Neoadjuvant Camrelizumab Plus Chemotherapy or Apatinib for Resectable Stage IIA-IIIA NSCLC: A Multicenter, Two-Arm, Phase II Exploratory Trial

Neoadjuvant Camrelizumab Plus Chemotherapy or Apatinib for Resectable Stage IIA-IIIA NSCLC: A Multicenter, Two-Arm, Phase II Exploratory Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neoadjuvant Camrelizumab Plus Chemotherapy or Apatinib for Resectable Stage IIA-IIIA NSCLC: A Multicenter, Two-Arm, Phase II Exploratory Trial Shuyu Ji, Zhenxin Sheng, Dongliang Bian, Minwei Bao, Kaiqi Jin, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5558939/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jul, 2025 Read the published version in BMC Medicine → Version 1 posted 15 You are reading this latest preprint version Abstract Background This study aimed to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 antibody, combined with either chemotherapy or apatinib, a VEGFR-2 inhibitor, as neoadjuvant treatment for stage IIA-IIIA NSCLC. Methods This prospective, multicenter, dual-arm, non-randomized phase II trial enrolled participants from four hospitals in China between September 2020 and March 2022. Patients received 2–4 cycles of neoadjuvant treatment followed by surgery. Arm-AR (n = 28) included patients treated with camrelizumab (200 mg every three weeks) plus platinum-based chemotherapy, regardless of PD-L1 status. Arm-BR (n = 10) included PD-L1-positive patients treated with camrelizumab (200 mg every three weeks) plus apatinib (250 mg daily). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, objective response rate (ORR), disease control rate (DCR), event-free survival (EFS), overall survival (OS), and safety profiles. Results In the ITT population, MPR rates were 25.0% (95% CI 10.7–44.9) in arm-AR and 60.0% (95% CI 26.2–87.8) in arm-BR. The 24-month EFS rates were 53.6% and 70.0%, respectively, after a median follow-up of 30.5 months. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 25% of arm-AR patients and 10% of arm-BR patients. Conclusions Camrelizumab combined with platinum-based chemotherapy demonstrated promising efficacy and tolerability for resectable IIA-IIIA NSCLC, regardless of PD-L1 status. In PD-L1-positive patients, camrelizumab plus apatinib showed improved safety and effectiveness, highlighting a potential treatment option for this subgroup. Trial registration: NCT04379739, initiated on July 26, 2020. Non-small-cell lung cancer Neoadjuvant Camrelizumab Apatinib Major pathologic response Figures Figure 1 Figure 2 Background Lung cancer is the most prevalent malignant tumor worldwide, with approximately 2.48 million new cases and 1.81 million deaths in 2022 [ 1 – 3 ]. Of these, non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, with adenocarcinoma, squamous cell carcinoma, and large cell carcinoma being the predominant subtypes. For NSCLC in early stage, surgery remains the most effective treatment, however, 30–77% of patients in stage II-III experience recurrence postoperatively [ 4 , 5 ]. For resectable NSCLC, the results of several randomized phase III trials (CheckMate 816, KEYNOTE-671, and Neotorch) demonstrate the feasibility of neoadjuvant immunochemotherapy [ 6 – 8 ], which could significantly improve the efficacy compared to neoadjuvant chemotherapy. Thus, several immunotherapy agents have been approved for the perioperative treatment of resectable NSCLC. Nevertheless, previous trials demonstrated that, for PD-L1 (an immune checkpoint protein mediating immune escape) highly expressed advanced NSCLC, patients received PD-1 mono-immunotherapy probably had similar therapeutic efficacy to those who received chemo-immunotherapy[ 9 , 10 ]. Therefore, the neoadjuvant chemotherapy-free regimens have also gained sustained attention in the fields of thoracic surgery and oncology. The published results in this trial demonstrated the efficacy and safety of neoadjuvant camrelizumab, a humanized high-affinity IgG4-kappa anti-PD-1 monoclonal antibody, combined with chemotherapy or apatinib, a tyrosine kinase inhibitor targeting VEGFR-2, for initially unresectable cohort [ 3 ]. Our phase II umbrella clinical trial in unresectable stage III NSCLC also confirmed this finding [ 11 ]. These findings were further corroborated by the EAST ENERGY trial (NCT04040361), in which the combination of pembrolizumab (PD-1 inhibitor)) and ramucirumab (VEGFR-2 inhibitor) achieved a 66.7% MPR rate in PD-L1-positive resectable NSCLC [ 12 ]. Mechanistically, the synergy between PD‑1 and VEGFR‑2 inhibitors stems from VEGF/VEGFR‑2 blockade–induced vascular normalization, which enhances T cell infiltration, augments dendritic cell activation, and suppresses regulatory T cell mediated immunosuppression [ 13 , 14 ]. To further explore the potential of neoadjuvant immunotherapy combination regimens, this multicenter, phase II trial evaluates the efficacy and safety of camrelizumab in combination with either platinum-based chemotherapy (arm-AR) or apatinib (arm-BR) as neoadjuvant treatments for patients with resectable stage IIA-IIIA NSCLC [ 15 , 16 ]. Methods Study Design This study is a prospective, multicenter, dual-arm, non-randomized, phase II exploratory trial conducted in China (NCT04379739). The trial was rigorously designed in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines, receiving ethical approval from the institutional review boards of all participating centers. Prior to enrollment, all patients provided written informed consent. The inclusion criteria for patients were: aged between 18 and 75 years old; histologically or cytologically confirmed, untreated stage II-III NSCLC (based on the eighth edition of the American Joint Committee on Cancer TNM staging system for lung cancer); an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; measurable lesions according to RECIST criteria version 1.1; and adequate functional reserve of key organs. arm-AR included all patients with any level of PD-L1 expression. arm-BR included patients exhibiting a baseline PD-L1 expression of 1% or greater, provided that they had no uncontrolled hypertension, no history of thrombotic events, and no significant bleeding tendencies. Key exclusion criteria for both arms included: known mutations in EGFR or ALK ; a history of autoimmune diseases; a history of other malignancies within the past five years; or prior receipt of systemic corticosteroid therapy (> 10 mg/day prednisone equivalent) or other immunosuppressive agents within 2 weeks preceding study initiation. Patients with tumors deemed initially unresectable were also excluded, based on assessments from a multidisciplinary clinical team (MDT). These unresectable cases were characterized by: (1) tumor invading vital structures, such as large blood vessels, the trachea or primary bronchus, but curative resection after tumor downgrading by neoadjuvant therapy was possible as judged by a preoperative assessment; (2) clinically confirmed lymph nodes with multistation metastasis or bulky fusion, and patients could tolerate hilar and mediastinal lymph node dissection after tumor downgrading by neoadjuvant therapy as determined by a preoperative evaluation, or (3) according to preoperative evaluation, even if pneumonectomy was performed, especially right pneumonectomy, R0 resection may not be achieved. Procedures All participants received predefined neoadjuvant therapy and were included in the ITT population. Both arm-AR and arm-BR underwent 2 to 4 cycles of camrelizumab-based treatment (200mg/3 weeks) : arm-AR combined with chemotherapy, and arm-BR with apatinib (250 mg daily). For those diagnosed with squamous NSCLC, the chemotherapy regimen comprised carboplatin (AUC 5 on day 1) alongside gemcitabine (1000 mg/m² on days 1 and 8), or alternatively paclitaxel (135–175 mg/m²), or nab-paclitaxel (260 mg/m²), all administered on day 1. In contrast, patients with non-squamous NSCLC were treated with carboplatin (AUC 5 on day 1) in combination with pemetrexed (500 mg/m² on day 1). For the assessment of surgical candidacy, patients who have completed two to four treatment cycles underwent a contrast-enhanced computed tomography (CT) scan of the chest. In cases where the tumor met the criteria for complete response (CR), partial response (PR) or stable disease (SD) as defined by RECIST version 1.1, the MDT conducted a further evaluation to determine surgical suitability. Assessment criteria include tumor location, extent of tumor invasion, lymph node status, and the patient's overall systemic condition. Surgery for eligible patients was anticipated to occur within 30 days following tumor evaluation. The pathological response will be evaluated as previously described. Postoperatively, patients underwent a chest CT scan 30 days after surgery, followed by CT examinations every three months during the first two years and every six months from the third to fifth years. Throughout the entire trial period, AEs were rigorously monitored and systematically graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Furthermore, the baseline PD-L1 tumor proportion score was quantitatively assessed using the 22C3 pharmDx assay (Agilent Technologies, CA, USA). Decisions regarding postoperative adjuvant therapy were individually tailored by a multidisciplinary team based on comprehensive postoperative pathological characteristics (including ypTNM stage and tumor regression grade), ECOG performance status, and organ functional reserve. Endpoints The primary endpoint was the MPR rate, defined as the percentage of patients with ≤ 10% viable tumor cells after resection. Secondary endpoints included the pCR rate (no viable tumor cells post-resection) and ORR (patients achieving CR or PR per RECIST 1.1). EFS was tracked from the start of neoadjuvant therapy to disease progression, recurrence, or death. Additionally, OS (time from therapy initiation to death), R0 resection rate (negative margins), and safety profiles were assessed. Statistical analysis Sample size calculations using R's clinfun package determined: 1) Arm-AR (n = 28) required to detect MPR improvement from 8.9% (historical control) to 30%; 2) Arm-BR (n = 10) to distinguish 8.9% vs 45% MPR rates, both with one-sided α = 0.05 and 80% power [ 3 , 6 ]. The response-related endpoints were assessed in the efficacy analysis population, which encompassed all patients who had received at least one dose of neoadjuvant therapy and subsequently underwent surgery. In contrast, analyses pertaining to survival and safety were conducted within the full analysis population, comprising all patients who had received at least one dose of neoadjuvant therapy. The 95% CIs for metrics such as MPR rate, pCR rate, ORR, and R0 resection rate were derived using the binom package, following the Clopper-Pearson method. Survival curves were fitted using the survival package, employing the Kaplan-Meier method, and 95% CIs were calculated using the log-log method to ensure robust estimates, particularly at the tails of the survival curves. TRAEs were reported as frequencies (percentages). Additionally, post-hoc analyses investigated EFS and OS by stratifying patients based on whether they had undergone surgery. All statistical analyses were conducted using R version 4.2.3. Results Patients Between September 11, 2020, and March 14, 2022, the MA-NSCLC-II-001 Study enrolled 89 participants: 51 initially unresectable and 38 resectable patients. The findings for the initially unresectable cohort have already been published[ 3 ]. Among the resectable patients, arm-AR and arm-BR enrolled 28 and 10 participants, respectively (Fig. 1) . Baseline characteristics for both groups were detailed in Table 1 . In arm-AR, the median diagnostic age was 65 (range, 62.8–69.0). The majority of participants in arm-AR were male (92.9%, 26/28), diagnosed with squamous cell carcinoma (LUSQ) (67.9%, 19/28), had an ECOG PS score of 0 (78.6%, 22/28), were categorized as clinical stage IIIA (64.3%, 18/28), and had PD-L1 expression < 1% or unknown (60.7%, 17/28). In arm-BR, the median diagnostic age was 67.5 (range, 66.0–69.8). Male, LUSQ (90%, 9/10), ECOG PS of 0 (60%, 6/10), and stage IIIA (70%, 7/10) participants accounted for the majority. Table 1. Baseline characteristics of patients with resectable NSCLC in Arm-AR and Arm-BR Characteristics Arm-AR (n = 28) Arm-BR (n = 10) Age (median [IQR]) 65.00 [62.8, 69.0] 67.50 [66.0, 69.8] Sex (%) Male 26 (92.9) 9 (90.0) Female 2 (7.1) 1 (10.0) ECOG performance status, n (%) 0 22 (78.6) 4 (40.0) 1 6 (21.4) 6 (60.0) Smoking, n (%) Former/Current smoker 20 (71.4) 9 (90.0) Non-smoker 8 (28.6) 1 (10.0) Clinical stage (%) IIA 1 (3.6) 0 (0.0) IIB 9 (32.1) 3 (30.0) IIIA 18 (64.3) 7 (70.0) Clinical nodal status, n (%) N0 8 (28.6) 2 (20.0) N1 12 (42.9) 4 (40.0) N2 8 (28.6) 4 (40.0) Histological type, n (%) Squamous cell carcinoma 19 (67.9) 8 (80.0) Non-squamous cell carcinoma 9 (32.1) 2 (20.0) PD-L1 expression , n (%) <1% 6 (21.4) 0 (0.0) 1% - 49% 5 (17.9) 7 (70.0) ≥50% 6 (21.4) 3 (30.0) Unknown 11 (39.3) 0 (0.0) Abbreviations: IQR, Interquartile Range; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1. Efficacy In the ITT patients of arm-AR, 25% (7/28, 95% CI 10.7–44.9) of patients achieved MPR, 17.9% (5/28, 95% CI 6.1–36.9) achieved pCR, and 67.9% had an ORR, while 85.7% had DCR. The proportion of CR, PR, and SD was 7.1%, 60.7%, and 17.9%, respectively (Table 2) . In arm-BR, the MPR and pCR rate were 60.0% and 10.0% respectively. The ORR and DCR were 70.0% and 90.0%, respectively (Table 2) . Pathological downstaging rates reached 77.3% (17/22) in arm-AR and 88.9% (8/9) in arm-BR (Supplementary Table 1) . The low response rates were linked to the predominance of stage IIIA in both arms and low PD-L1 expression in most arm-AR patients. Furthermore, 6 patients and 1 patient did not undergo surgery in arm-AR and arm-BR, respectively. Among patients undergoing surgery, the MPR, pCR, and ORR for arm-AR were 31.8% (7/22, 95% CI 13.9-54.9), 22.7% (5/22, 95% CI 7.8-45.4), and 81.8% (18/22, 95%CI 59.7-94.8), respectively. In arm-BR, these rates were 66.7% (6/9, 95% CI 29.9-92.5), 11.1% (1/9, 95% CI 0.3-48.2), and 77.8% (7/9, 95% CI 40-97.2), respectively ( Supplementary Table 1 and Supplementary Figure 1) . A correlative analysis was conducted between MPR and clinicopathologic variables within surgical cohorts. In arm-AR (n=22), numerical trends indicated a higher prevalence of PD-L1 expression ≥50% (42.9% vs. 20.0%, p=0.350) and squamous cell carcinoma predominance (85.7% vs. 60.0%, p=0.350) in the MPR group (Supplementary Table 2) . In arm-BR (n=9), the MPR group exhibited a greater frequency of N2 nodal involvement (50.0% vs. 0%, p=0.143) and stage IIIA disease (83.3% vs. 33.3%, p=0.226) (Supplementary Table 3) . By November 8, 2024, with a median follow-up of 30.5 months, the median EFS of arm-AR and arm-BR was 24.8 months (95% CI 12.1-NR) and 28.7 months (95% CI 2.4-NR). The 12-month/24-month EFS of arm-AR and arm-BR was 71.4%/53.6% and 70.0%/70.0% ( Figure 2a-b ). Patients achieving pathological downstaging showed higher 24-month EFS (67.4% vs 33.3%, p=0.068) (Supplementary Figure 2) . Additionally, there were 15 deaths in arm-AR and 3 in arm-BR. The median OS of arm-AR and arm-BR was 38.3 months (95% CI 21.7-NR) and NR. The 12-month/24-month OS of arm-AR and arm-BR was 89.3%/67.9% and 80.0%/70.0% ( Figure 2c-d ). Table 2. Response rates in intention-to-treat patients treated with neoadjuvant camrelizumab-based regimens Efficacy outcomes Arm-AR (n = 28) Arm-BR (n = 10) Pathological response, n (%, 95% CI) Major pathological response 7 (25.0, 10.7-44.9) 6 (60.0, 26.2-87.8) Pathological complete response 5 (17.9, 6.1-36.9) 1 (10.0, 0.3-44.5) Best overall response , n (%) Complete response 2 (7.1) 0 (0.0) Partial response 17 (60.7) 7 (70.0) Stable disease 5 (17.9) 2 (20.0) Progressive Disease 1 (3.6) 0 (0.0) Not evaluable 3 (10.7) 1 (10.0) Objective response rate, % ( 95% CI) 67.9 (47.6-84.1) 70.0 (34.8-93.3) Abbreviations: CI, Confidence Interval. Safety In arm-AR, TRAEs were observed in 78.6% (22/28) participants. Grade 3/4 TRAEs occurred in 6 participants with cases of neutropenia (10.7%), anemia (7.1%), and renal insufficiency (7.1%). One patient experienced a grade 5 TRAE with bone marrow suppression and immune myocarditis (Table 3) . Additionally, 8 participants experienced immune-related adverse events (irAEs). The most common cases were reactive cutaneous capillary endothelial proliferation (10.7%, 3/28) and elevated gamma-glutamyl transferase (10.7%, 3/28) (Supplementary Table 4) . In arm-BR, all patients experienced TRAEs, with only one (10%) participant experiencing grade 3 hypertension. No grade 4 or 5 events were observed (Table 3) . Additionally, irAEs were observed in 2 (20%) participants (Supplementary Table 4) . There were 3 (10.7%) participants in arm-AR who did not complete the pre-specified treatment, due to adverse events such as hyponatremia, hemoptysis, and immune myocarditis. Conversely, only one patient in arm-BR withdrew the informed consent and did not complete the pre-specified treatment. Table 3. Treatment-related adverse events (TRAEs) in patients receiving neoadjuvant camrelizumab-based regimens Events, n (%) * Arm-AR (n = 28) Arm-BR (n = 10) Any grade Grade ≥3 Any grade Grade ≥3 Any 22 (78.6) 7 (25.0) 10 (100.0) 1 (10.0) Anemia 9 (32.1) 2 (7.1) 1 (10.0) 0 (0.0) Neutrophil count decreased 7 (25.0) 3 (10.7) 1 (10.0) 0 (0.0) White blood cell count decreased 7 (25.0) 1 (3.6) 1 (10.0) 0 (0.0) Gamma glutamyl transferase increased 6 (21.4) 0 (0.0) 2 (20.0) 0 (0.0) Platelet count decreased 4 (14.3) 0 (0.0) 2 (20.0) 0 (0.0) Alanine aminotransferase increased 3 (10.7) 0 (0.0) 2 (20.0) 0 (0.0) Reactive capillary endothelial hyperplasia 3 (10.7) 0 (0.0) 1 (10.0) 0 (0.0) Blood glucose increased 0 (0.0) 0 (0.0) 2 (20.0) 0 (0.0) Alkaline phosphatase increased 1 (3.6) 0 (0.0) 1 (10.0) 0 (0.0) Aspartate aminotransferase increased 0 (0.0) 0 (0.0) 2 (20.0) 0 (0.0) Proteinuria 1 (3.6) 0 (0.0) 2 (20.0) 0 (0.0) Renal insufficiency 2 (7.1) 2 (7.1) 0 (0.0) 0 (0.0) Hypohepatia 1 (3.6) 1 (3.6) 0 (0.0) 0 (0.0) Bone marrow suppression 1 (3.6) 1 (3.6) 0 (0.0) 0 (0.0) Autoimmune myocarditis 1 (3.6) 1 (3.6) 0 (0.0) 0 (0.0) Hyponatremia 1 (3.6) 1 (3.6) 0 (0.0) 0 (0.0) Hypertension 0 (0.0) 0 (0.0) 1 (10.0) 1 (10.0) *Data presented for treatment-related adverse events (TRAEs) occurring in at least 5% of patients, or any TRAEs of grade 3 or above in either arm. Surgery In arm-AR, the surgical rate and R0 resection rate were 78.6% (22/28) and 95.5% (21/22), respectively, while in arm-BR, these rates were 90% (9/10) and 100% (9/9) (Supplementary Table 5) . Video-assisted thoracoscopic surgery (VATS) was the most common approach in both arms, with 72.7% (16/22) in arm-AR and 66.7% (6/9) in arm-BR. Lobectomy was the most frequent procedure, accounting for 72.7% (16/22) in arm-AR and 55.6% (5/9) in arm-BR (Supplementary Table 5 and Supplementary Figure 3) . Among the six non-surgically treated patients in arm-AR, two withdrew informed consent, two experienced grade ≥3 TRAEs (immune myocarditis and chemotherapy-induced nephrotoxicity), one had disease progression, and one died from tumor-related hemoptysis. In arm-BR, only one patient did not receive surgery after withdrawing the informed consent. Furthermore, two surgically treated patients (9.1%) in arm-AR experienced postoperative complications, including pulmonary embolism and bleeding. No postoperative complications occurred in arm-BR, and no deaths were reported within 90 days after surgery in either arm. Discussion This multicenter, two-arm, phase II trial met its primary endpoint, with 25.0% (7/28) of patients in arm-AR and 60% (6/10) in arm-BR achieving MPR. The pCR rates were 17.9% (5/28) for arm-AR and 10% (1/10) for arm-BR. Compared to historical controls from neoadjuvant chemotherapy (CheckMate 816's chemotherapy arm: MPR 8.9%, pCR 2.2%) [6] and neoadjuvant immunotherapy monotherapy (LCMC3: MPR 20.0%, pCR 6.0%) [17], the arm-AR regimen appeared to show improved efficacy in unselected PD-L1 populations. Additionally, the pCR rate of the arm-AR regimen (17.9%) approached that of the KEYNOTE-671's pembrolizumab-chemotherapy combination (18.0%) [18]. In PD-L1-positive subgroups, arm-BR achieved a 60.0% MPR rate, tripling LCMC3's immunotherapy-alone results and doubling KEYNOTE-671's chemo-immunotherapy outcomes. This aligns with Jun Zhao's camrelizumab-apatinib study (MPR 47% [19]). Across both arms, most camrelizumab-related AEs were mild (Grade 1/2), predominantly reactive cutaneous capillary endothelial proliferation, echoing results from camrelizumab-based therapies [20-23]. The safety profiles of both regimens support their clinical utility. Arm-AR showed a lower incidence of grade ≥3 TRAEs at 25.0%, compared with 33.5% in the nivolumab-chemotherapy arm of CheckMate 816 [6]. Additionally, immune-related adverse events were more manageable in arm-AR (28.6% vs. 41% in the atezolizumab monotherapy arm of LCMC3 [17]). Arm-BR exhibited minimal severe toxicities, with only 10% of patients experiencing grade ≥3 TRAEs and no grade ≥4 irAEs, outperforming other chemotherapy-free regimens such as SHR-1701 (PD-L1/TGF-β bifunctional antibody) monotherapy, which reported 40% grade ≥3 TRAEs [24]. In preceding research, we also investigated the efficacy and safety profile of neoadjuvant camrelizumab in combination with chemotherapy and apatinib in patients initially unresectable [3]. The MPR and pCR rates for arm-AuR (unresectable arm A) were both 10.0% (3/30). In contrast, arm-BuR (unresectable arm B) showed an MPR rate of 23.8% (5/21) and a pCR rate of 4.8% (1/21). These results suggest that both treatment regimens offer promising efficacy with a manageable safety profile [25, 26]. Building on the predominant use of neoadjuvant immunotherapy for resectable tumors, we broadened the study to encompass patients with initially operable disease. Within this same framework, a total of 58 patients were enrolled in arm-A (mixed resectable/unresectable arm-A) and 31 in arm-B (mixed resectable/unresectable arm-B). The MPR rates were 17.2% (10/58) for arm-A and 35.5% (11/31) for arm-B, while pCR rates were 13.8% (8/58) and 6.5% (2/31). The ORR was 46.6% (27/58) in arm-A and 45.2% (14/31) in arm-B, with surgery rates of 63.8% (37/58) in arm-A and 58.1% (18/31) in arm-B. This study extends our previous findings in patients with unresectable NSCLC by assessing the safety and efficacy of camrelizumab in combination with chemotherapy or apatinib in patients with resectable stage IIA-IIIA disease. Furthermore, a prospective single-arm, single-center study investigating neoadjuvant camrelizumab combined with apatinib produced results analogous to those of arm-BR in our study, reporting MPR and pCR rates of 57% and 23%, respectively [27]. Notably, our arm-BR cohort demonstrated overlapping efficacy ranges with Jun Zhao et al.'s study in MPR (60.0% vs 47%, 95%CI overlap) and pCR (10.0% vs 19.2%, CI overlap) , while exhibiting a higher surgical conversion rate (90% vs 83%) and consistent biomarker correlations (PD-L1-high subgroup MPR: 100% vs 90%). These findings collectively suggest that both neoadjuvant chemoimmunotherapy and neoadjuvant immunotherapy combined with anti-angiogenic therapy offer viable and effective treatment options for patients with resectable NSCLC. Particularly, the latter, as a chemotherapy-free regimen, holds promise as a valuable alternative for patients who are either unable to tolerate chemotherapy or are apprehensive about its adverse effects. The predictive role of PD-L1 expression levels in the efficacy of ICIs combined with anti-angiogenic agents remains debated. While PD-L1 status lacks predictive value in advanced solid tumors [28-30], some evidence in neoadjuvant settings suggests a correlation between higher PD-L1 levels and MPR [23, 27]. This supports selecting patients with PD-L1 expression ≥1% for arm-BR. Specifically, the HARMONi-5 study and findings by Zhaojun et al. demonstrated that NSCLC patients with PD-L1≥1% achieved significantly higher major pathological and objective response rates with immunotherapy–antiangiogenic therapy than those with lower PD-L1 levels [27, 31]. This study has several limitations. Primarily, due to its exploratory design, the sample size was relatively small, particularly the limited sample size in arm-BR, which may constrain the generalizability of conclusions derived from this group. The lack of a randomization or control group, which limits the ability to make definitive claims about the superiority of one regimen over another. Although no statistically significant differences in MPR rates were observed between chemotherapy groups, the heterogeneity inherent in the AR chemotherapy regimen remains a critical consideration. Additionally, imbalances in baseline characteristics between the two arms may introduce selection bias. Conclusion In synthesis, for patients diagnosed with resectable stage IIA-IIIA NSCLC, regardless of PD-L1 expression, the neoadjuvant administration of camrelizumab in combination with platinum-based doublet chemotherapy has preliminarily shown promising efficacy and manageable toxicity. Furthermore, the treatment strategy of camrelizumab combined with apatinib has also been demonstrated to be effective and safe for PD-L1-positive patients with stage IIA-IIIA NSCLC. Declarations Conflict of interest statement All authors affirm the absence of any conflicts of interest. Author contribution statement P.Z., Y.Z., H.W., N.S. and B.Q. conceived and designed the study. S.J., Z.S., D.B. and M.B. provided the materials and patients support. M.B., W.Z. and K.J. provided the administrative support. Z.S., D.B., X.Z., F.S., H.X., H.Z., Z.S., H.Y., L.Z. and J.H. collected the data. S.J., Z.S., D.B., and Z.S. analyzed and interpreted the data. S.J., Z.S. and D.B. wrote the draft of the manuscript. All authors approved the final version of the manuscript for submission. Funding statement This study was funded by the National Natural Science Foundation of China ( No. 82125001), the Innovation Program of the Shanghai Municipal Education Commission ( No. 2023ZKZD33), the Shanghai Pulmonary Hospital Fund (No. FKLY20004 and FKCX2304), and the Beijing Xisike Clinical Oncology Research Foundation (No. Y-HR2019-0451), alongside support from Jiangsu Hengrui Pharmaceuticals Co., Ltd. We extend our sincere appreciation to all participants, whose invaluable contributions were instrumental in ensuring the successful completion of this research. Author Contribution P.Z., Y.Z., H.W., N.S. and B.Q. conceived and designed the study. S.J., Z.S., D.B. and M.B. provided the materials and patients support. M.B., W.Z. and K.J. provided the administrative support. Z.S., D.B., X.Z., F.S., H.X., H.Z., Z.S., H.Y., L.Z. and J.H. collected the data. 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Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y et al : Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial . Lancet Respir Med 2021, 9 (3):305-314. Provencio M, Nadal E, González-Larriba JL, Martínez-Martí A, Bernabé R, Bosch-Barrera J, Casal-Rubio J, Calvo V, Insa A, Ponce S et al : Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer . N Engl J Med 2023, 389 (6):504-513. Chaft JE, Oezkan F, Kris MG, Bunn PA, Wistuba, II, Kwiatkowski DJ, Owen DH, Tang Y, Johnson BE, Lee JM et al : Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial . Nat Med 2022, 28 (10):2155-2161. Spicer JD, Garassino MC, Wakelee H, Liberman M, Kato T, Tsuboi M, Lee SH, Chen KN, Dooms C, Majem M et al : Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet 2024, 404 (10459):1240-1252. Chailangkarn T, Teeravechyan S, Attasombat K, Thaweerattanasinp T, Sunchatawirul K, Suwanwattana P, Pongpirul K, Jongkaewwattana A: Monkeypox virus productively infects human induced pluripotent stem cell-derived astrocytes and neural progenitor cells . J Infect 2022, 85 (6):702-769. Ren S, Chen J, Xu X, Jiang T, Cheng Y, Chen G, Pan Y, Fang Y, Wang Q, Huang Y et al : Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial . J Thorac Oncol 2022, 17 (4):544-557. Lei J, Zhao J, Gong L, Ni Y, Zhou Y, Tian F, Liu H, Gu Z, Huang L, Lu Q et al : Neoadjuvant Camrelizumab Plus Platinum-Based Chemotherapy vs Chemotherapy Alone for Chinese Patients With Resectable Stage IIIA or IIIB (T3N2) Non-Small Cell Lung Cancer: The TD-FOREKNOW Randomized Clinical Trial . JAMA Oncol 2023, 9 (10):1348-1355. Liu J, Li J, Lin W, Shao D, Depypere L, Zhang Z, Li Z, Cui F, Du Z, Zeng Y et al : Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, phase 2 study . Int J Cancer 2022, 151 (1):128-137. Ju WT, Xia RH, Zhu DW, Dou SJ, Zhu GP, Dong MJ, Wang LZ, Sun Q, Zhao TC, Zhou ZH et al : A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma . Nat Commun 2022, 13 (1):5378. Zhou Q, Pan Y, Yang X, Zhao Y, Han G, Pang Q, Zhang Z, Wang Q, Yao J, Wang H et al : Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial . Cancer Cell 2024, 42 (7):1258-1267.e1252. Tan WL, Chua KLM, Lin CC, Lee VHF, Tho LM, Chan AW, Ho GF, Reungwetwattana T, Yang JC, Kim DW et al : Asian Thoracic Oncology Research Group Expert Consensus Statement on Optimal Management of Stage III NSCLC . J Thorac Oncol 2020, 15 (3):324-343. Desai AP, Adashek JJ, Reuss JE, West HJ, Mansfield AS: Perioperative Immune Checkpoint Inhibition in Early-Stage Non-Small Cell Lung Cancer: A Review . JAMA Oncol 2023, 9 (1):135-142. Zhao J, Zhao L, Guo W, Wang S, Tao X, Li L, Mao Y, Tan F, Gao Y, Wu N et al : Efficacy, Safety, and Biomarker Analysis of Neoadjuvant Camrelizumab and Apatinib in Patients With Resectable NSCLC: A Phase 2 Clinical Trial . J Thorac Oncol 2023, 18 (6):780-791. Lan C, Shen J, Wang Y, Li J, Liu Z, He M, Cao X, Ling J, Huang J, Zheng M et al : Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial . J Clin Oncol 2020, 38 (34):4095-4106. Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, Shao G, Zhang Y, Xu L, Yin T et al : Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial . Clin Cancer Res 2021, 27 (4):1003-1011. Meng X, Wu T, Hong Y, Fan Q, Ren Z, Guo Y, Yang X, Shi P, Yang J, Yin X et al : Camrelizumab plus apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma (CAP 02): a single-arm, open-label, phase 2 trial . Lancet Gastroenterol Hepatol 2022, 7 (3):245-253. Wang L, Luo Y, Ren S, Zhang Z, Xiong A, Su C, Zhou J, Yu X, Hu Y, Zhang X et al : A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC . J Thorac Oncol 2024, 19 (3):465-475. Additional Declarations No competing interests reported. Supplementary Files SupplementaryProtocol.pdf SupplementaryTables.docx SupplementaryFigure1.pdf SupplementaryFigure2.pdf SupplementaryFigure3.pdf Cite Share Download PDF Status: Published Journal Publication published 18 Jul, 2025 Read the published version in BMC Medicine → Version 1 posted Editorial decision: Revision requested 02 Jun, 2025 Reviews received at journal 30 May, 2025 Reviews received at journal 29 Apr, 2025 Reviewers agreed at journal 17 Apr, 2025 Reviews received at journal 16 Apr, 2025 Reviewers agreed at journal 16 Apr, 2025 Reviewers agreed at journal 16 Apr, 2025 Reviews received at journal 15 Apr, 2025 Reviewers agreed at journal 15 Apr, 2025 Reviews received at journal 14 Apr, 2025 Reviewers agreed at journal 14 Apr, 2025 Editor assigned by journal 14 Apr, 2025 Reviewers invited by journal 14 Apr, 2025 Submission checks completed at journal 14 Apr, 2025 First submitted to journal 12 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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This phase II trial evaluated neoadjuvant camrelizumab\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(anti-PD-1) combined with chemotherapy (arms AR/AuR) or apatinib (VEGFR-2 inhibitor; arms BR/BuR) in resectable (n=38) and initially unresectable (n=51) NSCLC. Arm-AR, resectable arm A; Arm-BR, resectable arm B; Arm-AuR, unresectable arm A; Arm-BuR, unresectable arm B.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/a2b8dc36e54afcda5f0b472b.jpg"},{"id":80784027,"identity":"c9e1e68a-0300-41db-9698-583bbec7a363","added_by":"auto","created_at":"2025-04-17 05:32:45","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135724,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEFS and OS Outcomes in Resectable NSCLC Patients Treated with Neoadjuvant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCamrelizumab-Based Regimens. Kaplan-Meier curves illustrate EFS (left panels) and OS (right panels) for patients receiving camrelizumab combined with chemotherapy (Arm-AR, panels a and c) or apatinib (Arm-BR, panels b and d). EFS, Event-free survival; OS, overall survival.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/98de198371d01b1b854d91e4.jpg"},{"id":88506085,"identity":"3cb3cd1f-88c4-4b85-919e-c505cbf0543c","added_by":"auto","created_at":"2025-08-07 07:30:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3180939,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/81fe4f85-714b-477e-9a16-0887ce09c502.pdf"},{"id":80784029,"identity":"7156ca3c-cb93-4620-b926-d4b70403cd35","added_by":"auto","created_at":"2025-04-17 05:32:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":824370,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryProtocol.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/b180c803b60d148359ca5c84.pdf"},{"id":80785366,"identity":"113a4a75-e159-4194-a01b-94f552b7bf56","added_by":"auto","created_at":"2025-04-17 05:40:45","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":27888,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/0f014f502adf3363bd393c34.docx"},{"id":80785373,"identity":"a278eaf7-b421-4808-86d5-9e10090adcc9","added_by":"auto","created_at":"2025-04-17 05:40:45","extension":"pdf","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":290439,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/476757234ab4a306d0f13be6.pdf"},{"id":80785371,"identity":"ae953a8e-376a-43a7-8024-f0235be8426b","added_by":"auto","created_at":"2025-04-17 05:40:45","extension":"pdf","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":238047,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/6adc9b3d286284f25ff7bac8.pdf"},{"id":80784038,"identity":"f5ed4644-9f0d-428d-8b33-a523a101acc4","added_by":"auto","created_at":"2025-04-17 05:32:45","extension":"pdf","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":225891,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5558939/v1/c6c724536037bcb56d10f77f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neoadjuvant Camrelizumab Plus Chemotherapy or Apatinib for Resectable Stage IIA-IIIA NSCLC: A Multicenter, Two-Arm, Phase II Exploratory Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eLung cancer is the most prevalent malignant tumor worldwide, with approximately 2.48\u0026nbsp;million new cases and 1.81\u0026nbsp;million deaths in 2022 [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Of these, non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, with adenocarcinoma, squamous cell carcinoma, and large cell carcinoma being the predominant subtypes. For NSCLC in early stage, surgery remains the most effective treatment, however, 30\u0026ndash;77% of patients in stage II-III experience recurrence postoperatively [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. For resectable NSCLC, the results of several randomized phase III trials (CheckMate 816, KEYNOTE-671, and Neotorch) demonstrate the feasibility of neoadjuvant immunochemotherapy [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which could significantly improve the efficacy compared to neoadjuvant chemotherapy. Thus, several immunotherapy agents have been approved for the perioperative treatment of resectable NSCLC.\u003c/p\u003e \u003cp\u003eNevertheless, previous trials demonstrated that, for PD-L1 (an immune checkpoint protein mediating immune escape) highly expressed advanced NSCLC, patients received PD-1 mono-immunotherapy probably had similar therapeutic efficacy to those who received chemo-immunotherapy[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, the neoadjuvant chemotherapy-free regimens have also gained sustained attention in the fields of thoracic surgery and oncology. The published results in this trial demonstrated the efficacy and safety of neoadjuvant camrelizumab, a humanized high-affinity IgG4-kappa anti-PD-1 monoclonal antibody, combined with chemotherapy or apatinib, a tyrosine kinase inhibitor targeting VEGFR-2, for initially unresectable cohort [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Our phase II umbrella clinical trial in unresectable stage III NSCLC also confirmed this finding [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. These findings were further corroborated by the EAST ENERGY trial (NCT04040361), in which the combination of pembrolizumab (PD-1 inhibitor)) and ramucirumab (VEGFR-2 inhibitor) achieved a 66.7% MPR rate in PD-L1-positive resectable NSCLC [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Mechanistically, the synergy between PD‑1 and VEGFR‑2 inhibitors stems from VEGF/VEGFR‑2 blockade\u0026ndash;induced vascular normalization, which enhances T cell infiltration, augments dendritic cell activation, and suppresses regulatory T cell mediated immunosuppression [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo further explore the potential of neoadjuvant immunotherapy combination regimens, this multicenter, phase II trial evaluates the efficacy and safety of camrelizumab in combination with either platinum-based chemotherapy (arm-AR) or apatinib (arm-BR) as neoadjuvant treatments for patients with resectable stage IIA-IIIA NSCLC [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis study is a prospective, multicenter, dual-arm, non-randomized, phase II exploratory trial conducted in China (NCT04379739). The trial was rigorously designed in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines, receiving ethical approval from the institutional review boards of all participating centers. Prior to enrollment, all patients provided written informed consent.\u003c/p\u003e \u003cp\u003e The inclusion criteria for patients were: aged between 18 and 75 years old; histologically or cytologically confirmed, untreated stage II-III NSCLC (based on the eighth edition of the American Joint Committee on Cancer TNM staging system for lung cancer); an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; measurable lesions according to RECIST criteria version 1.1; and adequate functional reserve of key organs. arm-AR included all patients with any level of PD-L1 expression. arm-BR included patients exhibiting a baseline PD-L1 expression of 1% or greater, provided that they had no uncontrolled hypertension, no history of thrombotic events, and no significant bleeding tendencies. Key exclusion criteria for both arms included: known mutations in \u003cem\u003eEGFR\u003c/em\u003e or \u003cem\u003eALK\u003c/em\u003e; a history of autoimmune diseases; a history of other malignancies within the past five years; or prior receipt of systemic corticosteroid therapy (\u0026gt;\u0026thinsp;10 mg/day prednisone equivalent) or other immunosuppressive agents within 2 weeks preceding study initiation. Patients with tumors deemed initially unresectable were also excluded, based on assessments from a multidisciplinary clinical team (MDT). These unresectable cases were characterized by: (1) tumor invading vital structures, such as large blood vessels, the trachea or primary bronchus, but curative resection after tumor downgrading by neoadjuvant therapy was possible as judged by a preoperative assessment; (2) clinically confirmed lymph nodes with multistation metastasis or bulky fusion, and patients could tolerate hilar and mediastinal lymph node dissection after tumor downgrading by neoadjuvant therapy as determined by a preoperative evaluation, or (3) according to preoperative evaluation, even if pneumonectomy was performed, especially right pneumonectomy, R0 resection may not be achieved.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eAll participants received predefined neoadjuvant therapy and were included in the ITT population. Both arm-AR and arm-BR underwent 2 to 4 cycles of camrelizumab-based treatment (200mg/3 weeks) : arm-AR combined with chemotherapy, and arm-BR with apatinib (250 mg daily). For those diagnosed with squamous NSCLC, the chemotherapy regimen comprised carboplatin (AUC 5 on day 1) alongside gemcitabine (1000 mg/m\u0026sup2; on days 1 and 8), or alternatively paclitaxel (135\u0026ndash;175 mg/m\u0026sup2;), or nab-paclitaxel (260 mg/m\u0026sup2;), all administered on day 1. In contrast, patients with non-squamous NSCLC were treated with carboplatin (AUC 5 on day 1) in combination with pemetrexed (500 mg/m\u0026sup2; on day 1).\u003c/p\u003e \u003cp\u003eFor the assessment of surgical candidacy, patients who have completed two to four treatment cycles underwent a contrast-enhanced computed tomography (CT) scan of the chest. In cases where the tumor met the criteria for complete response (CR), partial response (PR) or stable disease (SD) as defined by RECIST version 1.1, the MDT conducted a further evaluation to determine surgical suitability. Assessment criteria include tumor location, extent of tumor invasion, lymph node status, and the patient's overall systemic condition. Surgery for eligible patients was anticipated to occur within 30 days following tumor evaluation. The pathological response will be evaluated as previously described. Postoperatively, patients underwent a chest CT scan 30 days after surgery, followed by CT examinations every three months during the first two years and every six months from the third to fifth years.\u003c/p\u003e \u003cp\u003eThroughout the entire trial period, AEs were rigorously monitored and systematically graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Furthermore, the baseline PD-L1 tumor proportion score was quantitatively assessed using the 22C3 pharmDx assay (Agilent Technologies, CA, USA). Decisions regarding postoperative adjuvant therapy were individually tailored by a multidisciplinary team based on comprehensive postoperative pathological characteristics (including ypTNM stage and tumor regression grade), ECOG performance status, and organ functional reserve.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was the MPR rate, defined as the percentage of patients with \u0026le;\u0026thinsp;10% viable tumor cells after resection. Secondary endpoints included the pCR rate (no viable tumor cells post-resection) and ORR (patients achieving CR or PR per RECIST 1.1). EFS was tracked from the start of neoadjuvant therapy to disease progression, recurrence, or death. Additionally, OS (time from therapy initiation to death), R0 resection rate (negative margins), and safety profiles were assessed.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSample size calculations using R's clinfun package determined: 1) Arm-AR (n\u0026thinsp;=\u0026thinsp;28) required to detect MPR improvement from 8.9% (historical control) to 30%; 2) Arm-BR (n\u0026thinsp;=\u0026thinsp;10) to distinguish 8.9% vs 45% MPR rates, both with one-sided α\u0026thinsp;=\u0026thinsp;0.05 and 80% power [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The response-related endpoints were assessed in the efficacy analysis population, which encompassed all patients who had received at least one dose of neoadjuvant therapy and subsequently underwent surgery. In contrast, analyses pertaining to survival and safety were conducted within the full analysis population, comprising all patients who had received at least one dose of neoadjuvant therapy. The 95% CIs for metrics such as MPR rate, pCR rate, ORR, and R0 resection rate were derived using the binom package, following the Clopper-Pearson method. Survival curves were fitted using the survival package, employing the Kaplan-Meier method, and 95% CIs were calculated using the log-log method to ensure robust estimates, particularly at the tails of the survival curves. TRAEs were reported as frequencies (percentages). Additionally, post-hoc analyses investigated EFS and OS by stratifying patients based on whether they had undergone surgery. All statistical analyses were conducted using R version 4.2.3.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e Between September 11, 2020, and March 14, 2022, the MA-NSCLC-II-001 Study enrolled 89 participants: 51 initially unresectable and 38 resectable patients. The findings for the initially unresectable cohort have already been published[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among the resectable patients, arm-AR and arm-BR enrolled 28 and 10 participants, respectively \u003cb\u003e(Fig.\u0026nbsp;1)\u003c/b\u003e. Baseline characteristics for both groups were detailed in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. In arm-AR, the median diagnostic age was 65 (range, 62.8\u0026ndash;69.0). The majority of participants in arm-AR were male (92.9%, 26/28), diagnosed with squamous cell carcinoma (LUSQ) (67.9%, 19/28), had an ECOG PS score of 0 (78.6%, 22/28), were categorized as clinical stage IIIA (64.3%, 18/28), and had PD-L1 expression\u0026thinsp;\u0026lt;\u0026thinsp;1% or unknown (60.7%, 17/28). In arm-BR, the median diagnostic age was 67.5 (range, 66.0\u0026ndash;69.8). Male, LUSQ (90%, 9/10), ECOG PS of 0 (60%, 6/10), and stage IIIA (70%, 7/10) participants accounted for the majority.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;1. Baseline characteristics of patients with resectable NSCLC in Arm-AR and Arm-BR\u003c/b\u003e \u003c/p\u003e\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"533\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArm-AR (n = 28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArm-BR (n = 10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Age (median [IQR])\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e65.00 [62.8, 69.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e67.50 [66.0, 69.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Sex (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e26 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e9 (90.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; ECOG performance status, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e22 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e4 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e6 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Smoking, n \u0026nbsp; \u0026nbsp; (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Former/Current smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e20 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e9 (90.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Non-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Clinical stage (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; IIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; IIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e9 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e3 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; IIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e18 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e7 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Clinical nodal status, n (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; N0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e12 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e4 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; N2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e4 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Histological type, n (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Squamous cell carcinoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e19 (67.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e8 (80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Non-squamous cell carcinoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e9 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;PD-L1 expression\u003c/strong\u003e\u003cstrong\u003e, n\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026lt;1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 1% - 49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e5 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e7 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026ge;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e3 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e11 (39.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e \u003c/div\u003e\u003cp\u003eAbbreviations: IQR, Interquartile Range; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the ITT patients of arm-AR, 25% (7/28, 95% CI 10.7\u0026ndash;44.9) of patients achieved MPR, 17.9% (5/28, 95% CI 6.1\u0026ndash;36.9) achieved pCR, and 67.9% had an ORR, while 85.7% had DCR.\u0026nbsp;The proportion of CR, PR, and SD was 7.1%, 60.7%, and 17.9%, respectively\u003cstrong\u003e\u0026nbsp;(Table 2)\u003c/strong\u003e. In arm-BR, the MPR and pCR rate were 60.0% and 10.0% respectively. The ORR and DCR were 70.0% and 90.0%, respectively \u003cstrong\u003e(Table 2)\u003c/strong\u003e. Pathological downstaging rates reached 77.3% (17/22) in arm-AR and 88.9% (8/9) in arm-BR \u003cstrong\u003e(Supplementary Table 1)\u003c/strong\u003e. The low response rates were linked to the predominance of stage IIIA in both arms and low PD-L1 expression in most arm-AR patients. Furthermore, 6 patients and 1 patient did not undergo surgery in arm-AR and arm-BR, respectively. Among patients undergoing surgery, the MPR, pCR, and ORR for arm-AR were 31.8% (7/22, 95% CI 13.9-54.9), 22.7% (5/22, 95% CI 7.8-45.4), and 81.8% (18/22, 95%CI 59.7-94.8), respectively. In arm-BR, these rates were 66.7% (6/9, 95% CI 29.9-92.5), 11.1% (1/9, 95% CI 0.3-48.2), and 77.8% (7/9, 95% CI 40-97.2), respectively \u003cstrong\u003e(\u003c/strong\u003e\u003cstrong\u003eSupplementary Table\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;1\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and Supplementary\u0026nbsp;Figure 1)\u003c/strong\u003e.\u0026nbsp;A correlative analysis was conducted between MPR and clinicopathologic variables within surgical cohorts. In arm-AR (n=22), numerical trends indicated a higher prevalence of PD-L1 expression \u0026ge;50% (42.9% vs. 20.0%, p=0.350) and squamous cell carcinoma predominance (85.7% vs. 60.0%, p=0.350) in the MPR group \u003cstrong\u003e(Supplementary\u0026nbsp;Table 2)\u003c/strong\u003e. In arm-BR (n=9), the MPR group exhibited a greater frequency of N2 nodal involvement (50.0% vs. 0%, p=0.143) and stage IIIA disease (83.3% vs. 33.3%, p=0.226) \u003cstrong\u003e(Supplementary Table 3)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eBy November 8, 2024, with a median follow-up of 30.5 months, the median EFS of arm-AR and arm-BR was 24.8 months (95% CI 12.1-NR) and 28.7 months (95% CI 2.4-NR). The 12-month/24-month EFS of arm-AR and arm-BR was 71.4%/53.6% and 70.0%/70.0% (\u003cstrong\u003eFigure 2a-b\u003c/strong\u003e). Patients achieving pathological downstaging showed higher 24-month EFS (67.4% vs 33.3%, p=0.068)\u003cstrong\u003e\u0026nbsp;(Supplementary Figure 2)\u003c/strong\u003e. Additionally, there were 15 deaths in arm-AR and 3 in arm-BR. The median OS of arm-AR and arm-BR was 38.3 months (95% CI 21.7-NR) and NR. The 12-month/24-month OS of arm-AR and arm-BR was 89.3%/67.9% and 80.0%/70.0% (\u003cstrong\u003eFigure 2c-d\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Response rates in intention-to-treat patients treated with neoadjuvant camrelizumab-based regimens\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"564\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Efficacy outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArm-AR (n = 28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArm-BR (n = 10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePathological response, n (%, 95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Major pathological response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e7 (25.0, 10.7-44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e6 (60.0, 26.2-87.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Pathological complete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e5 (17.9,\u0026nbsp;6.1-36.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e1 (10.0, 0.3-44.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;\u003cstrong\u003eBest overall response\u003c/strong\u003e\u003cstrong\u003e, n\u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Complete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Partial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e7 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Stable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e5 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Progressive Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Not evaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 272px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003cstrong\u003eObjective response rate, % ( 95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e67.9 (47.6-84.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\"\u003e\n \u003cp\u003e70.0 (34.8-93.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CI, Confidence Interval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn arm-AR, TRAEs were observed in 78.6% (22/28) participants. Grade 3/4 TRAEs occurred in 6 participants with cases of\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eneutropenia (10.7%), anemia (7.1%), and renal insufficiency (7.1%). One patient experienced a grade 5 TRAE with bone marrow suppression and immune myocarditis \u003cstrong\u003e(Table 3)\u003c/strong\u003e. Additionally, 8 participants experienced immune-related adverse events (irAEs). The most common cases were reactive cutaneous capillary endothelial proliferation (10.7%, 3/28) and elevated gamma-glutamyl transferase (10.7%, 3/28)\u003cstrong\u003e\u0026nbsp;(Supplementary Table 4)\u003c/strong\u003e. In arm-BR, all patients experienced TRAEs, with only one (10%) participant experiencing grade 3 hypertension. No grade 4 or 5 events were observed \u003cstrong\u003e(Table 3)\u003c/strong\u003e. Additionally, irAEs were observed in 2 (20%) participants\u003cstrong\u003e\u0026nbsp;(Supplementary Table 4)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere were 3 (10.7%) participants in arm-AR who did not complete the pre-specified treatment, due to adverse events such as hyponatremia, hemoptysis, and immune myocarditis. Conversely, only one patient in arm-BR withdrew the informed consent and did not complete the pre-specified treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Treatment-related adverse events (TRAEs) in patients receiving neoadjuvant camrelizumab-based regimens\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"589\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Events, n (%)\u003csup\u003e\u0026nbsp;*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArm-AR (n = 28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArm-BR (n = 10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade \u0026ge;3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade \u0026ge;3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Any\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e22 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e10 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e9 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Neutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;White blood cell count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Gamma glutamyl transferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Platelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Alanine aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Reactive capillary endothelial hyperplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Blood glucose increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Alkaline phosphatase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Aspartate aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Proteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Renal insufficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Hypohepatia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Bone marrow suppression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Autoimmune myocarditis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Hyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 277px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Data presented for treatment-related adverse events (TRAEs) occurring in at least 5% of patients, or any TRAEs of grade 3 or above in either arm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn arm-AR, the surgical rate and R0 resection rate were 78.6% (22/28) and 95.5% (21/22), respectively, while in arm-BR, these rates were 90% (9/10) and 100% (9/9) \u003cstrong\u003e(Supplementary Table 5)\u003c/strong\u003e. Video-assisted thoracoscopic surgery (VATS) was the most common approach in both arms, with 72.7% (16/22) in arm-AR and 66.7% (6/9) in arm-BR. Lobectomy was the most frequent procedure, accounting for 72.7% (16/22) in arm-AR and 55.6% (5/9) in arm-BR \u003cstrong\u003e(Supplementary Table 5 and Supplementary Figure\u0026nbsp;3)\u003c/strong\u003e. Among the six non-surgically treated patients in arm-AR, two withdrew informed consent, two experienced grade \u0026ge;3 TRAEs (immune myocarditis and chemotherapy-induced nephrotoxicity), one had disease progression, and one died from tumor-related hemoptysis. In arm-BR, only one patient did not receive surgery after withdrawing the informed consent.\u003c/p\u003e\n\u003cp\u003eFurthermore, two surgically treated patients (9.1%) in arm-AR experienced postoperative complications, including pulmonary embolism and bleeding. No postoperative complications occurred in arm-BR, and no deaths were reported within 90 days after surgery in either arm.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter, two-arm, phase II trial met its primary endpoint, with 25.0% (7/28) of patients in arm-AR and 60% (6/10) in arm-BR achieving MPR. The pCR rates were 17.9% (5/28) for arm-AR and 10% (1/10) for arm-BR.\u0026nbsp;Compared\u0026nbsp;to historical controls from neoadjuvant chemotherapy (CheckMate 816's chemotherapy arm: MPR 8.9%, pCR 2.2%) [6] and neoadjuvant immunotherapy monotherapy (LCMC3: MPR 20.0%, pCR 6.0%) [17], the arm-AR regimen appeared to show improved efficacy in unselected PD-L1 populations. Additionally, the pCR rate of the arm-AR regimen (17.9%) approached that of the KEYNOTE-671's pembrolizumab-chemotherapy combination (18.0%) [18]. In PD-L1-positive subgroups, arm-BR achieved a 60.0% MPR rate, tripling LCMC3's immunotherapy-alone results and doubling KEYNOTE-671's chemo-immunotherapy outcomes. This aligns with Jun Zhao's camrelizumab-apatinib study (MPR 47%\u0026nbsp;[19]).\u003c/p\u003e\n\u003cp\u003eAcross both arms, most camrelizumab-related AEs were mild (Grade 1/2), predominantly reactive cutaneous capillary endothelial proliferation, echoing results from camrelizumab-based therapies [20-23]. The\u0026nbsp;safety profiles of both regimens support their clinical utility. Arm-AR showed a lower incidence of grade ≥3 TRAEs at 25.0%, compared with 33.5% in the nivolumab-chemotherapy arm of CheckMate 816 [6]. Additionally, immune-related adverse events were more manageable in arm-AR (28.6% vs. 41% in the atezolizumab monotherapy arm of LCMC3 [17]). Arm-BR exhibited minimal severe toxicities, with only 10% of patients experiencing grade ≥3 TRAEs and no grade ≥4 irAEs, outperforming other chemotherapy-free regimens such as SHR-1701 (PD-L1/TGF-β bifunctional antibody) monotherapy, which reported 40% grade ≥3 TRAEs [24].\u003c/p\u003e\n\u003cp\u003eIn preceding research, we also investigated the efficacy and safety profile of neoadjuvant camrelizumab in combination with chemotherapy and apatinib in patients initially unresectable [3]. The MPR and pCR rates for arm-AuR (unresectable arm A) were both 10.0% (3/30). In contrast, arm-BuR (unresectable arm B) showed an MPR rate of 23.8% (5/21) and a pCR rate of 4.8% (1/21). These results suggest that both treatment regimens offer promising efficacy with a manageable safety profile [25, 26]. Building on the predominant use of neoadjuvant immunotherapy for resectable tumors, we broadened the study to encompass patients with initially operable disease. Within this same framework, a total of 58 patients were enrolled in arm-A (mixed resectable/unresectable arm-A) and 31 in arm-B (mixed resectable/unresectable arm-B). The MPR rates were 17.2% (10/58) for arm-A and 35.5% (11/31) for arm-B, while pCR rates were 13.8% (8/58) and 6.5% (2/31). The ORR was 46.6% (27/58) in arm-A and 45.2% (14/31) in arm-B, with surgery rates of 63.8% (37/58) in arm-A and 58.1% (18/31) in arm-B. This study extends our previous findings in patients with unresectable NSCLC by assessing the safety and efficacy of camrelizumab in combination with chemotherapy or apatinib in patients with resectable stage IIA-IIIA disease.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, a prospective single-arm, single-center study investigating neoadjuvant camrelizumab combined with apatinib produced results analogous to those of arm-BR in our study, reporting MPR and pCR rates of 57% and 23%, respectively [27]. Notably, our arm-BR cohort demonstrated overlapping efficacy ranges with Jun Zhao et al.'s study in MPR (60.0% vs 47%, 95%CI overlap) and pCR (10.0% vs 19.2%, CI overlap) , while exhibiting a higher surgical conversion rate (90% vs 83%) and consistent biomarker correlations (PD-L1-high subgroup MPR: 100% vs 90%). These findings collectively suggest that both neoadjuvant chemoimmunotherapy and neoadjuvant immunotherapy combined with anti-angiogenic therapy offer viable and effective treatment options for patients with resectable NSCLC. Particularly, the latter, as a chemotherapy-free regimen, holds promise as a valuable alternative for patients who are either unable to tolerate chemotherapy or are apprehensive about its adverse effects.\u003c/p\u003e\n\u003cp\u003eThe predictive role of PD-L1 expression levels in the efficacy of ICIs combined with anti-angiogenic agents remains debated. While PD-L1 status lacks predictive value in advanced solid tumors [28-30], some evidence in neoadjuvant settings suggests a correlation between higher PD-L1 levels and MPR [23, 27]. This supports selecting patients with PD-L1 expression ≥1% for arm-BR. Specifically, the HARMONi-5 study and findings by Zhaojun et al. demonstrated that NSCLC patients with PD-L1≥1% achieved significantly higher major pathological and objective response rates with immunotherapy–antiangiogenic therapy than those with lower PD-L1 levels [27, 31].\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. Primarily, due to its exploratory design, the sample size was relatively small, particularly the limited sample size in arm-BR, which may constrain the generalizability of conclusions derived from this group. The lack of a randomization or control group, which limits the ability to make definitive claims about the superiority of one regimen over another.\u0026nbsp;Although no statistically significant differences in MPR rates were observed between chemotherapy groups, the heterogeneity inherent in the AR chemotherapy regimen remains a critical consideration. Additionally, imbalances in baseline characteristics between the two arms may introduce selection bias.\u003c/p\u003e\n\n"},{"header":"Conclusion","content":"\u003cp\u003eIn synthesis, for patients diagnosed with resectable stage IIA-IIIA NSCLC, regardless of PD-L1 expression, the neoadjuvant administration of camrelizumab in combination with platinum-based doublet chemotherapy has preliminarily shown promising efficacy and manageable toxicity. Furthermore, the treatment strategy of camrelizumab combined with apatinib has also been demonstrated to be effective and safe for PD-L1-positive patients with stage IIA-IIIA NSCLC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest statement\u003c/h2\u003e \u003cp\u003eAll authors affirm the absence of any conflicts of interest.\u003c/p\u003e\u003ch2\u003eAuthor contribution statement\u003c/h2\u003e \u003cp\u003eP.Z., Y.Z., H.W., N.S. and B.Q. conceived and designed the study. S.J., Z.S., D.B. and M.B. provided the materials and patients support. M.B., W.Z. and K.J. provided the administrative support. Z.S., D.B., X.Z., F.S., H.X., H.Z., Z.S., H.Y., L.Z. and J.H. collected the data. S.J., Z.S., D.B., and Z.S. analyzed and interpreted the data. S.J., Z.S. and D.B. wrote the draft of the manuscript. All authors approved the final version of the manuscript for submission.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding statement\u003c/h2\u003e \u003cp\u003eThis study was funded by the National Natural Science Foundation of China ( No. 82125001), the Innovation Program of the Shanghai Municipal Education Commission ( No. 2023ZKZD33), the Shanghai Pulmonary Hospital Fund (No. FKLY20004 and FKCX2304), and the Beijing Xisike Clinical Oncology Research Foundation (No. Y-HR2019-0451), alongside support from Jiangsu Hengrui Pharmaceuticals Co., Ltd. We extend our sincere appreciation to all participants, whose invaluable contributions were instrumental in ensuring the successful completion of this research.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eP.Z., Y.Z., H.W., N.S. and B.Q. conceived and designed the study. S.J., Z.S., D.B. and M.B. provided the materials and patients support. M.B., W.Z. and K.J. provided the administrative support. Z.S., D.B., X.Z., F.S., H.X., H.Z., Z.S., H.Y., L.Z. and J.H. collected the data. S.J., Z.S., D.B., and Z.S. analyzed and interpreted the data. S.J., Z.S. and D.B. wrote the draft of the manuscript. All authors approved the final version of the manuscript for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A: \u003cstrong\u003eGlobal cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries\u003c/strong\u003e. \u003cem\u003eCA Cancer J Clin \u003c/em\u003e2024, \u003cstrong\u003e74\u003c/strong\u003e(3):229-263.\u003c/li\u003e\n\u003cli\u003eHan B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J: \u003cstrong\u003eCancer incidence and mortality in China, 2022\u003c/strong\u003e. \u003cem\u003eJ Natl Cancer Cent \u003c/em\u003e2024, \u003cstrong\u003e4\u003c/strong\u003e(1):47-53.\u003c/li\u003e\n\u003cli\u003eXia H, Zhang H, Ruan Z, Zhang H, Sun L, Chen H, Zhou Y, Zhang L, Bian D, Zhu X\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNeoadjuvant camrelizumab (an anti-PD-1 antibody) plus 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Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC\u003c/strong\u003e. \u003cem\u003eJ Thorac Oncol \u003c/em\u003e2024, \u003cstrong\u003e19\u003c/strong\u003e(3):465-475.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Non-small-cell lung cancer, Neoadjuvant, Camrelizumab, Apatinib, Major pathologic response","lastPublishedDoi":"10.21203/rs.3.rs-5558939/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5558939/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis study aimed to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 antibody, combined with either chemotherapy or apatinib, a VEGFR-2 inhibitor, as neoadjuvant treatment for stage IIA-IIIA NSCLC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e This prospective, multicenter, dual-arm, non-randomized phase II trial enrolled participants from four hospitals in China between September 2020 and March 2022. Patients received 2\u0026ndash;4 cycles of neoadjuvant treatment followed by surgery. Arm-AR (n\u0026thinsp;=\u0026thinsp;28) included patients treated with camrelizumab (200 mg every three weeks) plus platinum-based chemotherapy, regardless of PD-L1 status. Arm-BR (n\u0026thinsp;=\u0026thinsp;10) included PD-L1-positive patients treated with camrelizumab (200 mg every three weeks) plus apatinib (250 mg daily). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, objective response rate (ORR), disease control rate (DCR), event-free survival (EFS), overall survival (OS), and safety profiles.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the ITT population, MPR rates were 25.0% (95% CI 10.7\u0026ndash;44.9) in arm-AR and 60.0% (95% CI 26.2\u0026ndash;87.8) in arm-BR. The 24-month EFS rates were 53.6% and 70.0%, respectively, after a median follow-up of 30.5 months. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 25% of arm-AR patients and 10% of arm-BR patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCamrelizumab combined with platinum-based chemotherapy demonstrated promising efficacy and tolerability for resectable IIA-IIIA NSCLC, regardless of PD-L1 status. In PD-L1-positive patients, camrelizumab plus apatinib showed improved safety and effectiveness, highlighting a potential treatment option for this subgroup.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eNCT04379739, initiated on July 26, 2020.\u003c/p\u003e","manuscriptTitle":"Neoadjuvant Camrelizumab Plus Chemotherapy or Apatinib for Resectable Stage IIA-IIIA NSCLC: A Multicenter, Two-Arm, Phase II Exploratory Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 05:32:40","doi":"10.21203/rs.3.rs-5558939/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-02T11:10:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-30T14:46:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-30T01:54:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175233891702889944307997729955715109447","date":"2025-04-17T06:54:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-17T02:46:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279991914452201746135290429402100565917","date":"2025-04-17T02:40:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"118122715432661312190356386394497498440","date":"2025-04-16T14:10:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-15T05:09:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"55423948225115356131860197019040049781","date":"2025-04-15T05:04:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-14T22:56:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"273012483434660686238334851063810409658","date":"2025-04-14T22:38:35+00:00","index":"hide","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-14T12:48:26+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-14T12:47:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-14T11:55:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2025-04-13T03:06:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cc885382-9181-46eb-b18b-46d7c99a7d5e","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-07T07:12:14+00:00","versionOfRecord":{"articleIdentity":"rs-5558939","link":"https://doi.org/10.1186/s12916-025-04250-4","journal":{"identity":"bmc-medicine","isVorOnly":false,"title":"BMC Medicine"},"publishedOn":"2025-07-18 16:05:00","publishedOnDateReadable":"July 18th, 2025"},"versionCreatedAt":"2025-04-17 05:32:40","video":"","vorDoi":"10.1186/s12916-025-04250-4","vorDoiUrl":"https://doi.org/10.1186/s12916-025-04250-4","workflowStages":[]},"version":"v1","identity":"rs-5558939","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5558939","identity":"rs-5558939","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}