Sintilimab, Anlotinib Hydrochloride and Platinum-Containing Dual-Agent Chemotherapy in NSCLC

This is a single-arm, prospective, exploratory clinical study aiming to evaluate the efficacy and safety profile of sintilimab combined with anlotinib hydrochloride and platinum-containing dual-agent chemotherapy regimens in advanced or metastatic NSCLC as first-line treatment. Totally 40 patients with negative driver genes (20 patients of squamous cell carcinoma, 20 patients of non-squamous cell carcinoma) are to be enrolled.

Sintilimab (200 mg intravenously, once every 3 weeks; Cinda Bio-Suzhou Co., Ltd., Suzhou, Jiangsu, China) and anlotinib hydrochloride (12 mg orally, once daily before breakfast; CTTQ, Lianyungang, Jiangsu, China) are to be administered as first-line therapy in NSCLC. Besides, patients with non-squamous NSCLC will also receive pemetrexed and cisplatin or carboplatin. Meanwhile, patients with squamous NSCLC will also receive albumin paclitaxel and carboplatin. Patients assessing as CR/PR/SD will continue to receive a maintenance treatment after 4-6 cycles of treatment. Patients with non-squamous NSCLC will be treated with sintilimab + anlotinib hydrochloride + pemetrexed chemotherapy regimen while patients with squamous NSCLC will be treated with sintilimab + anlotinib hydrochloride to maintain treatment for 2 years until disease progression, intolerable toxicity, death, and patient request for discontinuation or starting new anti-tumor treatment.

Observations and assessments will be conducted before treatment, on day 7, 21 of cycle 1, on day 21 of cycle 2, every 2 cycles (42 days) during the following cycles, and after treatment. Follow-up for survival status and subsequent antineoplastic therapy data collecting will be performed by telephone interview or face-to-face every 6 weeks after treatment until disease progression, death, or end of the study (whichever occurs first).

This study will be divided into two stages: the safety lead-in period and the preliminary efficacy evaluation period. The first stage is the safety lead-in period. 3 patients with squamous NSCLC and 3 patients with non-squamous NSCLC will be enrolled to evaluate the combined therapy safety. The first 6 patients will continue to be observed from the beginning of the combined treatment until the 6th patient has been treated for 2 cycles (6 weeks). If there are less than or equal to 2 patients with intolerable side effects, they will enter the next stage. A total of 40 patients (20 patients with squamous NSCLC, 20 patients of non-squamous NSCLC) will be enrolled, and the safety and efficacy of the combined treatment will be initially evaluated. All statistics will be analyzed by statistical analysis software (SAS) 9.2 (or higher version). The single-sided 0.05 superiority hypothesis test will be used to test statistics and the comparison between groups will give a 95% confidence interval and p-value.

Efficacy is to be analyzed in the full analysis set (FAS), the response evaluable set (RES), and the per-protocol set (PPS). Safety is to be analyzed in safety set (SS) including all assigned patients who receive at least one dose of study combined therapy and have safety records of medication. Statistical descriptions of subject distribution, demographic data, and baseline characteristics will be performed. For study endpoints, the Kaplan-Meier method is to be applied for the PFS and OS curve with estimation for median PFS, median OS, and 95% CI. ORR= (CR+PR) / sample size×100%; DCR= (CR+PR+SD) / sample size×100%. The 95% CI of the ORR and DCR is to be calculated by an exact binomial method based on the F distribution. For safety analysis, only treatment-emergent adverse events (TEAE) will be included and analyzed in this experiment, which is defined as AEs that are post-dose or heavier than the baseline. Medical Dictionary for Regulatory Activities (MedDRA), system organ class (SOC), preferred terms (PT) and NCI CTCAE 5.0 will be used to standardize and classify all adverse events and summarize the incidence of AEs and association with treatments.

Eligibility Criteria:
Inclusion Criteria:

* 1. Voluntary provision of informed consent.
* 2. Males or females aged 18-75.
* 3. Histological or cytologically confirmed NSCLC, metastatic or recurrent (stage IV), non-resectable or radical radio-chemotherapy locally advanced (stage IIIB-IIIC).
* 4. Not suitable for targeted therapy (patients with non-squamous NSCLC have no EGFR, ALK, or ROS1 gene mutation)
* 5. At least one lesion can be measured by imaging.
* 6. Have not received systemic treatment in the past.
* 7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
* 8. Life expectancy ≥ 3 months.
* 9. Female of childbearing age must have a negative pregnancy test (serum or urine) within 7 days before enrolment.

Exclusion Criteria:

* 1. Histological or cytologically confirmed small cell lung cancer (SCLC), including lung cancer mixed with SCLC and NSCLC.
* 2. Received radiation therapy within 6 weeks.
* 3. Diagnosed with other malignant diseases other than NSCLC within 5 years.
* 4. Have participated in other interventional clinical research treatments now or within 4 weeks.
* 5. Have previously received targeted therapy.
* 6. Received Chinese patent medicines with anti-lung cancer indications or immunomodulatory drugs within 2 weeks.
* 7. Have active autoimmune diseases requiring systemic treatment within 2 years.
* 8. Received systemic glucocorticoid therapy or immunosuppressive therapy within 7 days.
* 9. Clinically uncontrollable pleural effusion/abdominal effusion.
* 10. Known allogeneic organ transplantation or hematopoietic stem cell transplantation.
* 11. Known to be allergic to study drug.
* 12. Have been vaccinated with the live vaccine within 30 days.
* 13. Pregnant or breastfeeding females.
* 14. Other serious hazards to the safety of patients.