Sintilimab Combined With Anlotinib Therapy for Initially Unresectable Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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Concurrent or sequential chemoradiotherapy has been recommended as the standard treatment for locally advanced and unresectable non-small cell lung cancer (NSCLC). However, its efficacy remains to be improved. PD-1/PD-L1 inhibitors have been proven to be effective for late-stage NSCLC, and anti-angiogenesis agents have also been used for the first-line treatment of advanced or metastatic NSCLC. Therefore, we designed this single-arm clinical trial, which aims to investigate the safety and feasibility of sintilimab combined with anlotinib therapy for patients with initially unresectable stage II-III NSCLC.

Detailed Description
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Concurrent or sequential chemoradiotherapy is the standard treatment for patients with locally advanced NSCLC, but patients receiving chemoradiotherapy have limited improvement in prognosis and are almost impossible to achieve a radical cure. Considering the excellent effect of immunotherapy and anti-angiogenesis therapy in NSCLC, we designed this single-arm clinical study, which aims to investigate the safety and feasibility of sintilimab combined with anlotinib therapy for patients with initially unresectable stage II-III NSCLC, in order to enable patients to achieve further surgical treatment and prolonged survival.

Official Title
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Sintilimab Combined With Anlotinib Therapy for Patients With Initially Unresectable Stage II-III Non-small Cell Lung Cancer: A Prospective, Single-arm Study

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Sintilimab
* Drug: Anlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: According to the 8th edition of the AJCC/UICC TNM staging system for NSCLC, patients with locally advanced (stage II-III C) NSCLC confirmed by histology who are initially unable to undergo surgery and concomitant radiochemotherapy and are confirmed to have at least one measurable lesion according to RECIST 1.1. Age ≥18 years and ≤75 years. ECOG PS score: 0 to 1. The main organs function is normal, that is, the following criteria met: Good hematopoietic function, defined as absolute neutrophil count ≥1.5×109 /L, platelet count≥100 ×109 /L, hemoglobin ≥90g/L [no blood transfusion or no erythropoietin (EPO) dependence within 7 days before enrollment]; Biochemical test results should meet the following criteria: BIL < 1.25 times the upper limit of normal value (ULN); ALT and AST < 2.5 × ULN; in case of liver metastases, ALT and AST < 5 × ULN; Cr ≤1.5×ULN or creatinine clearance (CCr) ≥60ml/min; Coagulation function is good, INR and PT ≤1.5 × ULN; The oxygen saturation of the finger tip ≥ 92% both at rest and during walking (without oxygen inhalation). The life expectancy ≥12 weeks. Signed and dated informed consent. Exclusion Criteria: Subjects at risk of massive hemoptysis or with blood in sputum, including but not limited to tumor lesions no more than 5 mm away from large vessels, tumors invading large vessels, and obvious lung cavity/necrotizing tumors. Small cell lung cancer (including mixed small cell and non-small cell lung cancer) or central squamous cell carcinoma. With driver mutation (EGFR/ALK/ROS1). With uncontrollable hypertension (systolic pressure > 160 mmHg, diastolic pressure > 100 mmHg) even receiving antihypertensive drug therapy. Has an active autoimmune disease, history of allogeneic stem cell transplantation or organ transplantation that has required systemic treatment. Replacement therapy is not considered a form of systemic treatment and is allowed. Has an active infection requiring systemic therapy. Has other malignant tumors (except radical cervical carcinoma in situ, non-melanoma skin cancer, etc.) or concomitant diseases that seriously endanger the patients or affect the patients completing the study at the same time. With immunodeficiency status, including but not limited to HIV infection and primary immunodeficiency diseases. Previously treated with ICIs. Is pregnant, breastfeeding, or expecting to conceive or father a child within the projected duration of the study including 120 days following the last dose of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>Sintilimab will be given intravenously at a dose of 200mg every 21 days. Anlotinib will be given at a dose of 12mg once daily on days 1-14 of a 21-day cycle. Tumor evaluation will be conducted after treatment of the tested regimen every 2 cycles. Subsequent treatment will be determined based on the evaluation results: If the patients are not suitable for radical surgery, but the result of efficacy evaluation is CR, PR, or SD, they can continue to receive the tested regimen. If the patients are still not suitable for radical surgery after 6 cycles of the tested regimen, the standard first-line or immunotherapy after chemoradiotherapy or radiotherapy will be given. If patients are eligible for radical surgery, surgery will be performed within 4 weeks after completion of the last tested regimen. | Drug: Sintilimab<br>* Sintilimab will be given intravenously at a dose of 200mg every 21 days.<br>* Other names: Tyvyt;Drug: Anlotinib<br>* Anlotinib will be given at a dose of 12mg once daily on days 1-14 of a 21-day cycle.<br>* Other names: AL3818;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical conversion rate | The surgical conversion rate was defined as the proportion of subjects with the successful conversion over all subjects who received the tested regime. | 18 weeks from the initiation of the tested regime therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is defined as the percentage of participants who have the best overall response (BOR) of complete response (CR) or partial response (PR) assessed based on RECIST 1.1. | 18 weeks from the initiation of the tested regime therapy | 
| R0 resection rate | R0 resection rate is defined as the complete resection rate of all tumor under microscope. | within 28 working days after operation | 
| Major pathological response rate | Major pathological response rate is defined as the percentage of patients who achieved a major pathological response (residual tumor ≤10%). | within 28 working days after operation | 
| Pathological complete response rate | Pathological complete response rate is defined as the percentage of patients who achieved a pathological complete response (residual tumor = 0%). | within 28 working days after operation | 
| Overall survival (OS) | OS is measured from the time from the treatment onset (date of first study dose) until the date of death from any cause. | 2 years from the initiation of the tested regime therapy | 
| Progression-free survival (PFS) | PFS is measured from the time from the treatment onset (date of first study dose) until the date of tumor progression or death from any cause. | 2 years from the initiation of the tested regime therapy | 
| Disease-free survival (DFS) | DFS is measured from the time from radical surgery until the date of tumor progression or death from any cause. | 2 years from the initiation of the tested regime therapy | 
| Treatment-related adverse events | Incidence and grade of treatment-related adverse events assessed based on CTCAE 5.0 | 3 months from the end of the tested regime therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small-cell lung cancer, Sintilimab, Anlotinib