First-Line Treatment for Advanced Non-squamous Non-Small-Cell Lung Cancer With Negative Driver Gene: a Single-center, Single-Arm Trial

To evaluate the efficacy and safety of sintilimab plus bevacizumab and platinum-based doublet chemotherapy as the first-line therapy for advanced nonsquamous non-small-cell lung cancer(NSCLC) with negative driver gene.

This study is an exploratory single-arm study. The specific treatment regimen is as follows: Non-squamous NSCLC: Sintilimab (200 mg) plus Bevacizumab (7.5mg/kg) is started on the first day of each treatment cycle and administered every three weeks. Nedaplatin (80-100 mg/m2) (d2) +pemetrexed 500 mg/m2 (d2) Q3W is administered in this regimen for 4 cycles followed by sintilimab plus bevacizumab until disease progression or intolerable toxicity.

Patients are assessed for measurable disease at baseline, 6 weeks, 12 weeks after starting treatment, and every 9 weeks thereafter according to RECIST 1.1 criteria during the treatment period until disease progression or intolerable toxicity withdrawal. Following discontinuation of treatment, subjects are followed for survival status every 3 months until death. Subject safety was assessed during treatment according to NCI CTCAE Version 4.0 criteria. Subjects who experience an AE should be followed until the AE returns to baseline. The primary endpoints is Progression-free survival (PFS) . Secondary endpoints include objective response rate (ORR), overall survival (OS) and safety (NCI CTCAE v 4.0). Statistical methods: The PFS curve was estimated using the Kaplan-Meier method for the largest population to be analyzed. The confidence interval method was used as the criterion for the main analysis. OS was calculated in the same way as the secondary endpoint. Descriptive statistics will be used to analyze ORR, DCR, etc. It is expected that sintilimab plus bevacizumab and platinum-based doublet chemotherapy as first-line treatment will prolong median PFS and OS in patients with driver gene-negative advanced Non-squamous NSCLC.

Lung cancer is the most common cause of cancer mortality worldwide\[1\]. NSCLC represents more than 80% of lung cancer cases\[2\], with most having nonsquamous histology\[3\].Current first-line treatment options in metastatic nonsquamous NSCLC without oncogenic driver alterations include checkpoint inhibitor monotherapy in patients with high programmed death-ligand 1 (PD-L1) expression and checkpoint inhibitor therapy in combination with platinum-doublet chemotherapy with or without bevacizumab\[4.5\].Despite the available standard-of-care first-line treatments, clinical outcomes have remained suboptimal and additional therapeutic options are needed.

Sintilimab is a recombinant, fully human IgG4 anti-PD-1 monoclonal antibody. Preclinical data have shown that sintilimab has a greater affinity against PD-1 than pembrolizumab or nivolumab\[6\].In a randomised, double-blind, phase 3 trial, sintilimab plus chemotherapy resulted in significantly longer progression-free survival and overall survival versus chemotherapy alone in patients with treatment-naive NSCLC without EGFR or ALK genomic tumour mutations, with a manageable safety profile\[7.8\].

Bevacizumab, in addition to its known anti-angiogenic effects, has immunomodulatory effects through inhibition of vascular endothelial growth factor (VEGF), including promotion of dendritic cell maturation; normalisation of the tumour vasculature, which might increase T-cell infiltration; and reprogramming of the tumour microenvironment from being immune suppressive to immune permissive\[9.10\]. Therefore, reversal of VEGF-mediated immunosuppression by bevacizumab could enhance the antitumour activity of sintilimab.

We aimed to evaluate the efficacy and safety of sintilimab with bevacizumab plus platinum-based doublet chemotherapy for the treatment of patients with driver gene-negative advanced nonsquamous NSCLC.

Objective: To evaluate the efficacy and safety of sintilimab plus bevacizumab and platinum-based doublet chemotherapy as the first-line therapy for advanced nonsquamous non-small-cell lung cancer with negative driver gene.

The research idea starts from the safety and efficacy of sintilimab plus bevacizumab and platinum-based doublet chemotherapy for NSCLC. Under the theoretical perspective of clinical research on cancer treatment, an exploratory single-center single-arm study method is used to perform sintilimab plus bevacizumab and platinum-based doublet chemotherapy regimen for first-line treatment of advanced nonsquamous NSCLC patients with negative driver gene. A database is established for the enrolled case report form, systematic data analysis is performed, and finally the study conclusions of above treatment safety and efficacy are obtained. It is expected that sintilimab plus bevacizumab and platinum-based doublet chemotherapy as first-line treatment will prolong median PFS and OS in patients with driver gene-negative advanced nonsquamous NSCLC.

This study is an exploratory single-arm study. The specific treatment regimen is as follows :Non-squamous NSCLC: Sintilimab (200 mg) plus Bevacizumab (7.5mg/kg) is started on the first day of each treatment cycle and administered every three weeks. Nedaplatin (80-100 mg/m2) (d2) +pemetrexed 500 mg/m2 (d2) Q3W is administered in this regimen for 4 cycles followed by sintilimab plus Bevacizumab until disease progression or intolerable toxicity.

Patients are assessed for measurable disease at baseline, 6 weeks, 12 weeks after starting treatment, and every 9 weeks thereafter according to RECIST1.1 criteria during the treatment period until disease progression or intolerable toxicity withdrawal. Following discontinuation of treatment, subjects are followed for survival status every 3 months until death. Subject safety was assessed during treatment according to NCI CTCAE Version 4.0 criteria. Subjects who experience an AE should be followed until the AE returns to baseline. The primary endpoints is Progression-free survival (PFS) . Secondary endpoints include objective response rate (ORR), overall survival (OS) and safety (NCI CTCAE v 4.0).

Statistical methods: The PFS curve was estimated using the Kaplan-Meier method for the largest population to be analyzed. The confidence interval method was used as the criterion for the main analysis. OS was calculated in the same way as the secondary endpoint. Descriptive statistics will be used to analyze ORR, DCR, etc.

Eligibility Criteria:
Inclusion Criteria:

1. Metastatic Non-squamous NSCLC is histologically or cytologically proven to be inoperable and cannot receive radical concurrent chemoradiotherapy. The conventional TNM stage was identified as stage IIIa-Ⅳb according to the International Association for the Study of Lung Cancer and the American Joint Committee on the Classification of Cancer 8th edition TNM Staging of Lung Cancer.
2. Patients with driver-negative advanced Non-squamous NSCLC.
3. Patients who had not previously received systemic radiotherapy and chemotherapy or who had relapsed for more than 6 months of follow-up after onset of adjuvant chemotherapy.
4. At least one measurable lesion as determined by RECIST criteria.
5. Male or female patients, age: 18-75 years of age.
6. Performance score 0-1 based on Eastern Cooperative Oncology Group (ECOG) test.
7. Expected survival period ≥12 weeks.
8. Serum absolute number of neutrophils≥ 1.5 x 10\^9/L, platelet ≥ 100 x10\^9/L, and hemoglobin≥ 90g/L.
9. Serum bilirubin≤1.5 times ULNL, aspartate aminotransferase (AST) and adenosine triphosphate(ALT) ≤ 2.5 times ULN, alkaline phosphatase ≤ 5 times ULN.
10. Serum creatinine≤ the ULN or creatinine clearance ≥ 60 mL/min.
11. Patients who had previously undergone surgery have recovered for more than 4 weeks from the beginning of the project.
12. Women with an intact uterus must have a negative pregnancy test within 28 days prior to enrolement in the study (unless it was 24 months after amenorrhea). If the pregnancy test is more than 7 days prior to initial dosing, a urine pregnancy test is required for verification (within 7 days prior to initial dosing).
13. If there is a risk of conception, all patients (whether male or female) are required to use contraceptive measures with an annual failure rate of less than 1% throughout the treatment period until 120 days after the last dose of the study drug.
14. Sign the inform consent form with good compliance.

Exclusion criteria:

1. Those who are known to be allergic to the study drug sintilimab, bevacizumab and and its any components.
2. Intolerance to study drug treatment or allergy to the active ingredients or excipients of combined chemotherapy drugs.
3. Pregnancy or breastfeeding women or women who may be pregnant but are unwilling to take appropriate contraception.
4. Existing severe acute infections that are not under control; Or suppurative and chronic infections with delayed healing.
5. Pre-existing serious heart disease, including: congestive heart failure, uncontrolled high-risk arrhythmias, unstable angina pectoris, myocardial infarction, severe valvular heart disease, and refractory hypertension.
6. People suffering from uncontrollable neuropsychiatric diseases or mental disorders had poor compliance and were unable to cooperate and describe treatment responses; The conditions of patients with primary brain tumor or central nerve metastatic tumor were uncontrollable and the symptoms of cranial hypertension or neuropsychiatric were obvious.
7. Patients with hereditary bleeding tendency or coagulation dysfunction, or history of thrombosis or bleeding, and abnormal detection results of coagulation function related indicators.
8. Patients who are receiving thrombolytic or anticoagulant therapy due to high risk of thrombosis.
9. Patients with unhealed wounds, unhealed ulcers or unhealed fractures.
10. Other conditions that the investigator considers to be inappropriate for the patient to participate in this trial.
11. Currently participating in interventional clinical research treatment, or have received other investigational drugs or used investigational device treatment within 4 weeks before the first dose.
12. Patients who have undergone major surgery within 4 weeks before the start of study treatment or are scheduled to undergo major surgery during the study period (except for surgery such as puncture or lymph node biopsy).
13. Pulmonary interstitial fibrosis with respiratory failure.
14. Chronic obstructive pulmonary disease with respiratory failure.
15. Active pulmonary tuberculosis;
16. Active autoimmune disease requiring systemic therapy (such as the use of disease-modifying drugs, glucocorticoids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (such as thyroxine) is not considered systemic therapy;
17. Those who are receiving systemic glucocorticoid therapy (excluding nasal spray, inhalation or other local glucocorticoids) or any other form of immunosuppressive therapy within 14 days before the first dose of the study;
18. Have previously received the following therapies: anti-pd1 drugs, anti-PD-L1 drugs.