased models that utilize PD-L1 expression, tumor mutational burden, and tumor-infiltrating lymphocytes is crucial for enhancing treatment precision.Ongoing research should focus on validating these biomarkers to refine patient stratification, thereby reducing unnecessary treatments and directing resources toward patients most likely to benefit.Further exploration of novel biomarkers and their interactions could enhance our understanding of the tumor immune environment and responsiveness to ICI.
However, some limitations are worth noting.First, the included studies were all noncontrolled trials with small sample sizes and some studies with low evidence; thus, we evaluated only the efficacy and adverse events without definite conclusions.Second, high heterogeneity existed among the included studies.We only performed a subgroup analysis of the different stages.Other factors, such as baseline characteristics, histological classification, mutation frequency, and different ICIs, could also result in heterogeneity.Thirdly, the reporting of baseline pulmonary function, smoking history, and performance status data was inconsistent and inadequate across the included studies, which impeded meaningful analyses of these factors.Fourth, due to the lack of sufficient data on patients with mutations, we were unable to analyze the effectiveness and safety of concurrent ICIs and chemoradiotherapy in these patients.However, further analysis is needed in the future to determine the optimal treatment.Fifth, most of the related research has not yet reached the endpoint, so there was no final analysis of survival data, and the credibility of the evidence was insufficient.Therefore, additional large-scale RCTs should be designed to systematically assess and report objective measures of baseline pulmonary function, detailed smoking history, and performance status, and to confirm the clinical effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in comparison to those of the currently adopted first-line treatment schemes.

Conclusion
In summary, our meta-analysis establishes the effectiveness and safety of concurrent administration of ICIs with chemoradiotherapy in patients with advanced NSCLC, particularly for individuals in stage III who may undergo disease progression before the commencement of ICIs following radiotherapy and chemotherapy.These findings offer valuable insights and provide a foundation for considering phase III large-scale, multicenter RCTs in advanced NSCLC.

Table 1 . Characteristics of the studies included in the meta-analysis. Study Year Study type Sample size
https://doi.org/10.1371/journal.pone.0304941.t001