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Non-small cell lung cancer (NSCLC) accounts for about 80%-85% of the total number of lung cancers, and surgical resection is the most effective means for the radical treatment of early NSCLC. However, with only a 15% reduction in recurrence and a 5% improvement in 5-year survival after perioperative chemotherapy, there is a huge unmet clinical need.

Perioperative immunotherapy for NSCLC is a new research hotspot in recent years, and the results of a number of phase 3 randomized controlled trials have established the important position of perioperative immunotherapy.

Immunotherapy for patients with operable early stage non-small cell lung cancer (NSCLC) has made significant progress in recent years, and this treatment strategy not only extends the survival of patients, but also improves the quality of life, providing an effective supplement to traditional surgery

Depending on when immunotherapy is administered, there are three main patterns of immunotherapy in the treatment of operable early-stage NSCLC:

1. Neoadjuvant immunotherapy alone: Immunotherapy is performed before surgery to reduce the size of the tumor and reduce the risk of recurrence. The CheckMate 816 study [1] showed that immunotherapy combined with chemotherapy significantly improved event-free survival (EFS) in the neoadjuvant phase compared to chemotherapy alone. In addition, neoadjuvant immunotherapy can also reduce the recurrence rate while improving the pathological complete response rate (pCR) of patients, thereby reducing the likelihood of postoperative recurrence.
2. Perioperative immunotherapy (neoadjuvant + adjuvant) : In this mode, immunotherapy is administered before and after surgery to maximize its antitumor effect and further remove the minimal residual lesions after surgery. The core goal of this treatment model is to improve long-term survival and cure rates for tumor patients by combining immunotherapy at the neoadjuvant (pre-operative) and adjuvant (post-operative) stages. Keykeynote 671 is a representative of this model [2]. As the only randomized controlled trial (RCT) with positive EFS and OS endpoints, it evaluated the efficacy of palizumab combined with chemotherapy in perioperatively resectable stage Ⅱ, ⅢA, and ⅢB (N2) NSCLC patients. Compared with chemotherapy alone, pembrolizumab combined with chemotherapy extended the median EFS by 2.5 years and reduced the risk of disease progression, recurrence, or death by 41%; KEYNOTE-671 was also the first immunotherapy study to demonstrate an overall survival (OS) benefit in resectable NSCLC, with a 28% reduction in the risk of death (HR, 0.72), a milestone in neoadjuvant and adjuvant immunotherapy for operable early-stage NSCLC

3. Adjuvant immunotherapy alone: In this mode, patients did not receive drug treatment before surgery, and immunodrugs were used after surgery to prevent the recurrence of residual tumors, which is suitable for patients with high recurrence risk. The IMpower010 study evaluated the efficacy of postoperative adjuvant attilizumab versus optimal supportive therapy in patients with completely resected stage IB to IIIA (AJCC 7th edition) NSCLC [3]. The results showed that adjunct therapy with attilizumab significantly prolonged disease-free survival (DFS) in PD-L1 positive patients at stage ⅱto ⅢA. In addition, the KEYNOTE-091/PEARLS study evaluated the effect of pembrolizumab as adjunctive therapy in completely resected patients with stage IB to IIIA NSCLC [4]. Pabolizumab was significantly prolonged in the overall population (HR, 0.76), with a median DFS of 53.6 months in the Pabolizumab group and 42 months in the placebo group. In the subgroup of patients with PD-L1 tumor proportion score (TPS) ≥50%, although the DFS was prolonged in the Pabolizumab group, the difference between the two groups was not statistically significant due to the relatively small sample size, and longer follow-up was needed to confirm.

According to whether immunotherapy is combined with other drugs or therapeutic measures and the combination mode, the program of neoadjuvant immunotherapy and adjuvant immunotherapy can be divided into the following three main modes:

1. Single immunotherapy: This type of therapy includes studies such as LCMC3 [5], IMpower010 [3], KEYNOTE-091/PEARLS [4], BR.31 [6], and ANVIL [7], characterized by the use of single immunotherapy drugs as (new) adjuvant therapy.
2. Combination of immunotherapy and chemotherapy: Such studies include KEYNOTE-671 [2], CheckMate 77T [8], AEGEAN [9], RATIONALE-315 [10], Neotorch [11], and IMpower030 [12]. These studies looked at the effects of combining immunotherapy and chemotherapy in the perioperative period.
3. Combination of immunotherapy with other treatment modes: (1) Combination with other immunodrugs: For example, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) was combined in NEOSTAR test [13], lymphocyte activation gene 3 (LAG-3) antibody was combined in NEO-Predict-Lung test [14], and T cell immunoglobulin and ITIM structures were combined in the SKYSCRAPER 15 test Studies such as TIGIT antibody combination [15] have enhanced the anti-tumor effect through the combination of immune drugs. (2) Combined with radiotherapy: for example, duvaliumab combined with stereotactic radiotherapy (SBRT) is designed to enhance the therapeutic effect of early NSCLC [16]; (3) Combination with anti-angiogenic drugs: For example, the EAST ENERGY study [17] explored the synergistic effect of ramumab combined with immunotherapy. The exploration of multiple immunotherapy modes shows that the application mechanism of immunotherapy in perioperative period is still not fully understood. Although immunotherapy alone has shown positive results in perioperative treatment, by combining chemotherapy, radiation therapy, antiangiogenic therapy, and other immune checkpoint inhibitors such as CTLA-4, LAG-3, and TIGIT, researchers hope to further enhance the efficacy of immunotherapy.

There is still no conclusion on the optimal mode of immunotherapy for operable early NSCLC, especially whether perioperative immunotherapy compared with neoadjuvant immunotherapy alone, and whether additional adjuvant immunotherapy can bring significant additional effects, there is still a lack of direct comparative trial results.
Forde et al. used exploratory propensity score weighted analysis to simulate the effect of randomized controlled trials, and adjusted the baseline demographics and disease characteristics among different study populations to reduce the confounding effect of these factors, making the results of CheckMate 816 [1] and CheckMate 77T [8] more comparable. The median follow-up time was 29.5 months (CheckMate 816) and 33.3 months (CheckMate 77T), respectively, providing ample follow-up time to observe EFS and other key efficacy measures.
In the weighted analysis, the HR of EFS was 0.61 (95% CI, 0.39 to 0.97), suggesting a 39% lower risk of recurrence or death in the perioperative nabuliumab combined chemotherapy group (CheckMate 77T mode) compared with the neoadjuvant nabuliumab combined chemotherapy group (CheckMate 816). The perioperative nebuliuzumab plus chemotherapy group showed a modest benefit in all patients at baseline stage, and the effect was more pronounced in patients with less than 1% tumor PD-L1 expression (49% reduction in risk of recurrence or death). In addition, for patients who failed to achieve pCR, the perioperative nabuliumab combined chemotherapy group showed a greater benefit of EFS (35% reduction in risk of recurrence or death) than the neoadjuvant nabuliumab combined chemotherapy group. These results suggest that the perioperative immunotherapy model is more beneficial than the neoadjuvant immunotherapy model alone, especially in patients with low PD-L1 expression and tumor remnants after initial treatment.
However, some indirect comparisons (such as meta-analyses) have shown no significant difference in survival between neoadjuvant immunotherapy and perioperative immunotherapy [18]. A meta-analysis based on individual patient data found that perioperative immunotherapy and neoadjuvant immunotherapy had similar results on EFS in both pCR and non-PCR subgroups in patients with operable early-stage NSCLC [19]. In addition, the contribution of the adjuvant immunotherapy phase, especially after patients achieve pCR, remains a controversial point in the clinic.
Recently, the US Food and Drug Administration (FDA) Oncology Drugs Advisory Committee discussed this issue, emphasizing that the specific role of adjuvant immunotherapy is still unclear [20]. It was discussed that: (1) It is difficult to distinguish the effects of each stage of treatment: because the perioperative program consists of two phases, neoadjuvant and adjuvant, it is difficult to determine the individual contribution of each phase to the overall effect, making it difficult to determine which phase is more critical, or whether both phases need to be carried out simultaneously; (2) The possibility of overtreatment: if immunotherapy is involved in both treatment phases, it may cause patients to receive overtreatment and increase the risk of side effects; (3) Increased treatment burden: Additional treatment in the adjuvant treatment phase can lead to a higher treatment burden for patients, especially if there is uncertainty about its contribution to overall efficacy. In response to the above debate, in order to draw a clear conclusion, more rigorously designed randomized controlled trials are needed for further verification in the future.