Camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide as first-line therapy for advanced, non-squamous non-small cell lung cancer: a prospective, single-arm, pilot study

Camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide as first-line therapy for advanced, non-squamous non-small cell lung cancer: a prospective, single-arm, pilot study | 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 Camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide as first-line therapy for advanced, non-squamous non-small cell lung cancer: a prospective, single-arm, pilot study Xiaobing Qin, Yong Hu, Haonan Liu, Wenlou Liu, Hongmei Wang, Yang Zhao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7506192/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The aim of this study was to evaluate whether the addition of thalidomide to camrelizumab plus pemetrexed disodium and carboplatin as first-line treatment would improve therapeutic efficacy in patients with non-squamous non-small cell lung cancer (NSCLC). Methods This prospective, single-arm, pilot study enrolled treatment-naïve patients with advanced non-squamous NSCLC. Patients received intravenous administration of camrelizumab (200 mg), carboplatin (area under curve, 5 mg/mL per min) and pemetrexed disodium (500 mg/m2) on day 1 of each three-week treatment cycle. Meanwhile, all the patients received the maintenance therapy with thalidomide (oral, 50 mg, twice a day). Primary endpoint was progression-free survival (PFS). Results At data cutoff (February 2025), 20 patients (median age 64.0 [Interquartile range, IQR:59.5–68.0]; 80% male) were evaluable. With median follow-up of 28.9 months (95%CI:16.1–45.7), the regimen achieved median overall survival (OS) of 43.3 months (95%CI:16.9–69.7) and PFS of 15.2 months (95%CI:7.6–27.5). Objective responses occurred in 70% (14/20; 95%CI:44.0–81.2%), with disease control in 95% (19/20). Treatment-related adverse events (TRAEs) affected 90% (18/20), predominantly grade 1–2 hypothyroidism (75%) and reactive cutaneous capillary endothelial proliferation (50%). Grade ≥ 3 TRAEs occurred in 5% (only pneumonia, elevated alanine aminotransferase, and rash). Conclusions The first-line treatment of camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide showed clinically meaningful survival improvement and reduced incidence rate of RCCEP in advanced non-squamous NSCLC patients. Trial registration: Registration number is ChiCTR2000038265, date of registration is 15/09/2020. Thalidomide camrelizumab PD-1 inhibitor advanced non-squamous NSCLC pemetrexed disodium carboplatin reactive cutaneous capillary endothelial proliferation Figures Figure 1 Figure 2 Introduction Immune checkpoint inhibitors (ICIs) have changed therapeutic paradigm of oncology since the landmark approval of ipilimumab (Yervoy®) in 2011 [ 1 ], heralding a new era in cancer immunotherapy. The clinical arsenal has expanded significantly with novel agents such as camrelizumab, a PD-1 inhibitor approved by Chinese regulatory authorities in 2019 [ 2 ], demonstrating promising antitumor activity across multiple malignancies. Despite these advancements, monotherapy with ICIs yields limited clinical responses [ 3 , 4 ], necessitating strategic combination approaches. Compelling evidence from pivotal clinical trials, including our prior investigations, has established the superiority of camrelizumab-chemotherapy combinations in diverse malignancies including gastric cancer, nasopharyngeal cancer, urothelial cancer, liver cancer, and non-small cell lung cancer (NSCLC) [ 5 – 8 ]. In this study, we focused on advanced non-squamous NSCLC, where platinum-based doublet chemotherapy remains a cornerstone of first-line treatment in China [ 9 ]. It has been reported that camrelizumab plus chemotherapy comprising carboplatin and pemetrexed significantly extended median overall survival (OS) of patients with advanced non-squamous NSCLC to 27.1 months compared to 19.8 months with chemotherapy alone [ 10 ]. Building upon this foundation, our study introduced an innovative therapeutic quartet by incorporating thalidomide into the camrelizumab-pemetrexed-carboplatin backbone. Thalidomide, a molecule with complex pharmacologic properties, demonstrates multifaceted antitumor properties beyond its historical notoriety. As a potent anti-angiogenic agent, it promotes vascular normalization, while simultaneously modulating immune responses via tumor necrosis factor-α suppression and enhanced natural killer cell activity [ 11 ]. Emerging clinical evidence suggests synergistic potential when combining thalidomide with cytotoxic regimens, particularly in thoracic malignancies [ 12 , 13 ]. This biological rationale underpins our hypothesis that thalidomide may augment the efficacy of immune-chemo combinations through dual modulation of tumor vasculature and immune microenvironment. Here we conducted this prospective, single-arm, pilot study to explore the efficacy and safety of camrelizumab, pemetrexed and carboplatin combined thalidomide as first-line therapy for advanced non-squamous NSCLC. Methods Study design and participants This was a prospective, single-arm, pilot study. Eligible patients were aged ≥ 18 years with histologically or cytologically confirmed advanced, non-squamous NSCLC. Key inclusion requirements included at least one measurable lesion confirmed by Computed Tomography/Magnetic Resonance Imaging (CT/MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, World Health Organization/Eastern United States Cooperative Oncology Group (ECOG) performance status score of 0 or 1 at the time of enrollment, the potential life expectancy ≥ 3 months, adequate hepatic and renal function. In addition, the full description of the exclusion criteria was detailed in the supplementary material . Treatments Patients received intravenous administration of camrelizumab (200 mg), carboplatin (area under curve, 5 mg/mL per min) and pemetrexed disodium (500 mg/m 2 ) on day 1 of each three-week treatment cycle. Meanwhile, all the patients received the maintenance therapy with thalidomide (oral, 50 mg, twice a day). Treatment continued until meeting the predefined termination criteria including development of intolerable treatment-related toxicities, disease progression or death. Endpoints and assessments The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Tumor response was evaluated per RECIST 1.1 criteria, using CT/MRI every two cycles, no later than 7 days after the end of the treatment cycle. The outcomes of efficacy were classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Patients with CR, PR or SD would be re-evaluated at 4 weeks post the first evaluation to confirm the tumor response. Safety evaluations encompassed physical examinations, laboratory tests and echocardiograms at baseline and each treatment cycle. Adverse events (AEs) were monitored and recorded until 28 days post-treatment, with grading according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Statistical analysis Descriptive statistics were applied to the analysis. Continuous variables were presented as the mean ± standard deviation (SD) or the median with the range (minimum and maximum), while categorical variables were shown as frequencies. The stratified log-rank test was used to evaluate the clinical efficiency. An exploratory analysis was carried out assessing the impact of baseline and treatment characteristic on OS using a Cox proportional hazard model. Additional analysis of OS was done using the rank-preserving structural failure time model. Survival outcomes were analyzed using the Kaplan-Meier method with PFS and OS presented as median values and 95% confidence intervals (CIs). P value < 0.05 was defined as statistically significant. All statistical analyses were executed with SAS software (version 9.4). Results Patient characteristics Between August 2020 and February 2025, twenty patients with advanced, non-squamous NSCLC were enrolled in this pilot study, comprising 4 females (20.0%) and 16 males (80.0%) with the median age as 64.0 years (IQR, 59.5–68.0 years). The majority of participants (90%) exhibited an ECOG performance status of 1, while 80% presented with stage IV disease. Metastatic involvement was observed in multiple sites including lung (15%), bones (40%), brain (20%) and others (75%). A history of smoking was reported in 75% of the patients. Baseline demographic and clinical characteristics were detailed in Table 1 . Table 1 Demographics and baseline characteristics Variable Patients (N = 20) Age, years, median (IQR) 64.0 (59.5–68.0) Gender, n (%) Male 16 (80.0) Female 4 (20.0) ECOG performance status, n (%) 0 2 (10.0) 1 18 (90.0) Disease stage, n (%) III 4 (20.0) Ⅳ 16 (80.0) Number of metastatic sites, n (%) 1 10 (50.0) 2 7 (35.0) 3 3 (15.0) Metastatic sites, n (%) Lung 3 (15.0) Bone 8 (40.0) Brain 4 (20.0) Other 15 (75.0) Smoking, n (%) Yes 15 (75.0) No 5 (25.0) IQR, inter-quartile range; ECOG, Eastern Cooperative Oncology Group. Treatments exposure As summarized in Table 2 , the median follow-up duration was 28.9 months (95% CI: 16.1–45.7). All the patients received at least two cycles of combined immune-chemotherapy of camrelizumab plus pemetrexed disodium and carboplatin, followed by the maintenance of thalidomide, with the median duration of combined chemotherapy and immunotherapy was 8.0 cycles (IQR: 5.8–11.3). In addition, twelve patients (60%) received camrelizumab and thalidomide-maintained therapy after completed combinate chemotherapy, with median total treatment cycles of the camrelizumab as 11.5 (IQR 9.8–21.3). Table 2 Treatment administration Therapy characteristics Patients (N = 20) Camrelizumab-based first-line treatment for advanced/metastatic cancer, n (%) 20 (100.0) Treatment duration, median (95% CI), months 10.4 (6.2, 15.5) Duration of follow-up, median (95% CI), months 28.9 (16.1, 45.7) Treatment cycle of camrelizumab and thalidomide, median (IQR) 11.5 (9.8–21.3) Treatment cycle of combinate chemotherapy, median (IQR) 8.0 (5.8, 11.3) CI, confidence interval; IQR, inter-quartile range. Antitumor Efficacy At the cut-off date (February 2025), the regimen elicited PR in 14 participants (70%) and SD in 5 (25%), yielding an ORR of 70.0% (95% CI: 44.0–81.2%) and a DCR of 95.0% (95% CI: 76.4–99.1%) (Table 3 ) . Kaplan-Meier survival analyses demonstrated a median OS of 43.3 months (95% CI: 16.9–69.7; Fig. 1 ) and a median PFS of 15.2 months (95% CI: 7.6–27.5; Fig. 2 ). This combination of camrelizumab, pemetrexed disodium and carboplatin with the maintenance of thalidomide produced a longer duration of tumor response/benefit for advanced, non-squamous NSCLC. Table 3 Summary of tumor responses Response Patients (N = 20) Best overall response Complete response, n (%) 0 Partial response, n (%) 14 (70.0) Stable disease, n (%) 5 (25.0) Progressive disease, n (%) 1 (5.0) ORR, n (%) (95%CI) 14 (70.0) (0.44, 81.2) DCR, n (%) (95%CI) 19 (95.0) (76.4, 99.1) Confirmed overall response Complete response, n (%) 0 Partial response, n (%) 14 (70.0) Stable disease, n (%) 5 (25.0) Progressive disease, n (%) 1 (5.0) ORR, n (%) (95%CI) 14 (70.0) (0.44, 81.2) DCR, n (%) (95%CI) 19 (95.0) (76.4, 99.1) ORR, objective response rate; DCR, disease control rate; CI, confidence interval. Safety During the follow-up period, treatment-related adverse events (TRAEs) were observed in 18 patients (90%), with grade ≥ 3 events occurring in 5% of the patients (Table 4 ). The most frequent AEs included hypothyroidism (75%), reactive cutaneous capillary endothelial proliferation (RCCEP; 50%), hematologic disturbances such as decreased white blood cell (40%) and neutrophil counts (40%), and nausea (40%). Severe TRAEs were limited to grade 3 pneumonia (5%), elevated alanine aminotransferase (5%), and rash (5%), all of which resolved with supportive care and protocol-defined dose modifications. No treatment-related deaths or discontinuations due to toxicity were reported. Table 4 Adverse events Adverse Event, n (%) Patients (N = 20) Any Grade Grade ≥ 3 Any adverse events 18 (90.0) 1 (5.0) Hypothyroidism 15 (75.0) 0 RCCEP 10 (50.0) 0 WBC count decreased 8 (40.0) 0 Neutrophil count decreased 8 (40.0) 0 Nausea 8 (40.0) 0 Hemoglobin decrease 3 (15.0) 0 ALT increased 3 (15.0) 1 (5.0) Vomiting 3 (15.0) 0 Asthenia 3 (15.0) 0 AST increased 2 (10.0) 0 Rash 2 (10.0) 0 Pneumonia 2 (10.0) 1 (5.0) Decreased appetite 1 (5.0) 0 RCCEP, reactive cutaneous capillary endothelial proliferation; WBC, white blood cell; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Discussion This prospective, single-arm pilot study demonstrates the clinical potential of integrating thalidomide into a camrelizumab-pemetrexed-carboplatin regimen for advanced non-squamous NSCLC, with the median OS of 43.3 months (95% CI, 16.9–69.7 months) and PFS of 15.2 months (95% CI, 7.6–27.5 months). Notably, these outcomes surpass those reported by Zhou et al. in their pivotal CAMEL study, where camrelizumab-chemotherapy without thalidomide yielded a median PFS of 11.0–11.3 months and OS of 27.1 months. And by combining thalidomide, only 50% (10/20) patients developed moderate (grade 1–2) RCCEP, lower than what reported in the CAMEL study of Zhou et al.[ 14 , 15 ]. The extended survival metrics observed in our study suggest a synergistic interaction between thalidomide and the immune-chemotherapy backbone, potentially mediated through dual modulation of vascular normalization and immune potentiation. The therapeutic potential of camrelizumab-based combinations has been substantiated across multiple malignancies, with significant improvements in both OS and PFS when integrated with chemotherapy in lung cancer, liver cancer and gastric cancer [ 5 , 16 , 17 ]. This efficacy derives from the foundational mechanism of ICIs in restoring cancer immunosurveillance, a physiological process wherein the immune system identifies and eliminates malignant cells through antigen-specific T-cell activation [ 18 , 19 ]. Cancer cells release tumor-associated antigens, which are presented to immune cells, especially T cells. These antigen-educated T cells then extravasate through the vascular endothelium, infiltrate tumor stroma, and execute cancer cell lysis [ 18 ]. However, tumors evolve sophisticated immune evasion strategies, most notably through upregulation of programmed death-ligand 1 (PD-L1), which engages PD-1 receptors on tumor-infiltrating lymphocytes to inhibit T cell activity [ 19 , 20 ]. By competitively blocking PD-L1/PD-1 interactions, ICIs such as camrelizumab reinvigorate antitumor immunity, enabling T-cell-mediated eradication of malignant cells [ 21 , 22 ]. Camrelizumab causes some immune-related adverse events, the most common one is RCCEP [ 23 ]. For some patients, the RCCEP is the major concern. Sometimes it causes the camrelizumab treatment to be postponed. It still remains unclear how does camrelizumab induce RCCEP. It is considering that immune and angiogenesis mechanisms are involved. Camrelizumab reactivates T cells, which may attack skin tissue [ 24 ]. Or probably, the activation of immune system induced by camrelizumab disrupts the balance between angiogenic factors and inhibitory vascular growth factors, which cause abnormal proliferation of skin capillary endothelial cells [ 25 ]. Thalidomide is a notorious sedative but also an effective anti-angiogenic agent which was reported being able to reduce camrelizumab induced RCCEP [ 26 ]. In this study, we observed that the occurrence of RCCEP dropped in patients who received thalidomide, even the patients who developed RCCEP, the vascular nevi were less and smaller. Beyond immune checkpoint modulation, the structural and functional integrity of tumor vasculature critically influences therapeutic outcomes. Malignant angiogenesis typically generates immature, hyperpermeable vessels that foster hypoxic microenvironments conducive to tumor progression, metastasis, and chemoresistance [ 27 , 28 ]. Meanwhile, these dysregulated vessels also impede immune cell trafficking; effective T-cell infiltration requires endothelial stability and controlled vascular permeability [ 29 ]. Thalidomide, a multifaceted agent with anti-angiogenic and immunomodulatory properties, addresses this challenge. Through promoting the maturation of tumor blood vessels, destroying immature blood vessels and normalizing tumor blood vessels, thalidomide is considered to be able to reprogram tumor microenvironment to be “hotter”, which leads to improved filtration and distribution of T cell in tumor stroma [ 11 ]. Concurrently, thalidomide is also an immunomodulator [ 30 – 32 ]. Studies have shown that thalidomide enhances T cell immune activation in multiple cancers, improving OS and/or PFS [ 33 ], aligned with what we observed in this pilot study. These findings provide translational validation of the hypothesis that vascular normalization enhances immune-chemo synergy by optimizing tumor microenvironmental conditions for antitumor immunity. This study has some limitations. As a single-center trial with a modest cohort (N = 20), the statistical power to detect rare adverse events, subgroup differences, or long-term survival trends remained limited. Additionally, the absence of biomarker stratification (e.g., PD-L1 expression) restricted mechanistic understanding of responder populations. While the median follow-up of 28.9 months captured intermediate outcomes, extended observation may be required to evaluate delayed toxicities or durability of response. To address these gaps, we have planned to enrolled more patients in different cohorts in an ongoing multi-centered study. In conclusion, the integration of thalidomide into a camrelizumab-pemetrexed-carboplatin regimen demonstrated clinically meaningful survival improvements and reduced the incidence rate of RCCEP in advanced non-squamous NSCLC patients. While larger randomized trials are warranted to confirm these findings, our results position thalidomide as a viable adjunct to immune-chemotherapy backbones, offering a novel strategy to potentiate treatment efficacy without compromising safety. Abbreviations AEs Adverse events CI Confidence interval CR Complete response CT/MRI Computed tomography/Magnetic resonance imaging DCR Disease control rate ECOG Eastern United States Cooperative Oncology Group ICIs Immune checkpoint inhibitors IQR Interquartile range NSCLC Non-small cell lung cancer ORR Objective response rate OS Overall survival PD Progressive disease PD-1 Programmed cell death protein 1 PD-L1 Programmed cell death ligand 1 PFS progression-free survival PFS Progression Free Survival PR Partial response RCCEP Reactive cutaneous capillary endothelial proliferation RECIST Response Evaluation Criteria in Solid Tumors SD Stable disease TRAEs Treatment-related adverse events Declarations Acknowledgements We thank all patients who participated in this study and their families. We also thank Jiangsu Hengrui Pharmaceuticals Co., Ltd. for statistical support and medical writing assistance. Authors' contributions X. Q., Y. H., Z. H. and J. T. designed study; X. Q., Y. H., J. T., Z. H. accessed and verified the data in this study; X. Q., Y. H., J. T., and Z. H. drafted the manuscript, Z. H. and J. T. supervised the study; All authors took part in data collection and analysis, reviewing and editing the entire manuscript and approved the final version of the manuscript. Funding This study was supported, in part, by the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 24KJB310020 to Y. H.). This work was also supported by Jiangsu Hengrui Pharmaceuticals Co., Ltd. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical guidelines of the Helsinki Declaration. 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University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Hu","suffix":""},{"id":531855644,"identity":"ab60bb53-9613-489b-b58d-a91a71be2f09","order_by":2,"name":"Haonan Liu","email":"","orcid":"","institution":"The Affiliated Hospital of Xuzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haonan","middleName":"","lastName":"Liu","suffix":""},{"id":531855645,"identity":"210f637b-e1ed-4792-9ef5-c1d4dee88588","order_by":3,"name":"Wenlou Liu","email":"","orcid":"","institution":"The Affiliated Hospital of Xuzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenlou","middleName":"","lastName":"Liu","suffix":""},{"id":531855646,"identity":"20c30ea2-634e-4397-9d9b-5036ed86cf01","order_by":4,"name":"Hongmei Wang","email":"","orcid":"","institution":"The Affiliated Hospital of Xuzhou Medical 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2","display":"","copyAsset":false,"role":"figure","size":82545,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier estimates for progression-free survival.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7506192/v1/7e61b3b21c531834291b8fe8.png"},{"id":99319796,"identity":"a6fb0e0b-749b-4e3e-b860-e0d0079e20c8","added_by":"auto","created_at":"2025-12-31 16:37:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2620808,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7506192/v1/57734b26-0fb9-427e-af75-bb14fc93c5d3.pdf"},{"id":94140945,"identity":"21708686-d60e-4f0a-8b6e-3986471986bb","added_by":"auto","created_at":"2025-10-22 19:51:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18821,"visible":true,"origin":"","legend":"","description":"","filename":"Thalidomidearticlesup20250816.docx","url":"https://assets-eu.researchsquare.com/files/rs-7506192/v1/db78db9730ddf196b4e81d0a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide as first-line therapy for advanced, non-squamous non-small cell lung cancer: a prospective, single-arm, pilot study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICIs) have changed therapeutic paradigm of oncology since the landmark approval of ipilimumab (Yervoy\u0026reg;) in 2011 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], heralding a new era in cancer immunotherapy. The clinical arsenal has expanded significantly with novel agents such as camrelizumab, a PD-1 inhibitor approved by Chinese regulatory authorities in 2019 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], demonstrating promising antitumor activity across multiple malignancies. Despite these advancements, monotherapy with ICIs yields limited clinical responses [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], necessitating strategic combination approaches. Compelling evidence from pivotal clinical trials, including our prior investigations, has established the superiority of camrelizumab-chemotherapy combinations in diverse malignancies including gastric cancer, nasopharyngeal cancer, urothelial cancer, liver cancer, and non-small cell lung cancer (NSCLC) [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, we focused on advanced non-squamous NSCLC, where platinum-based doublet chemotherapy remains a cornerstone of first-line treatment in China [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. It has been reported that camrelizumab plus chemotherapy comprising carboplatin and pemetrexed significantly extended median overall survival (OS) of patients with advanced non-squamous NSCLC to 27.1 months compared to 19.8 months with chemotherapy alone [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Building upon this foundation, our study introduced an innovative therapeutic quartet by incorporating thalidomide into the camrelizumab-pemetrexed-carboplatin backbone.\u003c/p\u003e\u003cp\u003eThalidomide, a molecule with complex pharmacologic properties, demonstrates multifaceted antitumor properties beyond its historical notoriety. As a potent anti-angiogenic agent, it promotes vascular normalization, while simultaneously modulating immune responses via tumor necrosis factor-α suppression and enhanced natural killer cell activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Emerging clinical evidence suggests synergistic potential when combining thalidomide with cytotoxic regimens, particularly in thoracic malignancies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This biological rationale underpins our hypothesis that thalidomide may augment the efficacy of immune-chemo combinations through dual modulation of tumor vasculature and immune microenvironment.\u003c/p\u003e\u003cp\u003eHere we conducted this prospective, single-arm, pilot study to explore the efficacy and safety of camrelizumab, pemetrexed and carboplatin combined thalidomide as first-line therapy for advanced non-squamous NSCLC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and participants\u003c/h2\u003e\u003cp\u003eThis was a prospective, single-arm, pilot study. Eligible patients were aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with histologically or cytologically confirmed advanced, non-squamous NSCLC. Key inclusion requirements included at least one measurable lesion confirmed by Computed Tomography/Magnetic Resonance Imaging (CT/MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, World Health Organization/Eastern United States Cooperative Oncology Group (ECOG) performance status score of 0 or 1 at the time of enrollment, the potential life expectancy\u0026thinsp;\u0026ge;\u0026thinsp;3 months, adequate hepatic and renal function. In addition, the full description of the exclusion criteria was detailed in the \u003cb\u003esupplementary material\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatments\u003c/h3\u003e\n\u003cp\u003ePatients received intravenous administration of camrelizumab (200 mg), carboplatin (area under curve, 5 mg/mL per min) and pemetrexed disodium (500 mg/m\u003csup\u003e2\u003c/sup\u003e) on day 1 of each three-week treatment cycle. Meanwhile, all the patients received the maintenance therapy with thalidomide (oral, 50 mg, twice a day). Treatment continued until meeting the predefined termination criteria including development of intolerable treatment-related toxicities, disease progression or death.\u003c/p\u003e\n\u003ch3\u003eEndpoints and assessments\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety.\u003c/p\u003e\u003cp\u003eTumor response was evaluated per RECIST 1.1 criteria, using CT/MRI every two cycles, no later than 7 days after the end of the treatment cycle. The outcomes of efficacy were classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Patients with CR, PR or SD would be re-evaluated at 4 weeks post the first evaluation to confirm the tumor response.\u003c/p\u003e\u003cp\u003eSafety evaluations encompassed physical examinations, laboratory tests and echocardiograms at baseline and each treatment cycle. Adverse events (AEs) were monitored and recorded until 28 days post-treatment, with grading according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics were applied to the analysis. Continuous variables were presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or the median with the range (minimum and maximum), while categorical variables were shown as frequencies. The stratified log-rank test was used to evaluate the clinical efficiency. An exploratory analysis was carried out assessing the impact of baseline and treatment characteristic on OS using a Cox proportional hazard model. Additional analysis of OS was done using the rank-preserving structural failure time model. Survival outcomes were analyzed using the Kaplan-Meier method with PFS and OS presented as median values and 95% confidence intervals (CIs). \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was defined as statistically significant. All statistical analyses were executed with SAS software (version 9.4).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003ePatient characteristics\u003c/h2\u003e\u003cp\u003eBetween August 2020 and February 2025, twenty patients with advanced, non-squamous NSCLC were enrolled in this pilot study, comprising 4 females (20.0%) and 16 males (80.0%) with the median age as 64.0 years (IQR, 59.5\u0026ndash;68.0 years). The majority of participants (90%) exhibited an ECOG performance status of 1, while 80% presented with stage IV disease. Metastatic involvement was observed in multiple sites including lung (15%), bones (40%), brain (20%) and others (75%). A history of smoking was reported in 75% of the patients. Baseline demographic and clinical characteristics were detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographics and baseline characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatients (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years, median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e64.0 (59.5\u0026ndash;68.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16 (80.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (20.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG performance status, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (10.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18 (90.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease stage, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (20.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅣ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16 (80.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of metastatic sites, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10 (50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7 (35.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (15.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetastatic sites, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (15.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (40.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (20.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (75.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (75.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eIQR, inter-quartile range; ECOG, Eastern Cooperative Oncology Group.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatments exposure\u003c/h3\u003e\n\u003cp\u003eAs summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the median follow-up duration was 28.9 months (95% CI: 16.1\u0026ndash;45.7). All the patients received at least two cycles of combined immune-chemotherapy of camrelizumab plus pemetrexed disodium and carboplatin, followed by the maintenance of thalidomide, with the median duration of combined chemotherapy and immunotherapy was 8.0 cycles (IQR: 5.8\u0026ndash;11.3). In addition, twelve patients (60%) received camrelizumab and thalidomide-maintained therapy after completed combinate chemotherapy, with median total treatment cycles of the camrelizumab as 11.5 (IQR 9.8\u0026ndash;21.3).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTreatment administration\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTherapy characteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatients (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCamrelizumab-based first-line treatment for advanced/metastatic cancer, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20 (100.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment duration, median (95% CI), months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10.4 (6.2, 15.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of follow-up, median (95% CI), months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e28.9 (16.1, 45.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment cycle of camrelizumab and thalidomide, median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11.5 (9.8\u0026ndash;21.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment cycle of combinate chemotherapy, median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8.0 (5.8, 11.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eCI, confidence interval; IQR, inter-quartile range.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eAntitumor Efficacy\u003c/h3\u003e\n\u003cp\u003eAt the cut-off date (February 2025), the regimen elicited PR in 14 participants (70%) and SD in 5 (25%), yielding an ORR of 70.0% (95% CI: 44.0\u0026ndash;81.2%) and a DCR of 95.0% (95% CI: 76.4\u0026ndash;99.1%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Kaplan-Meier survival analyses demonstrated a median OS of 43.3 months (95% CI: 16.9\u0026ndash;69.7; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and a median PFS of 15.2 months (95% CI: 7.6\u0026ndash;27.5; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This combination of camrelizumab, pemetrexed disodium and carboplatin with the maintenance of thalidomide produced a longer duration of tumor response/benefit for advanced, non-squamous NSCLC.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of tumor responses\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResponse\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatients (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBest overall response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplete response, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePartial response, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (70.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStable disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgressive disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (5.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eORR, n (%) (95%CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (70.0) (0.44, 81.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCR, n (%) (95%CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (95.0) (76.4, 99.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConfirmed overall response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplete response, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePartial response, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (70.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStable disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgressive disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (5.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eORR, n (%) (95%CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (70.0) (0.44, 81.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCR, n (%) (95%CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (95.0) (76.4, 99.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eORR, objective response rate; DCR, disease control rate; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSafety\u003c/h2\u003e\u003cp\u003eDuring the follow-up period, treatment-related adverse events (TRAEs) were observed in 18 patients (90%), with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events occurring in 5% of the patients (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The most frequent AEs included hypothyroidism (75%), reactive cutaneous capillary endothelial proliferation (RCCEP; 50%), hematologic disturbances such as decreased white blood cell (40%) and neutrophil counts (40%), and nausea (40%). Severe TRAEs were limited to grade 3 pneumonia (5%), elevated alanine aminotransferase (5%), and rash (5%), all of which resolved with supportive care and protocol-defined dose modifications. No treatment-related deaths or discontinuations due to toxicity were reported.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAdverse events\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAdverse Event, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003ePatients (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAny Grade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny adverse events\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18 (90.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (5.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypothyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (75.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRCCEP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWBC count decreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutrophil count decreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin decrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (5.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsthenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAST increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRash\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (5.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDecreased appetite\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1 (5.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eRCCEP, reactive cutaneous capillary endothelial proliferation; WBC, white blood cell;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eALT, alanine aminotransferase; AST, aspartate aminotransferase.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective, single-arm pilot study demonstrates the clinical potential of integrating thalidomide into a camrelizumab-pemetrexed-carboplatin regimen for advanced non-squamous NSCLC, with the median OS of 43.3 months (95% CI, 16.9\u0026ndash;69.7 months) and PFS of 15.2 months (95% CI, 7.6\u0026ndash;27.5 months). Notably, these outcomes surpass those reported by Zhou et al. in their pivotal CAMEL study, where camrelizumab-chemotherapy without thalidomide yielded a median PFS of 11.0\u0026ndash;11.3 months and OS of 27.1 months. And by combining thalidomide, only 50% (10/20) patients developed moderate (grade 1\u0026ndash;2) RCCEP, lower than what reported in the CAMEL study of Zhou et al.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The extended survival metrics observed in our study suggest a synergistic interaction between thalidomide and the immune-chemotherapy backbone, potentially mediated through dual modulation of vascular normalization and immune potentiation.\u003c/p\u003e\u003cp\u003eThe therapeutic potential of camrelizumab-based combinations has been substantiated across multiple malignancies, with significant improvements in both OS and PFS when integrated with chemotherapy in lung cancer, liver cancer and gastric cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This efficacy derives from the foundational mechanism of ICIs in restoring cancer immunosurveillance, a physiological process wherein the immune system identifies and eliminates malignant cells through antigen-specific T-cell activation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Cancer cells release tumor-associated antigens, which are presented to immune cells, especially T cells. These antigen-educated T cells then extravasate through the vascular endothelium, infiltrate tumor stroma, and execute cancer cell lysis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, tumors evolve sophisticated immune evasion strategies, most notably through upregulation of programmed death-ligand 1 (PD-L1), which engages PD-1 receptors on tumor-infiltrating lymphocytes to inhibit T cell activity [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. By competitively blocking PD-L1/PD-1 interactions, ICIs such as camrelizumab reinvigorate antitumor immunity, enabling T-cell-mediated eradication of malignant cells [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCamrelizumab causes some immune-related adverse events, the most common one is RCCEP [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For some patients, the RCCEP is the major concern. Sometimes it causes the camrelizumab treatment to be postponed. It still remains unclear how does camrelizumab induce RCCEP. It is considering that immune and angiogenesis mechanisms are involved. Camrelizumab reactivates T cells, which may attack skin tissue [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Or probably, the activation of immune system induced by camrelizumab disrupts the balance between angiogenic factors and inhibitory vascular growth factors, which cause abnormal proliferation of skin capillary endothelial cells [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Thalidomide is a notorious sedative but also an effective anti-angiogenic agent which was reported being able to reduce camrelizumab induced RCCEP [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this study, we observed that the occurrence of RCCEP dropped in patients who received thalidomide, even the patients who developed RCCEP, the vascular nevi were less and smaller.\u003c/p\u003e\u003cp\u003eBeyond immune checkpoint modulation, the structural and functional integrity of tumor vasculature critically influences therapeutic outcomes. Malignant angiogenesis typically generates immature, hyperpermeable vessels that foster hypoxic microenvironments conducive to tumor progression, metastasis, and chemoresistance [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Meanwhile, these dysregulated vessels also impede immune cell trafficking; effective T-cell infiltration requires endothelial stability and controlled vascular permeability [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Thalidomide, a multifaceted agent with anti-angiogenic and immunomodulatory properties, addresses this challenge. Through promoting the maturation of tumor blood vessels, destroying immature blood vessels and normalizing tumor blood vessels, thalidomide is considered to be able to reprogram tumor microenvironment to be \u0026ldquo;hotter\u0026rdquo;, which leads to improved filtration and distribution of T cell in tumor stroma [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Concurrently, thalidomide is also an immunomodulator [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Studies have shown that thalidomide enhances T cell immune activation in multiple cancers, improving OS and/or PFS [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], aligned with what we observed in this pilot study. These findings provide translational validation of the hypothesis that vascular normalization enhances immune-chemo synergy by optimizing tumor microenvironmental conditions for antitumor immunity.\u003c/p\u003e\u003cp\u003eThis study has some limitations. As a single-center trial with a modest cohort (N\u0026thinsp;=\u0026thinsp;20), the statistical power to detect rare adverse events, subgroup differences, or long-term survival trends remained limited. Additionally, the absence of biomarker stratification (e.g., PD-L1 expression) restricted mechanistic understanding of responder populations. While the median follow-up of 28.9 months captured intermediate outcomes, extended observation may be required to evaluate delayed toxicities or durability of response. To address these gaps, we have planned to enrolled more patients in different cohorts in an ongoing multi-centered study.\u003c/p\u003e\u003cp\u003eIn conclusion, the integration of thalidomide into a camrelizumab-pemetrexed-carboplatin regimen demonstrated clinically meaningful survival improvements and reduced the incidence rate of RCCEP in advanced non-squamous NSCLC patients. While larger randomized trials are warranted to confirm these findings, our results position thalidomide as a viable adjunct to immune-chemotherapy backbones, offering a novel strategy to potentiate treatment efficacy without compromising safety.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eAdverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eConfidence interval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eCT/MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eComputed tomography/Magnetic resonance imaging\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eDisease control rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eECOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eEastern United States Cooperative Oncology Group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eICIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eImmune checkpoint inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eIQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eInterquartile range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eNSCLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eNon-small cell lung cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eObjective response rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003ePD-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eProgrammed cell death protein 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003ePD-L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eProgrammed cell death ligand 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eprogression-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eProgression Free Survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eRCCEP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eReactive cutaneous capillary endothelial proliferation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eRECIST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eResponse Evaluation Criteria in Solid Tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22.2022%;\"\u003e\n \u003cp\u003eTRAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.7978%;\"\u003e\n \u003cp\u003eTreatment-related adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all patients who participated in this study and their families. We also thank Jiangsu Hengrui Pharmaceuticals Co., Ltd. for statistical support and medical writing assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX. Q., Y. H., Z. H. and J. T. designed study; X. Q., Y. H., J. T., Z. H. accessed and verified the data in this study; X. Q., Y. H., J. T., and Z. H. drafted the manuscript, Z. H. and J. T. supervised the study; All authors took part in data collection and analysis, reviewing and editing the entire manuscript and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported, in part, by the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 24KJB310020 to Y. H.). This work was also supported by Jiangsu Hengrui Pharmaceuticals Co., Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical guidelines of the Helsinki Declaration. This study was approved by the Human Ethics Committee of the Xuzhou Medical University Affiliated Hospital (Registration number is ChiCTR2000038265, 15/09/2020). Written informed consent was obtained from individual or guardian participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ehttps://www.chictr.org.cn/showproj.html?proj=58261\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared no conflicts of interest in this work.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHersh EM, O\u0026apos;Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD, Samlowski WE, Nichol GM, Yellin MJ, Weber JS: \u003cstrong\u003eA phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-na\u0026iuml;ve patients with advanced melanoma\u003c/strong\u003e. \u003cem\u003eInvest New Drugs \u003c/em\u003e2011, \u003cstrong\u003e29\u003c/strong\u003e(3):489-498.\u003c/li\u003e\n\u003cli\u003eHuang 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Z, Chai X, Xiong J, Bai Y, Yang L, Zhu H, Fang W\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCamrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial\u003c/strong\u003e. \u003cem\u003eThe Lancet Oncology \u003c/em\u003e2020, \u003cstrong\u003e21\u003c/strong\u003e(4):571-580.\u003c/li\u003e\n\u003cli\u003eSong G, Zhang FF, Cheng HD: \u003cstrong\u003eThalidomide for prevention of camrelizumab-induced reactive cutaneous capillary endothelial proliferation\u003c/strong\u003e. \u003cem\u003eAustralas J Dermatol \u003c/em\u003e2022, \u003cstrong\u003e63\u003c/strong\u003e(2):217-221.\u003c/li\u003e\n\u003cli\u003eLamplugh Z, Fan Y: \u003cstrong\u003eVascular Microenvironment, Tumor Immunity and Immunotherapy\u003c/strong\u003e. \u003cem\u003eFront Immunol \u003c/em\u003e2021, \u003cstrong\u003e12\u003c/strong\u003e:811485.\u003c/li\u003e\n\u003cli\u003eTr\u0026eacute;dan O, Galmarini CM, Patel K, Tannock IF: \u003cstrong\u003eDrug resistance and the solid tumor microenvironment\u003c/strong\u003e. \u003cem\u003eJ Natl Cancer Inst \u003c/em\u003e2007, \u003cstrong\u003e99\u003c/strong\u003e(19):1441-1454.\u003c/li\u003e\n\u003cli\u003eAbou Khouzam R, Brodaczewska K, Filipiak A, Zeinelabdin NA, Buart S, Szczylik C, Kieda C, Chouaib S: \u003cstrong\u003eTumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies\u003c/strong\u003e. \u003cem\u003eFront Immunol \u003c/em\u003e2020, \u003cstrong\u003e11\u003c/strong\u003e:613114.\u003c/li\u003e\n\u003cli\u003eSantana AC, Andraus W, Silva FMO, Dell\u0026ecirc; H, Pepineli R, de Moraes EL, Scavone C, de S\u0026aacute; Lima L, Degaspari S, Brasil S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eImmunomodulatory effects of thalidomide in an experimental brain death liver donor model\u003c/strong\u003e. \u003cem\u003eSci Rep 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\u003c/em\u003e2016, \u003cstrong\u003e48\u003c/strong\u003e(4):1270-1274.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Thalidomide, camrelizumab, PD-1 inhibitor, advanced non-squamous NSCLC, pemetrexed disodium, carboplatin, reactive cutaneous capillary endothelial proliferation","lastPublishedDoi":"10.21203/rs.3.rs-7506192/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7506192/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe aim of this study was to evaluate whether the addition of thalidomide to camrelizumab plus pemetrexed disodium and carboplatin as first-line treatment would improve therapeutic efficacy in patients with non-squamous non-small cell lung cancer (NSCLC).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis prospective, single-arm, pilot study enrolled treatment-na\u0026iuml;ve patients with advanced non-squamous NSCLC. Patients received intravenous administration of camrelizumab (200 mg), carboplatin (area under curve, 5 mg/mL per min) and pemetrexed disodium (500 mg/m2) on day 1 of each three-week treatment cycle. Meanwhile, all the patients received the maintenance therapy with thalidomide (oral, 50 mg, twice a day). Primary endpoint was progression-free survival (PFS).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAt data cutoff (February 2025), 20 patients (median age 64.0 [Interquartile range, IQR:59.5\u0026ndash;68.0]; 80% male) were evaluable. With median follow-up of 28.9 months (95%CI:16.1\u0026ndash;45.7), the regimen achieved median overall survival (OS) of 43.3 months (95%CI:16.9\u0026ndash;69.7) and PFS of 15.2 months (95%CI:7.6\u0026ndash;27.5). Objective responses occurred in 70% (14/20; 95%CI:44.0\u0026ndash;81.2%), with disease control in 95% (19/20). Treatment-related adverse events (TRAEs) affected 90% (18/20), predominantly grade 1\u0026ndash;2 hypothyroidism (75%) and reactive cutaneous capillary endothelial proliferation (50%). Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs occurred in 5% (only pneumonia, elevated alanine aminotransferase, and rash).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe first-line treatment of camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide showed clinically meaningful survival improvement and reduced incidence rate of RCCEP in advanced non-squamous NSCLC patients.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTrial registration:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRegistration number is ChiCTR2000038265, date of registration is 15/09/2020.\u003c/p\u003e","manuscriptTitle":"Camrelizumab plus pemetrexed disodium and carboplatin combined with thalidomide as first-line therapy for advanced, non-squamous non-small cell lung cancer: a prospective, single-arm, pilot study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-22 19:35:31","doi":"10.21203/rs.3.rs-7506192/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a4179ea5-3fb2-46cc-a450-6840abe87ac9","owner":[],"postedDate":"October 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-30T09:40:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-22 19:35:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7506192","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7506192","identity":"rs-7506192","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}