Background

Lung cancer is still among the most common cancer types reported worldwide. In fact, it is the most common cause of cancer-related deaths [1]. Importantly, 80% of the newly discovered lung cancers are contributed by non-small cell lung cancer (NSCLC). A large number of studies are being conducted to explore therapeutic strategies for NSCLC [2]. The emergence of targeted therapy enabled the treatment of patients with NSCLC tested positive for driver gene. Importantly, targeted therapy prolonged the survival in such patients. In the case of patients with driver gene negative profiles, only chemotherapy has been used for a long time [3]. Following this, immunotherapy emerged as a promising approach. Previous clinical studies on immunotherapy showed that immunotherapy incurred better clinical benefits than previously used chemotherapeutic strategies. Importantly, these benefits were observed when it was used alone with PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, or in combination with chemotherapy, antivascular drugs, or even in the case of dual immunotherapy agents [4,5,6,7,8,9,10,11,12,13,14].

Currently, immunotherapy is widely used for the treatment of various stages of NSCLC. Previous clinical studies confirmed the efficacy of immunotherapy in advanced NSCLC [5, 15, 16]. In fact, more and more clinical studies are being conducted to assess the efficacy of immunotherapy in NSCLC in a detailed manner [17,18,19]. In general, immunotherapy has prolonged the survival of patients with advanced NSCLC. However, there are cases where patients did not benefit significantly. In fact, the incidence of treatment-related adverse reactions remains high. Importantly, such incidences of adverse reactions are much lower than those reported in the case of chemotherapy. For early resectable NSCLC, single-arm trials and meta-analyses previously reported that patients exhibited good pathological responses following neoadjuvant immunotherapy. Several randomized controlled trials that were reported at the conference in the current year showed that neoadjuvant immunotherapy achieved significant efficacy in early resectable NSCLC, with a low incidence of treatment-related adverse events [20, 21].

Clinical cases and existing clinical research data showed that immunotherapy as a new adjuvant treatment incurred better curative effects in the case of resectable lung cancer as compared to late lung cancer. However, none of the currently available studies have established whether the application of immunotherapy in the early resection of lung cancer is beneficial or its application in advanced unresectable lung cancer.

In the present study, ORR and DCR were used as evaluation indexes/indices to assess the efficacy of immunotherapy in early and late lung cancer, while the rate of adverse reactions was used as an indicator to evaluate the safety of immunotherapy in early and late lung cancer.

Methods

Data source and searches

We searched all RCTs related to NSCLC from the PubMed, Embase, Cochrane Library, and other databases from inception until November 2021, with no start data limit, applied. In addition, we also conducted a manual search for all available reviews, abstracts, and meeting reports from the main international lung cancer meetings. The search keywords included “non-small cell lung cancer,” “early lung cancer,” “early stage of lung cancer,” “advanced lung cancer,” “immunotherapy,” “PD-1 inhibitor,” “PD-L1 inhibitor,” “programmed cell death-ligand 1,” “CTLA-4 inhibitor,” “cytotoxic T-lymphocyte antigen-4 inhibitor,” and others (Additional file 1: Supplemental Methods). The language the RCTs used was limited to English. Two authors accomplished the search independently, and any discrepancy was resolved through mutual discussion to reach a final consensus.

Selection criteria

According to the PICOS framework, papers that conformed to the following criteria were included: (I) only early non-small lung cancer patients or advanced non-small lung cancer patients; (II) papers involving an immunotherapy cohort and either immunotherapy alone cohort or immunotherapy combined with other therapies cohort; (III) papers that reported the outcomes included more than one of the following: ORR, DCR, and TRAEs; and (IV) papers that included all RCTs and multicenter single-arm studies. Case-control studies, retrospective studies, cohort studies, case reports, meta-analyses, and systematic reviews were excluded.

Data extraction and risk of bias assessment

The authors independently reviewed and evaluated the title, abstract, full text, and supplementary materials of the included studies and extracted all the data. All extracted data were tabulated including the country clinical trial number, publication date, first author, intervention, and the number of participants in each intervention group. In addition, data on the complete response (CR), partial response (PR), stable disease (SD), ORR, DCR, and TRAEs were also included. The risk ratio (RR) and the corresponding 95% CIs for ORR and DCR were also extracted. Items not reported in the included studies were represented by NR (not reported).

We applied The Cochrane Collaboration's Risk of Bias tool to evaluate the quality of the included articles. The evaluation factors included randomness, double-blindness, the integrity of the outcome data, and bias in selective reporting, among others. The risk of bias was assessed with reference to the following criteria: low risk, high risk, and ambiguous risk. Two authors independently completed the quality evaluation of the extraction of the review data for the included studies. Finally, the controversial portion was resolved through active discussion [22].

Data synthesis and analysis

ORR and DCR were considered as the primary endpoints in this systematic review. A Bayesian approach was accordingly adopted. ORR and DCR were treated as dichotomous variables; therefore, risk ratios (RRs) were applied to present these parameters. We applied the χ2 test and I2 statistics to evaluate the statistical heterogeneity of the included studies. A fixed-effects model was selected to count the pooled estimate when the p-value for χ2 > 0.1 and I2 was < 50%. Otherwise, a random-effects model was applied to combine the studies. At I2 statistic > 50% or P-value for χ2 < 0.1, the values were considered to be statistically significant for heterogeneity [23]. Subgroup analyses were conducted according to the treatment regimens across the entire cohort. Cohorts of immunotherapy alone or immunotherapy combined with other therapies were categorized for subgroup analyses. Based on the prearranged grouping factors, we collected the data of relevant subgroups in all included trials. We then applied the funnel plot and Egger's test and Begg's test to evaluate publication bias.

Stata v15.1 (Stata Corporation, College Station, TX, USA) was applied to perform all statistical analyses. P-values were two-sided and considered to be statistically significant, except for P < 0.05.

Results

Systematic review and characteristics

The present study initially identified a total of 4747 studies. Among these, 925 studies were excluded due to duplication. Finally, a total of 52 studies were included, following a screening of abstracts and full texts according to the selection criteria. The research selection process followed in the present study is shown in Additional file 1: Fig. S1. The main features of the included studies are shown in Table 1.

Table 1 Primary characteristics and the results of the applicable studies
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Altogether, a total of 52 studies were included in the present study. Among these, 43 studies focused on advanced lung cancer, while nine studies focused on early-stage lung cancer. Among the studies related to advanced lung cancer, 27 studies reported the use of immunotherapy alone, whereas 19 studies reported the use of immunotherapy in combination with other treatment strategies. Among these 19 studies on combined therapy, 13 studies explored its combination with chemotherapy, three studies reported immunodouble-drug usage, one study reported a combination of double immunotherapy with chemotherapy, and two studies reported a combination of immunotherapy with chemoradiotherapy. In the case of studies involving early-stage lung cancer, five studies reported immunotherapy alone and five studies reported a combination of immunotherapy with other treatment strategies. For the studies reporting application of immunotherapy combined with other treatment strategies, four studies reported its combination with chemotherapy, while one study reported application of immunodouble-drug.

ORR

The pooled RR for ORR was recorded to be 0.36 (0.14–0.57) and 0.40 (0.36–0.45) in the case of early-stage lung cancer (Fig. 1) and advanced lung cancer (Fig. 2), respectively. These results showed that immunotherapy incurred a slightly better effect in advanced lung cancer; however, the difference recorded between these two groups was statistically insignificant.

Fig. 1
figure 1

Forest plots presenting pooled ORR risk ratio analysis in early-stage lung cancer and ORR risk ratio analysis for the cohort of immunotherapy alone and immunotherapy combined with other therapies

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Fig. 2
figure 2

Forest plots presenting pooled ORR risk ratio analysis in advanced lung cancer and ORR risk ratio analysis for the cohort of immunotherapy alone and immunotherapy combined with other therapies

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For the immunotherapy alone cohort, pooled RR for ORR was recorded to be 0.23 (0.05–0.41) in early-stage lung cancer (Fig. 1) and 0.33 (0.27–0.38) in advanced lung cancer (Fig. 2). In terms of ORR results, immunotherapy alone exhibited a better effect in advanced lung cancer.

In the case of the cohort for a combination of immunotherapy with other therapies, pooled RR for ORR was recorded to be 0.51 (0.22–0.81) in early-stage lung cancer (Fig. 1) and 0.48 (0.43–0.53) in advanced lung cancer (Fig. 2). These results indicated that the benefit of immunotherapy in combination with other therapies was not significant in the case of early-stage lung cancer when compared with advanced lung cancer.

In cohort for a combination of immunotherapy with chemotherapy, pooled RR for ORR were 0.67 (0.49–0.84) in early-stage lung cancer (Additional file 1: Fig. S2) and 0.52 (0.46–0.58) in advanced lung cancer (Additional file 1: Fig. S3), which indicated that the combination of immunotherapy with chemotherapy regimen was more beneficial in early-stage lung cancer.

DCR

The pooled RR for DCR was recorded to be 0.90 (0.84–0.96) in early-stage lung cancer (Fig. 3) and 0.72 (0.67–0.77) in advanced lung cancer (Fig. 4), which showed that immunotherapy exhibited better efficacy in early-stage lung cancer.

Fig. 3
figure 3

Forest plots presenting with pooled DCR risk ratio analysis in early-stage lung cancer and DCR risk ratio analysis for the cohort of immunotherapy alone and immunotherapy combined with other therapies

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Fig. 4
figure 4

Forest plots presenting pooled DCR risk ratio analysis in advanced lung cancer and DCR risk ratio analysis for the cohort of immunotherapy alone and immunotherapy combined with other therapies

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In the immunotherapy alone cohort, immunomonotherapy significantly improved DCR in early-stage lung cancer as compared to advanced lung cancer. The pooled RR for DCR in early-stage lung cancer was recorded to be 0.88 (0.80–0.96) (Fig. 3) and 0.65 (0.56–0.73) in advanced lung cancer (Fig. 4).

In the case of the cohort for a combination of immunotherapy with other therapies, pooled RR for DCR in early-stage lung cancer was 0.91 (0.79–1.02) (Fig. 3), whereas in advanced lung cancer, it was recorded to be 0.81 (0.78–0.84) (Fig. 4). The number of studies on the combined treatment of DCR reported for early lung cancer was only greater than 1, so DCR data for combined treatment of early lung cancer represented the data for the combination of immunotherapy and chemotherapy.

In the case of the cohort for a combination of immunotherapy with chemotherapy, pooled OR for DCR was recorded to be 0.91 (0.79–1.02) in early-stage lung cancer (Fig. 3) and 0.84 (0.81–0.86) for advanced lung cancer (Additional file 1: Fig. S4). According to the results of DCR, the efficacy of the combination of immunotherapy with chemotherapy was found to be better in early-stage lung cancer than in advanced lung cancer.

Safety

In the case of immunotherapy alone cohort and cohort for a combination of immunotherapy with chemotherapy, the TRAEs and TRAEs of grade 3 or higher were reported to be significantly reduced by the effect of immunotherapy in early-stage lung cancer, when compared with advanced lung cancer.

The pooled TRAEs for patients with early-stage lung cancer was 72%, while the pooled TRAEs for grade ≥ 3 were 28%. In comparison to this, the pooled TRAEs for patients with advanced lung cancer were 80% and the pooled TRAEs for grade ≥ 3 were 41%.

For the immunotherapy alone cohort, TRAEs of grade 3 or higher were recorded to be 28% for patients with early-stage lung cancer and advanced lung cancer. The TRAEs and TRAEs of grade 3 or higher for patients with advanced lung cancer were 74% and 28%, respectively.

In the case of the cohort for a combination of immunotherapy with chemotherapy, the TRAEs and TRAEs of grade 3 or higher for patients with early-stage lung cancer were 93% and 47%, respectively. The TRAEs and TRAEs of grade 3 or higher for patients with advanced lung cancer were 94% and 68%, respectively.

Discussion

Recent clinical studies, including Camel-sq, RATIONALE 304 [19], and RATIONALE 307 [18], established/confirmed that immunotherapy achieved good/better outcomes in the treatment of advanced lung cancer. The ORR for the immunotherapy group in Camel-sq and RATIONALE 304 was recorded to be 68.4% and 57.4%, respectively. In the same year, clinical studies, like SAKK 16/14 [21], CheckMate 816, and NADIM [26], also showed that neoadjuvant immunotherapy exhibited a higher pathological remission rate and clinical benefit in early resectable lung cancer. However, none of the available studies proved whether immunotherapy incurred a better effect in early lung cancer or advanced lung cancer [46]. In the current systematic review, ORR and DCR were used as evaluation indexes/indices to discuss the efficacy of immunotherapy in early lung cancer and advanced lung cancer. The study also analyzed the safety of immunotherapy in both cases.

According to ORR data for the present analysis, immunotherapy combined with other treatments, especially chemotherapy, appeared to be better in early-stage lung cancer than advanced lung cancer, while immunotherapy alone appeared to be better in advanced lung cancer. In terms of DCR, both immunotherapy alone and immunochemotherapy combined with chemotherapy exhibited better efficacy in early-stage lung cancer than in late lung cancer. In terms of safety, both immunotherapy alone and a combination of immunotherapy with chemotherapy exhibited better safety in early-stage lung cancer than late lung cancer.

Altogether, the current systematic review suggested that immunotherapy, especially in combination with chemotherapy, improved disease response rates in early-stage lung cancer as compared to advanced lung cancer. Besides this, it also exhibited a higher/better safety profile.

Many previous clinical and preclinical evidence suggested that high tumor load incurs a negative impact on anticancer immunity [47, 48]. A recent review article summarized the evidence supporting tumor burden as a biomarker to guide the use of immune checkpoint inhibitors. The study also described the data and provided a perspective on various tools used for the assessment of tumor burden [49]. It has long been debated that ICIs act on the immune system, which is known to be active before the development of tumors. Therefore, an increase in tumor volume is likely to be suggestive of the fact that the immune system is unable to inhibit the growth of the tumor, and in some ways, it is less effective than the immune systems of patients with a lower tumor burden [50]. In addition to this, cancer itself might cause general damage to a patient’s biological functions, including the immune system. With the progression of cancer, the immune system is likely to get deteriorated further. It has been previously shown that the tumor load of early-stage lung cancer is not high, and the immune system is less damaged by the effect of cancer. Therefore, the efficacy of immunotherapy in early-stage lung cancer is generally recorded to be better than advanced lung cancer, and the probability of adverse reactions is also smaller than that for advanced lung cancer [51].

In addition to this, a growing body of clinical evidence supported the synergistic effects of the combination of ICIs with chemotherapy [52], which is consistent with the findings of the present study. In particular, ORR and DCR results for the cohort of a combination of immunotherapy with chemotherapy were better than those reported in the case of immunotherapy alone cohort, both in early-stage and advanced lung cancer. Some studies believe that chemotherapy can not only increase the immunogenicity of tumor cells through a variety of cellular reactions [53] but also eliminate MDSC and regulatory T cells and reduce the immunosuppressive factors in the tumor microenvironment [54]. However, the specific mechanism involved is still unclear.

The present study was associated with certain limitations. The current meta-analysis was dependent on published results instead of individual patient data. Moreover, enough clinical studies are not available on immunotherapy for early lung cancer. In particular, only three clinical studies reported DCR for a combination of immunotherapy with other therapies for early-stage lung cancer, which included two studies on the combination of immunotherapy with chemotherapy and only one study on dual immunotherapy. In the view of a limited number of clinical studies on early-stage lung cancer that reported DCR data for the combination of immunotherapy with other therapies, the related results must be interpreted with caution.

Conclusion

The findings of the present review highlighted that the benefits of immunotherapy were higher in early-stage lung cancer as compared to advanced lung cancer, especially for the combination of immunotherapy and chemotherapy. Additionally, the safety of immunotherapy, whether alone or in combination with chemotherapy, was recorded to be higher in early-stage lung cancer than in advanced lung cancer.

The results of the study recommended the application of immunotherapy, especially in combination with chemotherapy, for the improvement of survival in patients with early-stage lung cancer. These conclusions of the study need to be confirmed in the future.