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Abstract

Background

Squamous non-small cell lung cancer (sq-NSCLC) remains a major cause of cancer-related mortality in world. While immunotherapy combined with chemotherapy has improved outcomes, response rates and survival remain suboptimal. Anti-angiogenic agents, such as recombinant human vascular endothelial inhibitor (endostar), may enhance the efficacy of immune checkpoint inhibitors (ICIs) by modulating the tumor microenvironment. This phase II trial evaluates the combination of endostar, sintilimab, and chemotherapy in advanced sq-NSCLC.

Objective

To assess the efficacy and safety of endostar combined with sintilimab and chemotherapy in patients with advanced sq-NSCLC, focusing on progression-free survival (PFS) as the primary endpoint. Secondary endpoints include overall survival (OS), duration of response (DoR), disease control rate (DCR), and safety. Exploratory analyses will investigate biomarkers and quality of life.

Methods

This prospective, single-arm, multicenter phase II trial (NCT06746179) will enroll 64 patients with advanced sq-NSCLC (stage IIIB-IV) and negative driver gene mutations. Patients will receive endostar (210 mg/dose, 72 h), sintilimab (200 mg/dose), and chemotherapy (nab-pp, carboplatin/cisplatin + albumin-bound paclitaxel) every 3 weeks for up to 6 cycles, followed by maintenance therapy until progression or intolerable toxicity. Radiological assessments will occur every 8 weeks initially, then every 12 weeks. Biomarker analysis and quality of life assessments will be performed.

Keywords

Sq-nsclc recombinant human vascular endothelial inhibitor immunotherapy clinical trail

Background

Lung cancer is the malignant tumor with the highest morbidity and mortality rate in China, of which non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases.¹ With the advent of the immunotherapy era, immunotherapy has become the preferred option for first-line treatment of advanced NSCLC. However, due to the limited objective response rate (ORR) of the immunotherapy alone, it is difficult for most patients to achieve significant efficacy. Therefore, the combination of immunotherapy with chemotherapy and anti-angiogenic drugs has increasingly become the focus.² The theory of angiogenesis reveals the key role played by angiogenesis in the process of tumor growth and metastasis, and throughout the whole stage of tumor development and progression.³ Several studies have demonstrated that anti-angiogenic drugs can promote anti-tumor immune responses by remodeling the tumor vasculature and attenuating the tumor immunosuppressive microenvironment,^4,5 and that the combination with immune checkpoint inhibitors (ICIs) further improves the immune microenvironment, enhances the infiltration and activation of immune effector cells, and thus enhances the anti-tumor efficacy.

IMpower150 study has demonstrated that atelizumab combined with bevacizumab and chemotherapy significantly prolonged the overall survival (OS) of patients with driver-negative advanced NSCLC.⁶ On this basis, several studies such as ONO-4538-52/TASUKI-52 and LEAP-006 have further confirmed the clinical efficacy of immunotherapy combined with antiangiogenic drugs and chemotherapy in advanced NSCLC,^7,8 making this treatment modality a recommended first-line treatment option for advanced non-squamous NSCLC. However, previous clinical trial has reported significantly higher incidences of hemoptysis and treatment-related mortality in patients with squamous NSCLC (sq-NSCLC) receiving bevacizumab, leading to its contraindication in this population.⁹ In contrast, a phase II study demonstrated that recombinant human endostatin (Endostar), when combined with chemotherapy, offered favorable safety and efficacy in patients with sq-NSCLC.¹⁰ Nonetheless, the above studies have focused on non-squamous NSCLC, while sq-NSCLC—characterized by a high mutation burden, chromosomal instability, and strong immunogenicity—remains underexplored.¹¹ Recently, a phase II clinical study published data on the combination of the programmed cell death protein 1 (PD-1) / vascular endothelial growth factor (VEGF) dual-specific antibody, ivosizumab (AK112), with chemotherapy for the treatment of patients with primary advanced NSCLC without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations (squamous, n = 63; non-squamous, n = 72), with an ORR of 71.4% and a disease control rate (DCR) of 90.5% in patients with sq-NSCLC.¹² The results suggest that anti-angiogenesis combined with anti-PD-1 and chemotherapy may also have potential clinical benefits in sq-NSCLC.

Although there is established evidence for the efficacy of immunotherapy combined with chemotherapy in sq-NSCLC, there is still room for improvement. Based on the results of the previous study, we designed a phase II single-arm clinical study to further investigate the efficacy and safety of endostar in combination with sintilimab and chemotherapy (nab-pp, carboplatin/cisplatin + albumin-bound paclitaxel) in sq-NSCLC.

Materials and Methods

Study Design

This trial (NCT06746179) is an investigator-initiated, prospective, Phase II, open, multicentral, single-arm clinical study to evaluate the efficacy and safety of endostar in combination with sintilimab plus Nab-PP in patients with locally advanced/advanced and recurrent metastatic sq-NSCLC (Figure 1). Enrollment is expected to be 64 patients, with the first patient enrolled in December 2024 and the first dose administered in January 2025. Study completion is expected in the first quarter of 2027.

Figure 1.

Study Design.

Key Eligibility Criteria

Participants in this study must have histologically or cytologically confirmed advanced or metastatic (stage IIIB, IIIC, or IV) squamous NSCLC with negative driver gene testing. Patients were not eligible for enrollment if they had received prior vascular endothelial growth inhibitor therapy, such as bevacizumab and anlotinib. The remaining key inclusion or exclusion criteria are detailed in Table 1.

Table 1.

Eligibility Criteria for Enrollment.

Inclusion criteria	Exclusion criteria
1. Age 18 to 70 years, male or female. 2. Histologically or cytologically confirmed locally advanced or metastatic (stage IIIB, IIIC, or IV) squamous NSCLC without driver mutations. Patients who developed metastatic or locally advanced disease during or after neoadjuvant and/or adjuvant therapy are eligible. 3. At least one measurable lesion according to RECIST v1.1. If there is only one measurable lesion and it has been biopsied, baseline imaging must be performed at least 14 days after the biopsy. If the only measurable lesion is within a previously irradiated area, enrollment requires documented radiographic progression based on pre- and post-radiotherapy imaging, and at least 3 months must have passed since the end of radiotherapy. 4. ECOG performance status of 0 or 1. 5. Expected survival ≥ 3 months. 6. No prior systemic anti-tumor therapy（including radiotherapy, chemotherapy, targeted therapy, or immunotherapy), or patients who have relapsed at the end of adjuvant chemotherapy with more than 6 months of follow-up. 7. Major Organ Function Requirements Within 7 Days Prior to Treatment, must meet the following criteria: Hematological Parameters (without blood transfusion within 14 days): Hemoglobin (HB) ≥ 90 g/L, Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, Platelet count (PLT) ≥ 80 × 10⁹/L Biochemical Criteria: Total bilirubin (TBIL) ≤ 1.5 × the upper limit of normal (ULN), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (for patients with liver metastases, ALT and AST ≤ 5 × ULN), 3) Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 60 mL/min, 4)Serum albumin ≥ 35 g/L Coagulation Function: International Normalized Ratio (INR) ≤ 1.5, Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN Cardiac Function: Doppler ultrasound assessment indicating a left ventricular ejection fraction (LVEF) ≥ 50% (lower limit of normal) 8. Availability of tumor tissue and/or blood samples for biomarker analysis (eg, PD-L1). Preferably, freshly collected tissue samples; if unavailable, 5–8 paraffin sections (3-5 μm) collected within the past 2 years may be used. Patients lacking available tissue may still be enrolled upon investigator evaluation if other criteria are met. 9. Premenopausal women of childbearing potential must have a negative serum or urine pregnancy test within 7 days before treatment and must not be breastfeeding. All patients of childbearing potential must use effective barrier contraception during treatment and for 6 months after the last dose.	1. History of severe allergic or anaphylactic reactions to humanized antibodies or fusion proteins. 2. Known hypersensitivity to Endostar or any component of the antibody preparation. 3. Diagnosis of immunodeficiency or undergoing systemic glucocorticoid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of the study (physiological doses, eg, ≤ 10 mg prednisone daily, are permitted). 4. Patients with active, known or suspected autoimmune diseases (eg, interstitial pneumonitis, colitis, hepatitis, pituitary gland inflammation, vasculitis, nephritis, hypothyroidism, including, but not limited to, these diseases or syndromes) are excluded. Subjects with type I diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, skin disorders that do not require systemic therapy (eg, vitiligo, psoriasis, or alopecia areata) or have a condition that is not expected to recur in a state without external triggers can be enrolled. 5. Severe cardiovascular disease (eg, congestive heart failure, uncontrolled high-risk arrhythmia, unstable angina, myocardial infarction, severe heart valvular disease). 6. Prior treatment with VEGF/VEGFR-targeting agents (eg, bevacizumab, sunitinib, sorafenib, imatinib, famitinib, regorafenib, apatinib, and erlotinib). 7. Planned other systemic antitumor therapy within 4 weeks prior to enrollment or during the study treatment period. 8. Presence of active hepatitis B (HBV DNA ≧2000IU/ml or 104copies/ml), hepatitis C (hepatitis C antibody positive and HCV-RNA above the lower limit), need to be evaluated by a specialist for enrollment. 9. Active tuberculosis (TB) infection based on chest x-ray, sputum examination and clinical examination. A history of active TB within the past year is also exclusionary, even if treated. For TB history >1 year, patients must provide documentation of adequate prior treatment to be eligible. 10. Presence of active central nervous system (CNS) metastases. Previously treated brain metastases will be permitted to enroll if clinically stable for ≥2 weeks and off corticosteroids ≥3 days(counting from the time of the first administration of study). Untreated but asymptomatic brain metastases (eg, no neurologic symptoms requiring corticosteroids) are eligible. CNS lesions cannot be used as target lesions. 11. Major surgery, incisional biopsy, or serious trauma within 28 days prior to enrollment. 12. Imaging evidence of tumor invasion into major blood vessels, or high risk of fatal hemorrhage as assessed by the investigator. 13. History or signs of bleeding tendency, regardless of severity. Any bleeding or hemorrhagic event of CTCAE grade ≥3 within 4 weeks prior to enrollment. Presence of unhealed wounds, ulcers, or fractures. 14. Arterial or venous thromboembolic events within 6 months (eg, stroke, transient ischemic attacks, deep vein thrombosis, pulmonary embolism). 15. Any serious comorbidity, in the investigator's judgment, that may interfere with study conduct or patient safety.

Inclusion criteria

Exclusion criteria

1. Age 18 to 70 years, male or female.

2. Histologically or cytologically confirmed locally advanced or metastatic (stage IIIB, IIIC, or IV) squamous NSCLC without driver mutations. Patients who developed metastatic or locally advanced disease during or after neoadjuvant and/or adjuvant therapy are eligible.

3. At least one measurable lesion according to RECIST v1.1.

If there is only one measurable lesion and it has been biopsied, baseline imaging must be performed at least 14 days after the biopsy.

If the only measurable lesion is within a previously irradiated area, enrollment requires documented radiographic progression based on pre- and post-radiotherapy imaging, and at least 3 months must have passed since the end of radiotherapy.

4. ECOG performance status of 0 or 1.

5. Expected survival ≥ 3 months.

6. No prior systemic anti-tumor therapy（including radiotherapy, chemotherapy, targeted therapy, or immunotherapy), or patients who have relapsed at the end of adjuvant chemotherapy with more than 6 months of follow-up.

7. Major Organ Function Requirements Within 7 Days Prior to Treatment, must meet the following criteria:

Hematological Parameters (without blood transfusion within 14 days): Hemoglobin (HB) ≥ 90 g/L, Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, Platelet count (PLT) ≥ 80 × 10⁹/L

Biochemical Criteria: Total bilirubin (TBIL) ≤ 1.5 × the upper limit of normal (ULN), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (for patients with liver metastases, ALT and AST ≤ 5 × ULN), 3) Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 60 mL/min, 4)Serum albumin ≥ 35 g/L

Coagulation Function: International Normalized Ratio (INR) ≤ 1.5, Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN

Cardiac Function: Doppler ultrasound assessment indicating a left ventricular ejection fraction (LVEF) ≥ 50% (lower limit of normal)

8. Availability of tumor tissue and/or blood samples for biomarker analysis (eg, PD-L1). Preferably, freshly collected tissue samples; if unavailable, 5–8 paraffin sections (3-5 μm) collected within the past 2 years may be used. Patients lacking available tissue may still be enrolled upon investigator evaluation if other criteria are met.

9. Premenopausal women of childbearing potential must have a negative serum or urine pregnancy test within 7 days before treatment and must not be breastfeeding. All patients of childbearing potential must use effective barrier contraception during treatment and for 6 months after the last dose.

1. History of severe allergic or anaphylactic reactions to humanized antibodies or fusion proteins.

2. Known hypersensitivity to Endostar or any component of the antibody preparation.

3. Diagnosis of immunodeficiency or undergoing systemic glucocorticoid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of the study (physiological doses, eg, ≤ 10 mg prednisone daily, are permitted).

4. Patients with active, known or suspected autoimmune diseases (eg, interstitial pneumonitis, colitis, hepatitis, pituitary gland inflammation, vasculitis, nephritis, hypothyroidism, including, but not limited to, these diseases or syndromes) are excluded. Subjects with type I diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, skin disorders that do not require systemic therapy (eg, vitiligo, psoriasis, or alopecia areata) or have a condition that is not expected to recur in a state without external triggers can be enrolled.

5. Severe cardiovascular disease (eg, congestive heart failure, uncontrolled high-risk arrhythmia, unstable angina, myocardial infarction, severe heart valvular disease).

6. Prior treatment with VEGF/VEGFR-targeting agents (eg, bevacizumab, sunitinib, sorafenib, imatinib, famitinib, regorafenib, apatinib, and erlotinib).

7. Planned other systemic antitumor therapy within 4 weeks prior to enrollment or during the study treatment period.

8. Presence of active hepatitis B (HBV DNA ≧2000IU/ml or 104copies/ml), hepatitis C (hepatitis C antibody positive and HCV-RNA above the lower limit), need to be evaluated by a specialist for enrollment.

9. Active tuberculosis (TB) infection based on chest x-ray, sputum examination and clinical examination. A history of active TB within the past year is also exclusionary, even if treated. For TB history >1 year, patients must provide documentation of adequate prior treatment to be eligible.

10. Presence of active central nervous system (CNS) metastases. Previously treated brain metastases will be permitted to enroll if clinically stable for ≥2 weeks and off corticosteroids ≥3 days(counting from the time of the first administration of study). Untreated but asymptomatic brain metastases (eg, no neurologic symptoms requiring corticosteroids) are eligible. CNS lesions cannot be used as target lesions.

11. Major surgery, incisional biopsy, or serious trauma within 28 days prior to enrollment.

12. Imaging evidence of tumor invasion into major blood vessels, or high risk of fatal hemorrhage as assessed by the investigator.

13. History or signs of bleeding tendency, regardless of severity. Any bleeding or hemorrhagic event of CTCAE grade ≥3 within 4 weeks prior to enrollment. Presence of unhealed wounds, ulcers, or fractures.

14. Arterial or venous thromboembolic events within 6 months (eg, stroke, transient ischemic attacks, deep vein thrombosis, pulmonary embolism).

15. Any serious comorbidity, in the investigator's judgment, that may interfere with study conduct or patient safety.

Patients who comply with all the inclusion criteria and do not fulfill any of the exclusion criteria will be given the opportunity to participate in the study and will be provided with all relevant information both verbally and in writing. If they decide to participate in the study, they will be required to voluntarily sign an informed consent form and adhere to the protocol requirements.

Treatment Methods

All eligible patients will receive systemic therapy with carboplatin + albumin-bound paclitaxel and sintilimab combined with endostar：

Endostar: administered by intravenous pumping at a dose of 210 mg/dose, Day1–3 dosing, with each intravenous pumping lasting for 72 h.

Sintilimab: 200 mg/dose administered intravenously.

Albumin-bound paclitaxel: a dose of 260 mg/m² administered by intravenous drip over a duration of not less than 30 min.

Cisplatin (75 mg/m²) or carboplatin (AUC = 5, Calvert's formula), administered by intravenous drip. Each drip of cisplatin lasts more than 2 h and carboplatin about 60 min. At the end of the IV drip of albumin paclitaxel, cisplatin or carboplatin was infused 30 min later. The choice between cisplatin and carboplatin was based on patients’ preference and clinical judgment.

Dose is given every 3 weeks (Q3 W), taking 3 weeks as 1 treatment cycle. Cisplatin or carboplatin is administered for a maximum of 6 cycles. If disease progression does not occur after 4–6 cycles, maintenance therapy with sintilimab in combination with endostar may be continued until disease progression, initiation of a new antineoplastic therapy, intolerable toxicity, or termination of therapy for other reasons, whichever occurs first.

Study end Points & Evaluations

The primary endpoint was progression-free survival (PFS) as assessed by the Independent Review Committee (IRC) according to the Rating Criteria for the Evaluation of the Efficacy of Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included investigator-assessed PFS, and overall survival (OS), duration of response (DOR), disease control rate (DCR) and safety as assessed by the IRC and investigators according to RECIST v1.1.

Exploratory endpoints include the collection and analysis of tumor tissue specimens and blood samples for potential biomarkers, such as PD-L1 expression and CD8⁺ T-cell infiltration using immunohistochemistry (IHC), VEGF levels measured by ELISA or liquid-phase protein assays, RNA sequencing (RNA-seq) to assess gene expression profiles, whole exome sequencing (WES) and whole genome sequencing (WGS) to detect somatic mutations, copy number variations, and structural variants, and flow cytometric analysis to characterize immune cell populations. These biomarker analyses aim to evaluate the tumor microenvironment, immune response, and molecular characteristics, which may correlate with treatment efficacy, resistance mechanisms, and patient outcomes. In addition, quality of life will be assessed (using the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires). PD-L1 testing was not mandatory for enrollment and was only conducted for exploratory. Biomarker data will be explored for their potential predictive value and association with clinical outcomes. PD-L1 expression will be assessed using the Tumor Proportion Score (TPS), and patients will be stratified using a 1% cutoff (TPS ≥1% vs < 1%). VEGF levels will be analyzed as both continuous and categorical variables, with thresholds determined by cohort medians or exploratory statistical approaches.

After the start of treatment, radiological assessments will be evaluated every 8 weeks (± 7 days) during the 48 weeks of treatment and every 12 weeks (± 7 days) after 48 weeks. The investigator may increase the number of assessments based on clinical need. Assessments will continue until disease progression, initiation of new antineoplastic therapy, patient request for discontinuation of therapy, loss to follow-up, death, or end of study, whichever occurs first. If treatment is discontinued for reasons other than disease progression, patients will remain on their radiological assessments at the established times until one of the above events occurs. Radiological imaging was performed as scheduled regardless of delays or adjustments in dosing. In addition, for patients with CR or PR, confirmation of efficacy by the same measurements is required at least 4 weeks (28 days) after efficacy is first observed.

Adverse events include bleeding risks and cardiovascular toxicity associated with endostar and immune-related adverse events (irAEs) associated with PD-1 inhibition. All adverse events will be monitored and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Management will follow established clinical guidelines, including corticosteroid therapy for irAEs, and treatment interruption or discontinuation when necessary.

Statistical Analyses

Sample Size Calculation

The study was designed as a single-arm objective performance standard and statistical certainty was calculated based on the primary endpoint, PFS. According to the literature review, ORIENT-12 study reported median PFS of 5.5 months and 4.9 months for advanced squamous NSCLC treated with sintilimab in combination with chemotherapy versus chemotherapy, and the endostar's phase III trial had an ORR of 35.4% and a PFS of 6.3 months.¹³ Furthermore, ITT-WT's group (atezolizumab + bevacizumab + chemotherapy) of Impower150 study had a PFS of 8.3 months.⁶

Considering that the treatment regimen in this study was sintilimab combined with nab-pp and endostar, the median PFS in this study was predicted to be 8 months. Assuming a significance level of 0.05 (unilateral), statistical efficacy (80%), and an expected value of 8 months for mPFS, the sample size was estimated at 57 cases. Considering a 10% dropout rate, the planned enrollment was 64 cases.

Interim Analysis

A single interim analysis is planned for this study, which will be performed when 70% of the targeted PFS events have occurred. The O'Brien-Fleming boundaries will be determined using the Lan-DeMets alpha-spending function to control for type I error. This interim analysis will be conducted by an independent external statistician, who will assess the overall risk-benefit profile for participants. Based on predefined statistical assumptions and superiority criteria, the statistician will provide recommendations regarding whether the study should proceed to the final analysis as planned or if protocol modifications are warranted.

The reporting of this clinical study protocol conforms to the SPIRIT 2013 guidelines.¹⁴

Discussion and Prospective

Endostar, an anti-angiogenesis targeted agent, effectively inhibits tumor angiogenesis by specifically targeting vascular endothelial growth factor receptor (VEGFR), thereby blocking the binding of VEGF to its receptor.¹⁵ Additionally, it downregulates both the mRNA and protein expression of VEGF and suppresses the VEGFR signaling pathway. Notably, endostar is currently the only anti-angiogenic drug approved for first-line treatment of squamous non-small cell lung cancer (sq-NSCLC), demonstrating the ability to prolong patient survival without significantly increasing the risk of bleeding. In our study, Endostar was administered via a 72-h continuous infusion, based on exploratory clinical data from the ENPOWER study (NCT04063449) suggesting its feasibility and potential efficacy.¹⁶

Several preclinical studies have highlighted the potential of endostar in inducing tumor vascular normalization, improving the tumor immune microenvironment, and enhancing anti-tumor immune responses. Its combination with PD-1 inhibitors has shown significant synergistic effects, providing a strong theoretical rationale for the integration of endostar with ICIs and chemotherapy. In a Phase II clinical trial involving patients with advanced or metastatic non-squamous NSCLC, preliminary results demonstrated that the combination of recombinant human vascular endothelial inhibitor with immunotherapy and chemotherapy achieved an ORR of 53% and a DCR of up to 93%.¹⁷ Additionally, an ongoing Phase II clinical trial (NCT05243355) is currently evaluating the efficacy and safety of endostar in combination with envafolimab and chemotherapy in advanced sq-NSCLC.¹⁸

The above clinical trials, including this study, collectively focused on the efficacy and safety of recombinant human vascular endothelial inhibitor combined with PD-1 inhibitor and chemotherapy in advanced sq-NSCLC, and the results may jointly promote this combination therapy modality to become a viable treatment for advanced sq-NSCLC. Furthermore, by collecting tumor tissues and blood samples, our study also explores potential biomarkers to screen the optimal benefit population and provide a basis for the development of future individualized treatment strategies, which is expected to bring more clinical benefits to patients with advanced sq-NSCLC.

This study employs a single-arm design, which may introduce potential limitations such as the lack of a comparator group and selection bias. However, this design was selected to enable preliminary evaluation of the proposed combination therapy in sq-NSCLC, where limited clinical data exist. Moreover, considering the exploratory nature of the study and practical resource constraints, a randomized controlled trial was not feasible at this stage.

Conclusion

This study aims to evaluate the efficacy and safety of endostar combined with sintilimab and nab-pp in patients with advanced sq-NSCLC. The findings may provide preliminary evidence for a safe and effective treatment strategy in this population.

Footnotes

Abbreviations

Acknowledgments

The authors would like to thank all the patients and their families as well as the researchers at the centers for participating in this ongoing study.

ORCID iDs

Jie Peng

Jian-guo Zhou

Ethical Considerations

This study protocol (version 3.0) and the informed consent form were reviewed and approved by the institutional ethics committee or institutional review board (IRB) of each participating center. As the lead site, the Second Affiliated Hospital of Zunyi Medical University received approval from its Institutional Review Board (Approval No. KYLL-2024-061). The study procedures were designed to ensure that the conduct, evaluation, and documentation of the trial adhered to the ethical principles outlined in the Declaration of Helsinki and relevant regulatory requirements. Written informed consent was obtained from all participants prior to enrollment, including consent for publication of anonymized data.

Consent for Publication

The results of this study will be disseminated through peer-reviewed scientific journals, academic conferences, and relevant policy or clinical forums. The published findings will report on a single-arm, multicenter phase II clinical trial evaluating the efficacy and safety of sintilimab plus nab-paclitaxel in combination with a recombinant human vascular endothelial inhibitor for the treatment of patients with locally advanced, advanced, or recurrent metastatic squamous non-small cell lung cancer.

Author Contributions

Jian-Guo Zhou and Hu Ma led the overall conceptual and methodological design of the study, critically revised the manuscript. Shixiang Wang conducted statistical analyses. Junzhu Xu participated in the conception and design of the study, drafted themanuscript, made important revisions to the manuscript.Mi Meng, Sisi He, Jie Peng, Biao Yao, Yi Li, Yong Hu, Xiaobin Qian, Tianwu Wang were responsible for patient recruitment and randomization,obtaining informed consent, administering protocol treatments,assigning participants to interventions, providing medical care, andfollow-up. approved the final published version and agreed to be responsible for all aspects of the work.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2023ZD0502105), Ministry of Education in China Liberal arts and Social Sciences Foundation (Grant No. 24YJCZH462), the Foundation for Outstanding Young Talents in Higher Education Institutions, Guizhou (Grant No. QJJ[2024]333), China Lung Cancer Immunotherapy Research Project, Excellent Young Talent Cultivation Project of Zunyi City (Zunshi Kehe HZ (2023) 142), Future Science and Technology Elite Talent Cultivation Project of Zunyi Medical University (ZYSE 2023-02), the Key Program of the Education Sciences Planning of Guizhou Province (Grant No.7), Collaborative Innovation Center of Chinese Ministry of Education (Grant No. 2020-39).

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Materials and Data Accessibility Statement

In line with the criteria, the research datasets used in the study were supplied by the participating authors.

Trial registration

ClinicalTrials.gov identifier: NCT06746179.

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Sintilimab + Nab-PP Combined with Recombinant Human Vascular Endothelial Inhibitor for Locally Advanced/Advanced and Recurrent Metastatic Squamous Non-Small Cell Lung Cancer: Study Protocol for a Single-Arm,Multi-Centre Phase II Clinical Study

Abstract

Background

Objective

Methods

Keywords

Background

Materials and Methods

Study Design

Key Eligibility Criteria

Treatment Methods

Study end Points & Evaluations

Statistical Analyses

Sample Size Calculation

Interim Analysis

Discussion and Prospective

Conclusion

Footnotes

Abbreviations

Acknowledgments

ORCID iDs

Ethical Considerations

Consent for Publication

Author Contributions

Funding

Declaration of Conflicting Interests

Materials and Data Accessibility Statement

Trial registration

References