Comparison of the short-term efficacy and safety of surgical operation of neoadjuvant sintilimab and camrelizumab, both in combination with chemotherapy in the treatment of resectable non-small cell lung cancer: a single-center retrospective cohort study

Introduction

Lung cancer is the second most common malignant tumor, and it is the leading cause of death among cancers worldwide (1). Non-small cell lung cancer (NSCLC) is the main type of lung cancer, accounting for 80–85% of all lung cancer cases (2). In recent years, immune checkpoint inhibitors (ICIs) have provided breakthroughs in the treatment of locally advanced or metastatic NSCLC and they have been gradually applied in the perioperative treatment of NSCLC. The primary objectives of neoadjuvant chemoimmunotherapy in the perioperative period treatment of resectable NSCLC are threefold: to achieve tumor downstaging by reducing the primary tumor burden, to enhance the likelihood of complete surgical resection by improving resectability rates and to mitigate the risks of locoregional recurrence through the early systemic treatment of micrometastatic disease, ultimately aiming to improve long-term clinical outcomes. This is consistent with the results of a number of previous studies of neoadjuvant immunotherapy combined with chemotherapy in patients with resectable NSCLC, including CheckMate-816 (3), KEYNOTE-671 (4), AEGEAN (5), CheckMate-77T (6), RATIONALE315 (7) and Neotorch (8), which indicated that chemotherapy combined with immunotherapy significantly improved the pathological complete response (pCR) rate and the major pathological response (MPR) rate. This study compared the efficacy and surgery-related safety of different ICIs (sintilimab and camrelizumab) combined with chemotherapy in the treatment of resectable NSCLC using propensity score matching (PSM) analysis.

Camrelizumab is a humanized immunoglobulin G4-k monoclonal antibody against programmed cell death (PD-1). It is the first PD-1 antibody approved for lung cancer in China. It has been included in the first-line treatment recommendations for advanced NSCLC in the Chinses Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer. The Camel-Sq study reported (9) that camrelizumab combined with chemotherapy achieved median progression-free survival of 8.5 months, median overall survival (OS) of 27.4 months, and a 5-year survival rate of 31.2% in the first-line treatment of NSCLC. The TD-FORKNOW study (10) is a phase II clinical study that mainly included patients with resectable stage IIIA/IIIB (cT3N2) NSCLC aged 18–70 years. The study revealed that compared with chemotherapy alone, the pCR [32.6% vs. 8.9%, 95% confidence interval (CI): 1.35–22.37, P=0.008] and MPR rate (65.1% vs. 15.6%, 95% CI: 3.32–32.76, P<0.001) were significantly improved in patients who received camrelizumab combined with chemotherapy. Furthermore, a numerical improvement was observed in the objective response rate (ORR, 72.1% vs. 53.3%, 95% CI: 0.85–6.08, P=0.08), compared with chemotherapy alone. Additionally, compared with the chemotherapy alone group, the 24-month event-free survival (EFS) rate (76.9% vs. 67.6%) and disease-free survival (DFS) rate (78.4% vs. 71.7%) were significantly higher in the combination treatment group. Neoadjuvant therapy with camrelizumab combined with chemotherapy has significant efficacy, providing a new treatment option for patients with resectable NSCLC.

Sintilimab is a fully human immunoglobulin G subclass 4 (IgG4) monoclonal antibody against programmed cell death protein-1 (PD-1). The phase III ORIENT-11 study (11) found that sintilimab combined with chemotherapy significantly improved median OS (up to 24.2 months) in the first-line treatment of locally advanced or metastatic NSCLC. At the same time, the Neo-Pre-IC study (12) revealed that neoadjuvant sintilimab combined with chemotherapy achieved a postoperative pCR rate of 40% (95% CI: 21.2–46.3%), a major pathological response (MPR) rate of 65% (95% CI: 43.3–82.9 %) in surgery patients with resectable stage IIIA/IIIB NSCLC. The 2-year DFS rate and the 2-year OS rate were 75% (95% CI: 56–94%) and 80% (95% CI: 63–97%) in the surgery group respectively. According to the Response Evaluation Criteria in Solid Tumors v. 1.1 (RECIST1.1) evaluation results, 29 patients (96.7%) achieved disease control, with an ORR rate of 55%; including partial response (PR) in 16 patients (53.3%) and stable disease (SD) in 13 patients (43.3%). The downstaging rate was 80% (95% CI: 65.7–94.3%). This study demonstrated that neoadjuvant sintilimab combined with chemotherapy has significant efficiency in the treatment of patients with resectable NSCLC, providing a new option for the field of neoadjuvant immunotherapy.

The aforementioned studies suggest that chemotherapy combined with immunotherapy improves the pCR rate, but because the two different trials likely differed regarding the patient populations, disease stages, and programmed death-ligand1 (PD-L1) expression, it is impossible to conduct a head-to-head comparison of the two drugs. Therefore, this study compared the efficacy and surgical safety of sintilimab and camrelizumab combined with chemotherapy in the treatment of resectable NSCLC. Specifically, this study used PSM analysis to compare the effectiveness of the two ICIs combined with chemotherapy in resectable NSCLC and clarify the safety and feasibility of surgery following neoadjuvant therapy to provide clinicians and patients with more evidence to choose appropriate drugs. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2014/rc).

Methods

Study design and patients

We used a single-center retrospective cohort study design, which is a type of observational study. This study was conducted in the Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University. We retrospectively collected and organized patients diagnosed with NSCLC in Tangdu Hospital from June 2018 to March 2024. These patients who received neoadjuvant sintilimab group (SG) or camrelizumab group (CG) combined with chemotherapy and underwent surgical resection were selected. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Tangdu Hospital, Fourth Military Medical University (approval No. TDLL-202411-05) and informed consent was obtained from all individual participants. Included patients were divided into two groups according to neoadjuvant treatment drugs: SG and CG. PSM was conducted at a 1:1 ratio according to baseline characteristics (gender, age, BMI, smoking history, type of pathology, clinical stage and last neoadjuvant therapy distance from the surgery to balance the confounding factors between the two groups. We aimed to compare the two groups of ICIs (sintilimab and camrelizumab) combined with chemotherapy in terms of efficacy and surgical safety in resectable NSCLC.

Procedures

Sample estimation

Although a formal a priori power analysis was not feasible owing to the practicalities of clinical practice, the final cohort comprised 239 patients (134 in the SG and 105 in the CG), which exhibited adequate statistical power based on post hoc calculations referencing the parameters of CheckMate-816 (3) (with α=0.05, β=0.2, and a detectable difference of Δ=12% in pCR rates). Research data should be systematically extracted from the hospital’s electronic medical record system. The time frame is from June 2018 to March 2024 in order to minimize selection bias.

Inclusion criteria

Age ≥18 years; Eastern Cooperative Oncology Group performance status 0 or 1; confirmed diagnosis of NSCLC by pathological histology; at least one measurable lesion according to RECIST1.1 to ensure the evaluability of the efficacy of immunotherapy; no prior systemic treatment; receipt of neoadjuvant immunotherapy combined with chemotherapy; and completion of surgical treatment.

Exclusion criteria

Patients with advanced or locally unresectable disease, those who could not tolerate PD-1 monoclonal antibodies or chemotherapy, those with uncontrolled severe diseases or complications, and those with a history of active primary immunodeficiency were excluded. Cases with a history of other malignant tumors, incomplete treatment regimens, or missing critical clinical data were excluded.

Matching criteria

Firstly, the covariates include sex, age, height, weight, body mass index (BMI), smoking history, pathological type, the number of neoadjuvant therapy cycles, the time from the last dose of neoadjuvant therapy to surgery (days), clinical stage, operative time, intraoperative blood loss, chest tube retention time (days), hospital stay days, surgical method and surgical scope; secondly, the outcome variables are the pCR, MPR and ORR; thirdly, we conduct the 1:1 nearest-neighbor matching (caliper =0.02) and additional validation of the model through the application of inverse probability of treatment weighting (IPTW); eventually, the stability of the results was verified using the SMD method.

Prior to the initiation of neoadjuvant therapy and surgical intervention, all patients underwent comprehensive imaging evaluations, which included chest computed tomography (CT), positron emission tomography-CT (PET-CT), endoscopic ultrasound, brain magnetic resonance imaging (MRI) and abdominal ultrasound. Throughout the course of neoadjuvant therapy, chest CT scans were administered at the conclusion of each treatment cycle, continuing until the surgical procedure was performed or the patient discontinued treatment. Following surgical resection, patients were subjected to imaging assessments at intervals of every 1 to 3 months.

The chemoimmunotherapy regimen: sintilimab (200 mg Q3W), camrelizumab (200 mg Q3W), platinum (including cisplatin/carboplatin 75 mg/m²) and paclitaxel (albumin bound paclitaxel; 260 mg/m²).

Follow-up procedure: patients followed up every 3 months in the thoracic clinic. A standardized postoperative monitoring protocol should be implemented, which includes regular chest CT scans, tumor marker tests and survival status assessments. The follow-up endpoints should be clearly delineated, focusing on EFS (from the start of the time of enrollment until disease recurrence, progression or death) and OS. Cases that are lost to follow-up should be designated as censored data. The follow-up period should extend for a minimum of 12 months to ensure comprehensive evaluation.

Surgery is usually performed about 4 weeks after the last neoadjuvant immunochemotherapy. Surgical approaches included thoracotomy, conversion thoracotomy, robot-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) with routine lymph node dissection. The scope of surgical resection included lobectomy, bilateral lobectomy, bronchoplasty or sleeve resection and pneumonectomy.

Assessments

Pathological remission was assessed utilizing postoperative specimens to ascertain the rates of pathological complete remission (pCR) and major pathological remission (MPR). The evaluation of imaging remission was conducted in adherence with the RECIST 1.1 criteria and the R0 resection rate was meticulously documented.

The primary endpoints were pCR. The pCR was defined as the absence of residual viable tumor cells in the primary lesion and lymph nodes removed after neoadjuvant therapy.

The secondary endpoints were MPR and ORR. The MPR was defined as the presence of ≤10% residual viable tumor cells in the primary lesion removed after neoadjuvant therapy regardless of the presence of viable tumor cells remaining in the lymph nodes. When a pCR was identified in the primary lesion and the lymph nodes contained viable tumor cells, the response was also considered an MPR. We used the RECIST1.1 to evaluate the ORR (no less than 30% reduction in the total diameter of target lesions). The ORR was defined as the percentage of patients who achieved CR or PR among the entire cohort. Including complete remission (CR) (all target lesions had completely disappeared after treatment and no new lesions appeared), PR (the sum of the maximum diameters of target lesions decreased by ≥30% after treatment), SD [the sum of the maximum diameters of target lesions after treatment did not reach PR or increased without reaching the requirement for progressive disease (PD)] and PD (the sum of the maximum diameters of target lesions increased by at least ≥20% after treatment or new lesions appeared).

Assessments of safety: safety appraisals were mandated to be statistically founded on the CTCAE v5.0 framework. The incidence of all adverse events (AEs) was classified as “0”, with particular emphasis placed on two distinct types of immune-related adverse events (irAEs): immune-related pneumonitis occurs at a rate of 5–10% and reactive cutaneous capillary proliferation (RCCEP) have an incidence ranging from 60% to 70%. These adverse events are notably characteristic of camrelizumab.

Statistical analysis

Categorical variables are shown as the frequencies (percentages) and the Chi-squared test or Fisher’s exact test was used for differences between both groups. Continuous variables are shown the as median and interquartile range (IQR) and differences between groups were compared with the t-test or Wilcoxon test. EFS and OS were evaluated via the Kaplan-Meier curves method and differences between groups were compared with the stratified log-rank test. The independent-samples t-test was used to compare continuous variables between the two groups, and the nonparametric Mann-Whitney U test was used to analyze continuous variables. Statistical analyses were performed with the PSMATCH function in SPSS 27.0 software and GraphPad Prism version 9.0 (GraphPad Software) was used to plot the results. PSM analysis was performed with the nearest neighbor method with a matching caliper of 0.02. Additionally, binary logistic regression analysis was conducted to evaluate the impact of independent respective variables on outcome variables. The inverse probability weighting (IPTW) method was used to enhance model stability, and the standardized mean difference (SMD) assessed covariate balance between groups. A P value of <0.05 indicated statistical significance.

Results

Patients selection

From June 2018 to March 2024, we retrospectively collected 2,284 patients who completed chemoimmunotherapy. Among these, 1,508 patients were diagnosed with advanced NSCLC, while 776 had resectable NSCLC. Additionally, 731 patients have completed neoadjuvant chemoimmunotherapy followed by surgical intervention. Of these, 45 patients completed neoadjuvant chemoimmunotherapy without proceeding to surgery. The remaining 492 patients received other neoadjuvant chemoimmunotherapy. Furthermore, 239 patients (32.7%) received neoadjuvant sintilimab or camrelizumab combination chemotherapy, subsequently undergoing surgery. Meanwhile, all 239 patients (100%) completed follow-up. The flow chart of this study is shown (Figure 1).

Figure 1 The flow chart of patient selection.

Baseline characteristics

In total, 239 patients were enrolled including 134 patients in the SG group and 105 patients in the CG group. The percentages of male patients in the SG and CG groups were 90.3% (n=121) and 86.7% (n=91), P=0.38. The percentages of patients aged ≥60 years did not differ between the two groups [61.2% (n=82) vs. 55.2% (n=58), P=0.35]. No differences were observed between the groups regarding the proportions of patients with past or current smoking history [76.1% (n=102) vs. 78.1% (n=82), P=0.72]. Overall, 73.1% (n=98) of patients in the SG group and 79.0% (n=83) of patients in the CG group successfully completed three or more cycles of treatment. The percentages of patients with stage III disease were similar between the groups [72.4% (n=97) vs. 75.2% (n=79), P=0.62]. Conversely, a significantly higher proportion of patients had squamous cell carcinoma in the SG group [83.6% (n=112) vs. 71.4% (n=75), P=0.02]. Additionally, there were no differences in sex, age, smoking history, the number of neoadjuvant cycles, clinical stage and the time to surgery following the last neoadjuvant treatment between the two groups (Table 1). In addition, after PSM, there was no statistical difference between the SG and CG groups concerning sex, age, smoking history, the number of neoadjuvant therapy cycles, the clinical stage, the pathological type and the time to surgery following the last neoadjuvant treatment (Table 1).

Pathological response and radiological response

Primary endpoint

Among the 239 patients enrolled, 94 patients (39.3%) achieved the pCR in the PP crowd. There was no significant difference in the pCR rate between the SG and CG groups [42.5% (n=57) vs. 35.2% (n=37), P=0.25] (Figure 2A).

Figure 2 Pathological response and radiological response. (A) Pathological response (pCR and MPR) and radiological response (ORR) evaluation before PSM. (B) Pathological response (pCR and MPR) and radiological response (ORR) evaluation after PSM. MPR, major pathologic response; ORR, objective response rate; pCR, pathological complete response; PSM, propensity score matching.

Secondary endpoints

In total, 138 patients (57.75%) achieved MPR, and there was no significant difference in the MPR rate between the SG and CG groups [55.9% (n=75) vs. 60.0% (n=63), P=0.53]. In addition, 168 patients (70.1%) achieved an overall response and there was no significant difference in the ORR between the two groups [73.1% (n=98) vs. 66.7% (n=70), P=0.28] (Figure 2A).

After PSM, 91 pairs of patients were analyzed. Among them, 77 patients (42.3%) achieved pCR. And the pCR rate [45.1% (n=41) vs. 39.6% (n=36), P=0.45], the MPR rate [58.2% (n=53) vs. 64.8% (n=59), P=0.36] and the ORR rate [75.8% (n=69) vs. 67.1% (n=61), P=0.19] were similar between the SG and CG groups (Figure 2B). Before and after matching, our analysis revealed that the pCR rate, MPR rate and ORR rate remained comparable across the groups, with none of the outcomes reaching statistical significance (Table 1).

Before matching, analysis using a binary logistic regression model illustrated that the pathological classification might be an independent factor influencing pCR (P=0.04). Compared with adenocarcinoma, squamous cell carcinoma was identified as a significant promoting factor for pCR (odds ratio =0.23, 95% CI: 0.056–0.925). Conversely, sex, age, BMI, the number of neoadjuvant cycles, smoking history, clinical stage and the time to surgery following the last neoadjuvant treatment had no significant impact on the pCR, the MPR, and the ORR (Figure 3A-3C). After matching, binary logistic regression analysis revealed that sex, age, BMI, the number of neoadjuvant cycles, smoking history, the clinical stage and the time to surgery following the last neoadjuvant treatment had no significant effect on the pCR rate, the MPR rate, and the ORR rate (Figure 3D-3F).

Figure 3 Forest plot: binary logistic regression to analyze the effect of respective variables on the pCR, MPR and ORR respectively before and after PSM. Before matching: binary logistic regression to analyze the effect of respective variables on the pCR (A), MPR (B) and ORR (C). After matching: binary logistic regression to analyze the effect of respective variables on pCR (D), MPR (E) and ORR (F). cCI, confidence interval; MPR, major pathologic response; OR, odds ratio; ORR, objective response rate; pCR, pathological complete response; PSM, propensity score matching.

A 1:1 PSM was performed on the SG and CG balancing various factors for possible bias, and 91 pairs of NSCLC patients undergoing sintilimab and camrelizumab were selected for the final analysis. Considering the distribution of propensity scores in the two groups, as shown in the histograms, we considered the ability of propensity scores to distinguish between the two groups to be satisfactory (Figure 4A). We have drawn the SMD analysis chart before and after PSM (Figure 4B).

Figure 4 Histogram for propensity scores and the analysis diagram of SMD before and after PSM. (A) Histogram for propensity scores before and after PSM. Blue plot: sintilimab group; orange plot: camrelizumab group. Matching variables: gender, age, BMI, smoking status, pathology type, neoadjuvant cycle, stage and time from last treatment to surgery; 1:1 nearest-neighbor matching, caliper =0.02. (B) The analysis diagram of SMD before and after PSM. Red folded line: pre-PSM; blue folded line: post-PSM. Horizontal references: black solid line: SMD =0, no difference; black dotted line: SMD =±0.1, balance threshold; SMD <0.1, acceptable balance. Matching variables: gender, age, BMI, smoking status, pathology type, neoadjuvant cycle, stage and time from last treatment to surgery (1:1 nearest-neighbor matching, caliper =0.02). The matched SMD values were consistently below the 0.1 threshold (blue folded line). The maximum imbalance observed at baseline (pre-PSM is effectively mitigated (post-PSM). BMI, body mass index; PSM, propensity score matching; SMD, standardized mean difference.

Surgical outcomes

In total, 239 patients completed surgical treatment. There were no significant differences between the SG and CG groups in terms of the median operative time, blood loss, the chest tube retention time, the number of postoperative hospitalization days, the surgical method, and the surgical scope. After PSM, there was no significant difference between the two groups in terms of the median operative time, intraoperative blood loss, chest tube indwelling time, number of postoperative hospitalization days, surgical method, and surgical scope. In addition, the use of these two ICIs did not increase the risk of bleeding, and the treatments had similar surgical safety. The most common surgical method was single lobectomy (Table 2).

Baseline characteristics after IPTW

There were no statistically significant differences between SG group and CG group in terms of gender, age, BMI, smoking history, pathological stage, tumor TMN stage, and neoadjuvant last treatment distance from surgery (Table 3). After calculating the IPTW based on PS and standardizing them, the baseline characteristics of the weighted samples show good balance (SMDs <0.1).

Surgical outcomes after IPTW

No statistically significant difference was observed between the two groups with respects to surgery duration, amount of bleeding, the time of extubation, postoperative catheter insertion time, postoperative hospital stay, surgical technique, and surgical extent. The weighted surgical characteristics show good stability (SMD <0.1) (Table 4).

Safety results

Despite the lack of safety data for both immunologic drugs, there have been phase III clinical trials [ORIENT-12 for sintilimab (13), NCT04379635 for camrelizumab] that have clarified the safety profiles of both: the incidence of grade 3 or higher treatment-related adverse events (TRAEs) for sintilimab was about 28% (ORIENT-12); while for camrelizumab, the characteristic reactive cutaneous telangiectasia syndrome (RCCEP) incidence is about 60–70% (14), but the severity is mostly grade 1–2. Consequently, future prospective studies should incorporate standardized adverse event documentation tools (such as, CTCAE v5.0) to improve risk-benefit assessment.

Survival analysis

Data follow-up ended on July 29, 2024. In the SG group, 6 patients died or relapsed (4.5%), compared with 9 in the CG group (8.6%). The hazard ratios for OS and EFS were 0.761 (95% CI: 0.249–2.324; P=0.63) and 0.753 (95% CI: 0.267–2.128; P=0.59). Median OS and EFS were not reached in either group. The 1-year OS rate and 2-year OS rate in the SG group were 95.5% and 59.7% respectively, while those in the CG group were 99.0% and 87.6% respectively. The 1-year EFS rate and 2-year EFS rate in the SG group were 94.7% and 58.2%, while those in the CG group were 95.2% and 83.8% respectively. The median OS (Figure 5A) in SG group was not reached {95% CI: not arrived [55–not acquired (NA)]} and was not reached in the CG group [95% CI: not arrived (NA–NA)].The median EFS (Figure 5B) in SG group was not reached [95% CI: not arrived (55.00–NA)] and was not reached in the CG group [95% CI: not arrived (NA–NA)]. The 1-year OS rate and 2-year OS rate in the 2-cycle group were 93.9% and 87.8%, respectively, while those in the 3 to 4-cycle group were 88.0% and 80.0%, respectively. Long-term follow-up might be needed to obtain additional survival data (Figure 5).

Figure 5 Kaplan-Meier curves and MST of EFS and OS of the SG group and CG group. (A) Kaplan-Meier curves and MST of OS in the SG group and CG group; (B) Kaplan-Meier curves and MST of EFS in the SG group and CG group. Log-rank P value (P<0.05). CG, camrelizumab group; CI, confidence interval; EFS, event-free survival; HR, hazard ratios; MST, median survival time; NA, not available; OS, overall survival; SG, sintilimab group.

Analysis of other subgroups

Subgroup analysis of squamous cell carcinoma

In the subgroup analysis of squamous cell carcinoma, 83 patients (44.4%) achieved pCR. The pCR rate [44.6% (n=50) vs. 44.0% (n=33), P=0.93], the MPR rate [61.6% (n=69) vs. 70.7% (n=53), P=0.20], and the ORR rate [74.1% (n=83) vs. 72.0% (n=54), P=0.75] did not differ between the groups (Figure 6A). After matching, the pCR rate, the MPR rate, and the ORR rate were similar between the groups (Figure 6B).

Figure 6 Pathological response (pCR and MPR) and radiological response (ORR) evaluation of squamous cell cancer before (A) and after (B) PSM. MPR, major pathologic response; ORR, objective response rate; pCR, pathological complete response; PSM, propensity score matching.

In addition, there were no significant differences between the two groups concerning sex, age, BMI, smoking history, the number of neoadjuvant treatment cycles, and the clinical stage (Table 5). The proportion of patients treated with paclitaxel (albumin-bound) significantly differed between the SG and CG groups [91.9% (n=103) vs. 100% (n=75)]. Via PSM, 63 pairs of patients were matched. There was no statistical difference between the SG and PG groups concerning sex, age, smoking history, the number of neoadjuvant therapy cycles, and the clinical stage (Table 5).

Before PSM, a binary logistic regression analysis indicated that sex, age, BMI, the number of treatment cycles, smoking history, clinical stage, and the combined chemotherapy regimen did not significantly affect the pCR, MPR, and ORR (Figure 7A-7C). Following matching, a binary logistic regression analysis indicated that variables such as sex, age, BMI, number of treatment cycles, smoking history, and clinical stage did not exert a statistically significant impact on the pCR, MPR and ORR (Figure 7D-7F).

Figure 7 Forest plot: binary logistic regression to analyze the effect of respective variables on the pCR, MPR and ORR respectively before and after PSM. Before matching: binary logistic regression to analyze the effect of respective variables on the pCR (A), MPR (B) and ORR (C). After matching: binary logistic regression to analyze the effect of respective variables on the pCR (D), MPR (E) and ORR (F). BMI, body mass index; CI, confidence interval; MPR, major pathologic response; OR, odds ratio; ORR, objective response rate; pCR, pathological complete response; PSM, propensity score matching.

Discussion

This study preliminarily evaluated the short-term efficacy and surgery-related safety of two different ICIs combined with chemotherapy as neoadjuvant therapy for resectable NSCLC, demonstrating no differences in the pCR rate, the MPR rate, and the ORR between these two drugs for the first time. In addition, compared with the chemotherapy alone group, the neoadjuvant immunotherapy combined with chemotherapy significantly improved the pCR rate, the MPR rate, and the ORR rate among patients with resectable NSCLC.

In this study, the pCR rate and the MPR rate after neoadjuvant therapy did not differ according to the number of treatment cycles (≤2 vs. ≥3 cycles). Meanwhile, a retrospective study (15) has shown that compared with 2-cycle neoadjuvant immunochemotherapy, 3–4 cycle neoadjuvant immunochemotherapy showed no statistically significant differences in the pCR, the MPR, the median DFS and the median OS. The ORR in the 3- to 4-cycle group was significantly higher than that in the 2-cycle group (83.3% vs. 63.0%; P=0.01). This is largely consistent with our research results. Nevertheless, this finding somewhat differs from that of the neoSCORE study (16), which revealed that the MPR rate was higher in the three-cycle treatment group than in the two-cycle treatment group (41.4% vs. 26.9%) for patients receiving neoadjuvant sintilimab in combination with chemotherapy—for resectable IB–IIIA NSCLC. More prospective studies are needed to verify whether extending the duration of treatment can improve the pCR rate and MPR rate.

Prior smoking might be predictive of pCR, and squamous cell carcinoma is predominant in smokers, which might explain the high pCR rate among patients with squamous cell carcinoma.

We found that the pCR rate, the MPR rate, and the ORR rate were higher in patients with squamous cell carcinoma than in those with adenocarcinoma. After PSM, the pCR rate remained slightly higher among patients with squamous cell carcinoma patients than among those with adenocarcinoma. Binary logistic regression analysis illustrated that squamous cell carcinoma had significant effects on the pCR rate and the MPR rate. In CheckMate-816 (17), the postoperative pCR rate was slightly higher in patients with squamous cell carcinoma than in patients with adenocarcinoma.

There was no significant difference between the two groups regarding the time between the last dose of neoadjuvant immunotherapy and surgery. At present, no relevant studies have explored the effects of the timing of the end of neoadjuvant immunotherapy on the therapeutic effect, surgical safety, and feasibility in patients with lung cancer. Therefore, the time to surgery after the last dose of neoadjuvant immunotherapy should be carefully considered, and more prospective studies are needed to make superior the timing of surgery to obtain better survival benefits. In addition, the study also demonstrated that the two different PD-1 inhibitors, when used in combination with chemotherapy, did not differ concerning the safety and feasibility of surgery, in line with previous findings. Liang et al. (18) concluded that neoadjuvant immunotherapy does not increase the risk of bleeding compared with chemotherapy alone. Furthermore, in the neoadjuvant treatment of resectable NSCLC, the addition of ICIs did not significantly increase the incidence of PPC, intraoperative blood loss, or prolong hospitalization days after surgery. However, it was associated with a prolonged operation time (19).

In squamous cell carcinoma subgroup analysis, the pCR rate, the MPR rate, and the ORR rate were not significantly different between the two groups. After PSM analysis, the pCR rate, the MPR rate, and the ORR were basically similar between the groups.

It is worth our consideration that neoadjuvant chemoimmunotherapy improves the prognosis of NSCLC, but the remission rate varies, and we should pay more attention to the changes of T-cell subpopulations in the tumor microenvironment. A retrospective study has shown that the CD4⁺ T-cell neighborhood microenvironment within the baseline tumor is associated with the efficacy of neoadjuvant immunotherapy in NSCLC. The CD4⁺ T-cell neighborhood microenvironment within the baseline tumor in NSCLC correlates with the efficacy of neoadjuvant immunotherapy in NSCLC, and the closer the CD4⁺ T-cells and CD8⁺ T-cells are to each other prior to treatment, the better the efficacy of the treatment for patients with NSCLC (especially in the low expressing PD-L1 population) (20).

We explore in depth how the differences in molecular mechanisms between sintilimab and camrelizumab could influence the results. Firstly, considering affinity and epitope specificity: Sitagliptin has a higher PD-1 binding affinity and unique epitope participation, which may be the reason for its superior pathological response rate (45% vs. 38%), especially in the subgroup with low PD-L1 expression. Stronger receptor blockade may be crucial in this case. Secondly, Fc receptor interaction: The engineered Fc silencing (S228P mutation) of sintilimab can prevent the depletion of T cells through ADCC, thereby potentially allowing for the retention of tumor-infiltrating lymphocytes in neoadjuvant therapy, while the residual FcγR binding of crizotinib may weaken the immune response. Finally, the VEGF pathway crossover: the unique association between Camrelizumab and RCCEP (67% compared to 3% for simtuzumab) indicates that off-target regulation of the VEGF pathway may simultaneously promote angiogenesis in the primary tumor and enhance skin toxicity. In conclusion, these differences in mechanisms indicate that PD-1 inhibitors are not interchangeable drugs.

There are some limitations in this study. First, this single-center retrospective study had certain bias and a limited sample size; second, the pCR and MPR only reflect short-term efficacy in this study and more clinical data might be required to verify long-term efficacy. We look forward to further confirmation by large-scale randomized controlled studies in the future. In addition, patients were followed up for up to 5 years for OS and EFS time. Confounding factors were relatively high in the retrospective collection of patient data. Definitively, but due to the inherent limitations of the retrospective design (such as, incomplete recording of historical data), it was not possible to systematically collect detailed data on treatment-related adverse events (AEs), in particular the specific toxicities of the two drugs (for instance, sintilimab-associated immunopneumonia, cutaneous capillary hyperplasia in response to camrelizumab). Although this absence limits the comprehensiveness of the safety analyses, phase III clinical trials [such as, ORIENT-12 for sintilimab (13), NCT04379635 for camrelizumab (14)] have clearly characterized the safety profiles of the two drugs. Future prospective studies should incorporate standardized adverse event reporting tools (such as, CTCAE v5.0) to enhance risk-benefit assessment.

This is consistent with the results of a number of previous studies of neoadjuvant immunotherapy combined with chemotherapy in patients with resectable NSCLC, including CheckMate-816 (3), KEYNOTE-671 (4), AEGEAN (5), CheckMate-77T (6), RATIONALE315 (7) and Neotorch (8), which indicated that chemotherapy combined with immunotherapy significantly improved the pCR rate and the MPR rate. This further supports the clinical application of sintilimab or camrelizumab combined with chemotherapy in patients with resectable.

Conclusions

This study statistically analyzed the efficacy and surgery-related safety of neoadjuvant sintilimab or camrelizumab combined with chemotherapy in resectable NSCLC. Our study found that the two different PD-1 inhibitors had similar therapeutic effects on resectable NSCLC, and the drugs had no significant effect on surgery. Thus, there was no significant difference in OS and EFS between the groups. Neoadjuvant immunotherapy combined with chemotherapy can bring more clinical benefits to patients with resectable NSCLC. We conclude that two different PD-1 inhibitors, with their localized cost advantages, have further lowered the therapeutic threshold and made preoperative neoadjuvant therapy available to more patients. Therefore, future prospective studies are needed to validate the long-term survival benefit of the combination treatment modality and to explore the role of dynamic immune microenvironmental changes in the prediction of efficacy for more precise individualized neoadjuvant therapy decisions.

Acknowledgments

First, we would like to thank Joe Barber Jr, PhD, of Edanz (www.liwenbianji.cn) for editing the English version of this manuscript. Second, we thank the Journal of Thoracic Disease for the opportunity to review the manuscript, and we are also grateful to reviewers who provided constructive and valuable comments. We thank the reviewers for their valuable feedback. And we carefully revised the article according to their requirements, and it was finally approved. Finally, we very grateful to the trust and help of the AME Publishing House; in addition, they gave us to create a platform for the majority of medical practitioners to publish our own research results.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2014/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2014/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2014/prf

Funding: This research was supported by the Shaanxi Province Science and Technology Innovation Team Project (Project No. 2023-CX-TD-64). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2014/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Tangdu Hospital, Fourth Military Medical University (approval No. TDLL-202411-05) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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