For decades, lung cancer (LC) has been the leading global cause of cancer-related deaths, with over 80% attributed to non-small cell lung cancer (NSCLC) (1, 2). Comprehensive treatment based on surgery is the standard of care for selected resectable stages II-III NSCLC (3). In previous approaches to neoadjuvant and adjuvant treatment for stage II-III NSCLC, chemotherapy played a vital role, but its solitary use yielded unsatisfactory results (4). In recent years, immunotherapy has gained widespread acceptance in solid tumor treatment, demonstrating superior efficacy in both neoadjuvant and adjuvant treatment for resectable NSCLC (5–7). Nevertheless, controversy persists in clinical settings regarding whether perioperative immunotherapy (neoadjuvant+adjuvant) can yield superior results (8).

The use of immunotherapy in the perioperative period of resectable lung cancer has been a hot topic in recent years. In neoadjuvant therapy, the CheckMate 816 study demonstrated that the addition of nivolumab to platinum-based chemotherapy (PBC) could significantly increase event-free survival (EFS) and drug responses (9). Similar results were also validated in the TD-FOREKNOW study (Camrelizumab) (10). In adjuvant therapy, the KEYNOTE-091 study showed that the addition of pembrolizumab to PBC could significantly increase disease-free survival (DFS) (11). The IMpower010 study also confirmed that adding atezolizumab to PBC could improve DFS and overall survival (OS), especially in patients with programmed cell death 1 ligand 1 (PD-L1)-positive NSCLC (12). Regarding the use of immunotherapy in combination of neoadjuvant and adjuvant therapy, both the KEYNOTE-671 study (pembrolizumab) and the AEGEAN study (durvalumab) found that perioperative immunotherapy could significantly improve OS and EFS, and similar results were also validated in the NADIM II study (nivolumab) (13–15).

This study conducted a meta-analysis based on randomized controlled trials (RCTs) to evaluate the impact of perioperative immunotherapy with neoadjuvant PBC on survival, pathological responses, and adverse reactions.

This study was conducted in accordance with PRISMA guidelines and registered in PROSPERO (ID: CRD42023487475) ( Supplementary Table S1 ).

Symmetrical funnel plots were observed for survival summary ( Figure 6A ), pathological responses ( Figure 6B ), and AEs ( Figures 6C-F ), indicating acceptable publication bias.

Resectable stage II-III NSCLC cases can have improved outcomes if neoadjuvant and/or adjuvant treatment is given in addition to surgery (20–22). However, although traditional PBC can improve patient survival, it is very limited (23, 24). In recent years, the introduction of immunotherapy in neoadjuvant therapy and adjuvant therapy for resectable NSCLC has brought new hope to the long-term survival of these patients (9–15). This study represents the first meta-analysis analyzing the perioperative use (neoadjuvant+adjuvant) of immunotherapy for stage II-III NSCLC based on RCTs. The results suggested that PIO exhibited superior efficacy in OS, EFS, ORR, PCR, MPR, R0 resection rate, and rate of adjuvant treatment compared with PP. In safety assessment, more serious AEs and ALTD were found in the PIO group.

The primary advantage of PIO treatment lies in improved survival, particularly in terms of OS. In this study, the HR for survival was 0.63 [0.49-0.81] for OS and 0.61 [0.52, 0.72] for EFS. EFS is currently the primary endpoint in most RCTs on the perioperative treatment of NSCLC. In neoadjuvant therapy, the HR of EFS was 0.63 [0.43-0.91] in the CheckMate 816 study (9). In adjuvant therapy, the HR of EFS was 0.66 [0.50-0.88] in the Impower 010 study and 0.76 [0.63-0.91] in the KEYNOTE-091 study (11, 12). In addition, the Neotorch study (toripalimab) has reported interim research results with EFS (HR, 0.40 [0. 277-0. 565]) in ASCO 2023 (25). Thus, many scholars believed that the combined use of immunotherapy during the perioperative period might bring more survival benefits to patients than using neoadjuvant therapy and adjuvant therapy alone (8, 26). Meanwhile, this study also confirmed that PIO demonstrated an increasing advantage in survival (OS, EFS) compared to PP, which was consistent with the tail effect of immunotherapy (27). In the subgroup analysis, EFS tended to favor the PIO group in almost all subgroups. BMI (>25), T stage (IV), N stage (N1-N2) and pathological response (with PCR) were favorable factors in the PIO group, as substantiated in several studies (28, 29). Additionally, the EFS advantage of the PIO group increased with increasing PD-L1 expression (PD-L1 TPS, < 1%, RR: 0.77 [0.59-1.00]; 1-49%, RR: 0.56 [0.42-0.73]; > 50%, RR: 0.48 [0.35-0.67]).

Neoadjuvant immunotherapy may have improved survival benefits, although a direct comparative randomized trial would need to be conducted to determine this (30, 31). Therefore, the pathological response and its impact on surgical treatment are crucial indicators for evaluating drug efficacy. In summary, the ORR, PCR and MPR were 51.46%, 19.02% and 32.44% in the PIO group, which was similar to the results of NADIM study and SAKK 16/14 study (32, 33). In this study, patients in the PIO group achieved better ORR (RR: 2.21 [1.91, 2.54]), PCR (RR: 4.36 [3.04, 6.25]) and MPR (RR: 2.79 [2.25, 3.46]) compared to patients in the PP group. Similar results were also confirmed by the CheckMate 816 study and the Neotorch study (9, 25). Better pathological response was also associated with increased surgery rate (82.07% vs. 79.58%) and R0 resection rate (75.24% vs. 67.87%), playing a crucial role in the long-term survival of patients. Furthermore, we confirmed that the EFS advantage in the PIO group was particularly notable in the PCR subgroup. Therefore, it can be indirectly confirmed that a better pathological response could lead to a better prognosis in perioperative immunotherapy.

Safety is another concern in the perioperative and long-term use of immunotherapy after surgery. The IMpower010 trial reported that Atezolizumab-related adverse events leading to hospitalization occurred in 7% of the surgery groups (34). In clinical practice, although the incidence of AEs in immunotherapy is often much lower than that in chemotherapy, immune related AEs (such as pneumonitis, myocarditis, etc.) are often challenging to manage and can substantially impact the quality of life (35). At different periods of this study, it was observed that the incidence of total AEs, grade 3-5 AEs, serious AEs, and fatal AEs was higher in the PIO group than in the PP group in varying degrees, especially during the neoadjuvant treatment phase. In this phase, the top 5 AEs in the PIO group were nausea (41.15%), anemia (36.17%), neutrophil count decreased (30.28%), constipation (26.87%), and fatigue (23.17%), similar to those in the PP group. These common AEs are often associated with chemotherapy (13). The incidences of rash, pruritus, alanine aminotransferase increased, hypothyroidism, and pneumonitis were significant higher in the PIO group. These significantly increased AEs are often associated with immunotherapy (36). Therefore, although PIO can substantially improve survival, the monitoring and treatment of AEs at different phases still requires close attention.

This meta-analysis has limitations. Firstly, the inclusion of only English articles may introduce language bias. Secondly, including only 3 RCTs may reduce the overall clinical value. Thirdly, all the data analyzed were extracted from previously published articles, leading to increased data heterogeneity. Fourthly, the absence of individual patient data prevented a meta-analysis at the patient level, potentially decreasing the clinical value. Fifthly, variations in median follow-up times across studies might contribute to increased data heterogeneity.

PIO appears superior to PP for resectable stage II-III NSCLC, exhibiting better survival (OS and EFS) and improved pathological responses. Survival tended to favor the PIO group across almost all subgroups. Additionally, PIO demonstrated an increased advantage in survival compared to PP with longer follow up and increased PD-L1 expression. However, the higher rate of AEs in the PIO group warrants serious consideration.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

AY: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. FF: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. XL: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. MW: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. MY: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. WZ: Conceptualization, Data curation, Formal analysis, Funding acquisition, Writing – original draft, Writing – review & editing.