1 INTRODUCTION

Recent research indicates that lung cancer remains the leading cause of cancer-related morbidity and mortality worldwide, with approximately 2 million newly diagnosed cases and 1.8 million deaths reported annually.1 Approximately 85% of new lung cancer cases constitute non–small cell lung cancer (NSCLC), among which 50% present as metastatic NSCLC (stage IV) and the remaining 50% present as an early-stage disease (stages I and II) or locally advanced cancer (stage III). Surgery in combination with chemotherapy is by far the best treatment currently available for early-stage NSCLC. However, the 5-year survival rates of postoperative patients are approximately 50%, only, moreover, owing to high postoperative recurrence rates, these rates decrease with increasing tumor stage.2 Furthermore, even in patients with very early-stage primary tumors, prognosis is often unclear. Therefore, the current major objectives in the treatment of early resectable NSCLC are preventing neoplasm recurrence and improving the cure rate.

Neoadjuvant chemotherapy is currently widely applied as a general therapy approach for resectable NSCLC based on extensive research regarding systematic therapy in the perioperative period. Studies have suggested that neoadjuvant chemotherapy shrinks tumor, improves the complete resection rates, decreases postoperative recurrent rates, and provides better survival benefits than surgery alone.3-5 However, the benefits of neoadjuvant chemotherapy in terms of improving the 5-year survival rates constituted a minor 5% increase.6 In recent years, immunotherapy has revolutionized the fixed therapy pattern for advanced NSCLC with the emergence of immune checkpoint inhibitors (ICIs). The significant increase in treatment efficacy achievable with immunotherapy based on ICIs has gradually made this approach becoming the first-line treatment choice in patients with advanced NSCLC. The higher response rates, improved survival benefits, fewer adverse events, and better tolerability offered by immunotherapy have been proven in multiple randomized clinical trials. In the CheckMate 003 trial, the 5-year survival rate was improved to 16% in patients with advanced NSCLC who received immunotherapy with nivolumab.7 In addition, in a clinical trial investigating pembrolizumab, the 5-year survival rate of patients with advanced cancer improved to 15.5%.8 Combination therapy regimens, including chemotherapy plus ICIs, were shown to improved survival benefits without additional chemocytotoxicity.9

The significant benefits of immunotherapy based on PD-1 and PD-L1 antibodies in regarding the improving long-term survival have increased scholars’ interests in translating the benefits of ICIs for early-stage resectable NSCLC treatment. In trials exploring the effects of ICIs in the perioperative period, neoadjuvant immunotherapy was shown to improve the survival rates of patients with melanoma and glioma.10, 11 In a clinical trial of early-stage NSCLC, the major pathologic response (MPR) because of neoadjuvant immunotherapy was as high as 43%.12 Hence, the present reviews focused on the current status of neoadjuvant therapy in resectable NSCLC and reviewed its potential application in early-stage NSCLC.

2 RATIONALE FOR IMMUNOTHERAPY IN RESECTABLE NSCLC

Immunotherapy based on ICIs, anti-programmed death (PD)-1/PD-ligand 1 (L1), and anti-cytotoxic T lymphocyte-associated protein (CTLA)-4, is at the most advanced stage of treatment in the field of metastatic NSCLC. However, ICIs are still at the primary stage in the case of early-stage resectable NSCLC. At the initial signs of cancer or cellular transformation in an organism, the immune system is alerted through immune surveillance mechanisms, which in turn activate various antitumor mechanisms.13 On identifying specific antigens, the immune system's natural killer (NK) cells, which form the front-line defense against cancer, induce an innate immune response to attack malignant cells.14 Antigen-presenting cells (APCs) subsequently absorb and process lysed cancer cell fragments and present tumor antigen ligands to B cells and CD4+ or CD8+ cytotoxic T cells, which results in the release of inflammatory factors.15 Then, the secondary immune response is initiated, and plasma cells and memory B cells express relevant antibodies to attack and lyse the cancer cells.16, 17 In addition, costimulatory molecules play an important role in immune response. As part of the double-signaling regulatory mechanism, costimulatory molecules function along with APCs to activate T cells.18 For example, negative costimulatory molecules act via inhibitory pathways such as the PD-1/PD-L1 pathway and play a crucial role in controlling T cell responses. In general, the immune system is unable to eliminate all malignant cells, and tension is created between cancer cells and immune cells. Cancer cells develop genetic variations and may evolve into less immunogenic phenotypes under persistent pressure from the immune system. This results in an immune escape that occurs when immune-resistant cancer cells downregulate APC expression and secrete immune inhibitory molecules to escape from immune surveillance.19 The primary mechanism of immune escape formed the basis of immunotherapy, in which immune regulatory molecules (such as CTLA-4 and PD-1 and their ligands) are manipulated to alter the activity of immune cells, thereby prompting them to attack tumor cells.20, 21

Some completed clinical trials indicated that abundant tumor-specific cytotoxic T cells were found in the blood of patients with early-stage NSCLC treated with ICIs22 and that regulatory T cells in tumor tissues were markedly increased, and NK cells and dendritic cells were decreased.23 This phenomenon suggests that neoadjuvant immunotherapy, which functions as a primer, triggers more release of tumor antigens to activate T cells. Meanwhile, these T cells migrate to micrometastasis lesions via the blood and lymphatic system, triggering more extensive antitumor reactions. This is the theoretical basis for applying neoadjuvant immunotherapy to early-stage resectable NSCLC.

3 ADVANTAGES OF NEOADJUVANT IMMUNOTHERAPY IN RESECTABLE NSCLC

First, early-stage resectable tumor tissues have a greater host immunity fitness and lower tumor clonal heterogeneity, which determines whether the primary tumor becomes malignant and whether antigens spread and activate specific antitumor T cells.24 To visualize this phenomenon, the resectable lung tumor can be thought of as a special vaccine that can be activate by an ICI to create specific antitumor immunity, build early-phase immunologic memory, and eliminate potential metastatic lesions.25 Second, the survival benefits of neoadjuvant immunotherapy may be chronic. A trial on breast cancer found that there was an obvious and permanent increase in antitumor T cells in peripheral blood and that this increase persisted even after the primary tumor was removed.26 Third, some trials indicated a synergetic effect of neoadjuvant immunotherapy and chemotherapy.27 Hence, we hypothesized that cytotoxic chemotherapy enhances the immunogenicity of tumor cells and that ICIs enhance patients’ responsiveness to chemotherapy. Based on the abovementioned findings, there is a great deal of optimistic expectation that ICIs will provide an effective neoadjuvant therapeutic option for early-stage resectable NSCLC.

4 CLINICAL TRIALS INVESTIGATING NEOADJUVANT IMMUNOTHERAPY IN RESECTABLE NSCLC

In early-stage resectable NSCLC, the immune-suppressive microenvironment reportedly leads to an increase in regulatory T cells and decrease in NK cells,23 suggesting that patients benefit from early activation of the immune system. Hence, the application of ICIs in resectable early-stage NSCLC offers an attractive antitumor strategy.

4.1 NCT02987998 trial

In the NCT02987998, a phase I trial, nine patients with stage IIIA NSCLC received cisplatin, etoposide, and concurrent pembrolizumab.28 Owing to progression and pleural metastases, only six patients achieved R0, with a high pathologic complete response (pCR) rate of 67% (four of six). However, two severe grade 5 adverse events were noted, which had not been observed in the other trials.

4.2 Chinese clinical trial register (ChiCTR)-OIC-17013726 trial

The phase IB ChiCTR-OIC-17013726 trial explored the safety and efficacy of sintilimab(anti-PD-1) in patients with resectable (stage IA to IIIB) NSCLC.29 A total of 40 patients received two cycles of neoadjuvant immunotherapy, and 37 patients ultimately underwent surgical treatment. With 40.5% MPR (16 of 37) and 16.2% (6 of 37) pCR rates, similar research results were observed with sintilimab as those found in the CheckMate 159 trial.

4.3 CheckMate 159 trial

The CheckMate 159 trial pioneered the exploration of neoadjuvant immunotherapy for NSCLC. It was published in 2018 and included 21 patients with resectable NSCLC.12 Forde et al recruited patients with resectable NSCLC (ranging from stage I to IIIA) who were willing to undergo surgery. They formulated a neoadjuvant strategy wherein the enrolled patients received two cycles of neoadjuvant therapy with the PD-1 inhibitor—nivolumab (3 mg/kg of body weight once every 2 weeks)—followed by surgery at 4 weeks after the first dose. The safety and feasibility of this treatment were confirmed by the trial results with only one patient experiencing a grade 3 adverse event and no patient experiencing grade 4 or grade 5 adverse events. All surgeries were performed according to schedule, and 20 patients achieved R0 resection (no residual tumor tissue and cells at the incisal margin under the microscope confirmed by postoperative pathology). The MPR rate in postoperative patients was 45% (nine patients), which was nearly twice the MPR rate of patients who received neoadjuvant chemotherapy30; more significantly, the number of T cells and the clonality were higher in tumor sites, which indicates an effective immune response.

4.4 Lung cancer mutation consortium trial

The lung cancer mutation consortium (LCMC3) trial is an ongoing single-arm phase II study that reported results in WCLC 2021. Patients(n = 181) with stage IB to IIIA and selected IIIB NSCLC were recruited and scheduled to receive two cycles of immunotherapy with atezolizumab (PD-L1 inhibitor).31, 32 One hundred fifty-nine patients have accepted surgical treatment, and the rate of R0 resection is 92% (145/159) . Only 8% (n = 12) experienced grade 3 or 4 adverse events. In 144 patients, no EGFR/ALK mutations, MPR, and pCR rates accounted for 21% and 7%, respectively. The MPR rate in the PD-L1-positive group was as high as 19%, and surgery was delayed only in one patient owing to grade 3 pneumonia.

4.5 NADIM trial

In the NADIM trial, patients with stage IIIA resectable NSCLC were enrolled and received three cycles of neoadjuvant therapy with nivolumab plus carboplatin or paclitaxel before surgery.33 The latest results indicated that 46 patients received a combination neoadjuvant therapy, and 41 patients achieved R0. The MPR rate of postoperative patients reached 83%, and the pCR rate reached 63%. The trial presented promising implications for the safety of this regimen, with only 1 grade 4 adverse event.

4.6 NCT02716038 trial

In addition to clinical trials of ICI monotherapy, there have also been clinical trials exploring the efficacy and safety of neoadjuvant immunotherapy in combination with chemotherapy. In the NCT02716038 trial, 14 patients with stage IB to IIIA NSCLC received four cycles of neoadjuvant therapy with atezolizumab plus carboplatin or paclitaxel. The MPR rate was 57%, and 11 patients underwent surgery.34

4.7 NCT03366766 trial

The NCT03366766 trial published its research outcomes at the 56th American Society of Clinical Oncology conference in 2020.35 Notably, 13 patients received three courses of combination therapy with nivolumab plus cisplatin/pemetrexed or cisplatin/gemcitabine and then underwent scheduled surgery. Finally, the trial reported an MPR rate of 46% (6 of 13) and a pCR rate of 38% (5 of 13); with two grade 3 adverse events.

Other published phase II studies on neoadjuvant therapy with ICIs, such as the NEOSTAR trial and NEOMUN trial,36 have also reported the pathologic benefits and potential survival benefits of this treatment regimen. And recently CheckMate 816 trial released the results on AACR 2021. The CheckMate 816 trial reported an MPR rate of 36.9% and a pCR rate of 24%.37 Neoadjuvant immunotherapies, particularly combination therapies, have distinct advantages in providing better pathologic responses and improved safety, and do not reduce the possibility of surgery compared with chemo-monotherapy (Table 1). However, it should be noted that the results of phase II trials are often misleading owing to their small sample size. Therefore, all-aspect advantages remain to be confirmed in larger phase III trials. The currently ongoing phase III studies are presented in Table 2.

TABLE 1. Early findings in trials reports on neoadjuvant immunotherapy R0 resection Phase Trial Patient population N Treatment regimen Initial findings AEs N Rate (%) I NCT02987998 stage IIIA NSCLC 9 ChT + Pembrolizumab pCR 67% (4/6) Grade 3: 55% (5/9); Grade 5: 22% (2/9) 6 66.7 ChiCTR-OIC-17013726 stage IA–IIIB NSCLC 40 Sintilimab MPR 40.5% (15/37); pCR 16.2% (6/37) Grade 3–4: 10% (4/40); Grade 5: 2.5% (1/40) 37 92.5 II CheckMate 159 stage I-IIIA NSCLC 22 Nivolumab MPR 45% (9/20) Grade 3–4: 5% (1/22) 20 100 LCMC3 stage IB–IIIB(T3N2) NSCLC 181 Atezolizumab MPR 21% (30/144); pCR 7% (10/144) Grade 3–4: 8% (12/159); Grade 5: 0.6%(1/159) 145 80.1 NADIM stage IIIA(N2) NSCLC 46 ChT + Nivolumab postop Nivolumab MPR 83%; pCR 63% Grade 3: 30% (14/46); Grade 4: 4% (2/46) 41 89.1 NCT02716038 stage IB–IIIA NSCLC 14 ChT + Atezolizumab postop SoC MPR 50% (7/14); pCR 21% (3/14) Grade 3–4: 85.7% (12/14) 11 78.6 NCT03366766 stage IB–IIIA NSCLC 13 ChT + Nivolumab MPR 40.5% (6/13); pCR 38% (5/13) Grade 3: 31% (4/13) 13 100 NEOSTAR stage I–IIIA NSCLC 44

arm A: Nivolumab

arm B: Nivo + Ipilimumab

arm A: MPR 22%; pCR 9%

arm B: MPR 38%; pCR 29%

Grade 3–5 13% (3/23)

Grade 3–5: 10% (2/21)

21

16

84 NEOMUN stage II-IIIA NSCLC 15 Pembrolizumab MPR 27% (4/15); pCR 13% (2/15) Grade 2–3: 33% (5/15) – – III CheckMate 816 stage IB-IIIA NSCLC 358

arm A: ChT + Nivolumab

arm B: ChT

arm A: MPR 36.9%; pCR 24%

arm B: MPR 8.9%; pCR 2.2%

Grade 3–4: 34%

Grade 3–4: 37%

124

105

83

75

Abbreviations: ChT, chemotherapy treatment; MPR, major pathological response; N, number of patients; pCR, pathological complete response; -, not mentioned; R0, complete resection. TABLE 2. Ongoing phase III randomized clinical trials with neoadjuvant immune checkpoint inhibition immunotherapy Study Status N Recruitment criteria Start data Intervention PE CA209-77T Recruiting 452 Resectable, stage IIA (>4 cm) to IIIB (T3N2) NSCLC September 16, 2019 Neoadjuvant chemotherapy plus nivolumab versus neoadjuvant chemotherapy plus placebo EFS  NCT0415844 Not yet recruiting 406 Resectable stage IIIA (AJCC staging system version 8) NSCLC December 31, 2019 Toripalimab or placebo plus chemotherapy  MPR KEYNOTE-671 Recruiting 786 Resectable Stage II, IIIA, or IIIB (N2) NSCLC. April 24, 2018 Platinum doublet chemotherapy +/-pembrolizumab (MK-3475) EFS, OS IMpower030 Recruiting 374 Resectable Stage II, IIIA, or Select IIIB (T3N2 only) NSCLC April 24, 2018 Neoadjuvant treatment with atezolizumab or placebo in combination with platinum-based chemotherapy  MPR,EFS AEGEAN Recruiting 800 Resectable (Stage IIA to select [ie, N2] Stage IIIB)  December 6, 2018 Durvalumab/placebo + platinum-based chemotherapy MPR,EFS Abbreviations: EFS, event-free survival; MPR, major pathological response; N, number of patients; OS, overall survival; pCR, pathological complete response; PE, primary endpoint. 5 FUTURE DIRECTION AND RELEVANT PROBLEMS OF NEOADJUVANT IMMUNOTHERAPY IN RESECTABLE NSCLC

Although the efficacy and safety of neoadjuvant immunotherapy have been proven in phase II trials, some relevant problems surrounding its application in resectable NSCLC are worth exploring (Table 3).

TABLE 3. Some relevant problems surrounding its application in resectable NSCLC Relevant problems Possible solution Population screening We may select the appropriate patients by expression of PD-1/L1, CTLA4 or TMB. Treatment strategies Immunotherapy monotherapy/chemotherapy plus immunotherapy/immunotherapy plus immunotherapy. Duration and cycles We often set the treatment duration 2–4 cycles with empirical regularity. Appropriate endpoints MPR, pCR, EFS, OS,PFS Pseudoprogression We should find an appropriate way to effectively identify pseudoprogression. 5.1 Population screening and formulation of treatment strategies

At present, clinicians do not have sufficient knowledge of the specific population groups that would benefit highly from neoadjuvant immunotherapy, and there is still a long way from achieving the goal of formulating individualized therapy strategies as per individual patient characteristics. However, the next step in this process involves searching the evaluation of appropriate immune checkpoints to screen specific population groups who would not respond to ICIs.

ICIs act as a type of negative regulatory molecules in the immune system and play a crucial role in maintaining self-tolerance, preventing autoimmune response, and controlling the time and intensity of immune response to minimize tissue injury. PD-1/L1 and CTLA4 are currently the most widely used immune checkpoints relevant to NSCLC. ICIs can prevent the immune suppression by blocking the interaction between the tumor and immune cells. Anti-PD-1 and PD-L1 antibodies have shown promise in the phase II trials of resectable NSCLC. Nevertheless, data from the CheckMate 159, LCMC3, and NEOSTAR trials indicated that pathologic and imaging responses could also be observed in patients with negative PD-1/PD-L1 expressions. The relationship between the efficacy of ICIs and the expression of immune checkpoints has yet to be elucidated in phase III studies.

Tumor mutational burden (TMB) is defined as the number of mutant genes per million bases; it is another promising new biomarker for predicting the efficacy of immunotherapy. Patients with higher TMBs showed better MPR rates in the CheckMate 159 trial.12 However, the results of the LCMC3 trial did not support the abovementioned observation.31

Another important aspect that requires further investigation is how to formulate treatment strategies. Certain phase II trials adopted the approach of ICI monotherapy, whereas other trials employed the strategy of a combination therapy. Neoadjuvant therapy includes chemotherapy and chemoimmunotherapy. Which treatment model works optimally is a question worth of a deeper exploration. According to existing research, combination therapy is the best treatment model but monotherapy is the safer one. The MPR rate of neoadjuvant immunotherapy is approximately 20%–45%, whereas the rate of neoadjuvant chemoimmunotherapy is >50%. In conclusion, the advantages of combination therapy are a higher MPR rate as well as good safety and tolerability. However, the risk of combination therapy is slightly higher than that of monotherapy. In view of the small sample size of phase II trials, neoadjuvant chemoimmunotherapy cannot be considered as the optimal choice.

Although no final conclusion has yet been reached regarding these 2 challenges, phase II trials offer hope to patients with early-stage NSCLC and may be instrumental in changing the fixed therapy pattern in resectable NSCLC. Whether neoadjuvant immunotherapy should be combined with other adjuvant treatments and which biomarkers are best used in screening appropriate patients must be decided based on the basis of further research involving diversified experimental designs.

5.2 Duration and course of immunotherapy

There has been no agreement with regard to the duration and cycles of neoadjuvant immunotherapy. Clinicians often set the treatment duration at two to four cycles with empirical regularity, and the duration is usually no more than four cycles. For example, in the CheckMate 159 and NEOMUN trials, patients received two cycles of neoadjuvant ICI therapy.12, 36 Moreover, patients received three cycles of ICI therapy in NADIM trials7, 38 and four cycles of immunotherapy in the NCT02716038 trial. In a clinical study involving other solid tumors, the reactivation of T cells peaked after only 1 week of neoadjuvant immunotherapy, and 30% of patients acquired MPR and pCR within 3 weeks.39 It should be noted that neoadjuvant therapy is applied to reduce the difficulty of surgery. Hence, surgery is the basis of anticancer therapy, and neoadjuvant time should not be lengthy, which might delay surgery or reduce opportunities for performing surgery. Hence, a complete response evaluation criterion in solid tumors (RECIST) assessment should be performed after two cycles of neoadjuvant therapy. Continuing neoadjuvant immunotherapy or receiving surgery is then decided according to the evaluation results. Therefore, in terms of the duration and course of neoadjuvant immunotherapy in NSCLC, clinicians and researchers face a wide range of experimental design choices, indicating the need for further research.

5.3 Appropriate primary endpoint and formulation of immune-related pathologic response criteria

Neoadjuvant ICIs may improve prognosis of patients with early-stage resectable NSCLC and provide an important window period for pathologic examination and evaluation of residual tumors. In Table 2, we can see that different primary endpoints were chosen for different trials, such as overall survival (OS), event-free survival (EFS), and MPR. Actually most clinical trials chose OS, PFS, or EFS as the primary endpoints over the decades. OS is considered to be the best primary endpoint for oncology clinical trials, and it is the preferred endpoint when patients’ survival time can be adequately assessed. OS has the virtue of more easily measured and precision. And the obvious disadvantages are that the follow-up period is longer, usually requires a larger sample size, and is easily affected by follow-up treatment. Compared to OS, PFS, or EFS usually requires less sample size and less follow-up time and have a great correlation with OS. The disadvantage is that the evaluation is prone to bias and does not always translate into survival benefits, statistically significant may not have clinical significance. Therefore, selecting different standards and appropriate primary points is crucial. Under this trend, surrogate endpoints emerged, such as MPR, pCR, and event-free survival, which are considered to be associated with OS. For example, in the studies mentioned earlier, most researchers selected MPR or pCR as the primary or secondary endpoints. MPR means ≤10% residual viable tumor after neoadjuvant chemotherapy or immunotherapy. Residual cancer cells are positively correlated not only with the risk of mortality after neoadjuvant chemotherapy but also with pCR and survival time.39 Therefore, MPR provides a suitable replacement for a long-term survival index as the primary endpoint under these circumstances. The question of MPR or pCR as the primary endpoint is that whether it can be used as an effective alternative end point for OS. More prospective trials are needed to verify the validity and correlation of these endpoints. Hence, we can see multiple trial designs about endpoints in phase II and phase III trials. Pataer et al40 showed that MPR is particularly associated with OS or PFS. Other study showed that the forecasting of MPR for OS is better than clinical RECIST response,41 so that we could believe that MPR is a promising primary endpoint to replace survival index. The ideal MPR is 10%.

In evaluating the survival benefits of neoadjuvant therapy, MPR still face many limitations. First is how to weigh and unify differences between the RECIST assessment of imaging and histopathological response. Second, different to chemotherapy, pathological changes after neoadjuvant immunotherapy are varied, which makes the measurement criterion of MPR difficult to set. Third is the inability to establish the effect of treatment-related adverse events; hence, the risk-to-benefit ratio of treatment should be fully evaluated.

Another crucial consideration is how to standardize irPRC. Tumor beds are filled with necrotic and fibrotic tissue after traditional adjuvant chemotherapy. However, in the case of immunotherapy, ICIs activate the immune system to attack tumor cells instead of directly eliminating the tumor. Therefore, the characteristics of the tumor bed after regression are as follows: 1. tumor-infiltrating lymphocytes with macrophages and complete lymphoid structures; 2. extensive tumor cell death—cholesterol clefts; and 3. neovascularization and proliferative fibrosis.42 Therefore, the previous standard pathologic response criteria no longer meet the demands of neoadjuvant immunotherapy. Cottrell and Thompson put forward a new irPRC defined as follows: %irRVT = viable tumor area/total tumor bed area, whereby the total tumor bed = regression bed + RVT + necrosis.42 A significant feature of the new irPRC is that the regression tumor bed is included in the total tumor bed.

In conclusion, the new pathologic primary endpoint and the novel irPRC to evaluate regression of tumor cells and pathologic response of neoadjuvant immunotherapy require further standardization.

5.4 Pseudoprogression in neoadjuvant immunotherapy and the impact on surgery strategy

Imaging is most often used to evaluate treatment effects in neoadjuvant immunotherapy, except for the MPR and pCR rates. However, patients may undergo pseudoprogression after receiving ICIs. In the CheckMate 159 trial, in a typical example of radiological pseudoprogression, two patients exhibited tumor enlargement during image diagnosis after receiving neoadjuvant nivolumab, whereas the pathologic examinations of their postoperative solid tumor tissue samples revealed MPR or Pcr.42 The influx of tumor-infiltrating lymphocytes that may enlarge the tumor lesion may explain this specific phenomenon. In this trial, the participant response rate was 10% (two of 21) when evaluated by image examination, whereas the MPR rate was 42.9% (nine of 21). Homoplastically, this discrepancy between imageology and pathology was also found in the LCMC3 trial.31 When evaluated by image examination, 10 patients reached MPR but only three cases reached major or complete response.

Research shows that the incidence of pseudoprogression ranges from 5%–10%. Of note, patients with pseudoprogression still show survival benefits from immunotherapy, as opposed to a small group of patients who experience an actual deterioration of tumor conditions.43 The implications of pseudoprogression are greatest when it results in delayed surgery or leads to a missed opportunity for surgery. Hence, effective identification of pseudoprogression and a thorough study of its pathologic characteristics are critical for proper preoperative evaluation.

6 CONCLUSION AND FUTURE PERSPECTIVES

Therapy patterns in advanced NSCLC have seen major improvements with the emergence of ICIs, such as the anti-PD-1 and anti-PD-L1. In randomized controlled trials, immunotherapy has shown better efficacy and safety than chemotherapy. These advantages have prompted research to evaluate whether the benefits of ICIs can be extended to patients with early-stage resectable NSCLC. With favorable clinical tolerability, safety, and virtually no surgical delays, neoadjuvant immunotherapy has shown impressive potential benefits in several phase II trials. However, in addition to these advantages, several challenges, including screening appropriate patients to receive neoadjuvant therapy, the duration and course of immunotherapy, selecting appropriate primary endpoints to replace traditional survival indices, and identifying pseudoprogression effectively to avoid surgical delays, exist in the implementation of immunotherapy in patients with early-stage cancer. More phase III studies are required to validate the benefits and resolve the issues with respect to the use of ICIs in early-stage NSCLC. As a newly developed approach, which is entirely different from typical chemotherapy, neoadjuvant immunotherapy shows promise as an accurate and individualized treatment with improved survival benefits for patients with early-stage resectable NSCLC.

ACKNOWLEDGEMENTS

This work was supported by grants from the National Natural Science Foundation of China (grant numbers: 81773207 and 82072595), the Natural Science Foundation of Tianjin (grant numbers: 17YFZCSY00840, 18PTZWHZ00240, and 19YFZCSY00040), and the Special support program for High Tech Leader & Team of Tianjin (grant number: TJTZJH-GCCCXCYTD-2-6). Funding sources had no role in study design, data collection, and analysis; in the decision to publish; or in the preparation of the manuscript.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.