Phase I / II Clinical Study on the Safety and Preliminary Efficacy of Anlotinib Hydrochloride Combined With Platinum-containing Simultaneous Radiotherapy in the Treatment of Locally Advanced Non-small Cell Lung Cancer

Lung cancer is the most common cancer, accounting for 20% of cancer-related deaths worldwide. In 2015, an estimated 610,200 patients (22 per cent of cancer-related deaths) died of lung cancer. Non-small cell lung cancer ((NSCLC)) accounts for 80% to 85% of lung cancer. Most patients are locally advanced or metastatic diseases at the time of diagnosis. Some IIIA tumors are considered resectable, but many IIIA (with larger N2) and IIIB (T4, any NM0, any TN3M0) are not considered suitable for surgery.

Since the 1990s, simultaneous radiotherapy and chemotherapy ((CHRT)) has become the cornerstone of (NSCLC) in locally advanced non-small cell lung cancer (NSCLC). At present, there is no clinical evidence of survival benefits of synchronous radiotherapy plus TKI targeted therapy for unresectable stage Ⅲ A and stage Ⅲ B non-small cell lung cancer. However, a HELPER STUDY study was conducted to evaluate the efficacy and safety of continuous intravenous infusion combined with EP regimen plus concurrent radiotherapy in the treatment of unresectable stage Ⅲ NSCLC. The median survival time was 34.7 months and the 3-year survival rate was 47.7%. anlotinib capsule is a small molecule multi-target tyrosine kinase inhibitor. Compared with bevacizumab, its anti-tumor therapy has three unique advantages: 1. Inhibition of multiple targets, such as VEGFR, PDGFR, FGFR, c-Kit, etc., improves the effectiveness against a variety of malignant tumors, mainly in the following three aspects: first, it is aimed at several fatal pathways of tumor cells themselves, namely, driving gene pathways. Seal them all off one by one; Secondly, blocking vascular targeting: inhibition of vascular endothelial cell receptors such as VEGFR, PDGFR, FGFR and so on. These three tyrosine kinase receptors and their corresponding ligands play an important role in angiogenesis: VEGF can proliferate cells, FGF and PDGF make vascular endothelial cells chemotactic to the vicinity of the tumor to form neovascularization. Let the pericytes of the blood vessels be covered to form a complete structure of the blood vessels; Finally, it can inhibit both tumor cells and tumor angiogenesis: because only suppressing tumor growth, tumor cells secrete some factors to save themselves, resulting in dense compensation for the vascular network, so that the tumor is supplied with blood. Will madly proliferate again, forming drug-resistant tumors. two。. Oral drug, convenient and effective: pharmacokinetic studies on the metabolism of anlotinib in vivo have found that the peak time of the drug in blood is 4 to 11 hours after administration, and the half-life is about 90 hours. Stopping for one week for two weeks can keep the blood drug concentration in the treatment window stably, which is safe and effective, more tolerant, convenient to use, and can improve the quality of life of patients. 3. Compared with the macromolecular monoclonal antibody represented by bevacizumab, the half-life of the drug is shorter, the long-term use of TKI, is smaller, the corresponding side effects are less, and the incidence of adverse events is lower than that of bevacizumab. In the II phase study of erlotinib combined with bevazumab, the incidence of hypertension with JO25567,3 degree or above was as high as 60%, and the tolerance of the patients was relatively poor. In the ALTER 0303 test, the common adverse reactions in the anlotinib group were fatigue, hypertension, skin toxicity and so on, but the incidence of grade 1-2 AE,SAE was lower (15.3%). And most of them can be relieved by symptomatic treatment or reduction, and the safety of the drug is good. This study was a clinical study on the treatment of locally advanced unresectable NSCLC with anlotinib hydrochloride combined with platinum-containing simultaneous radiotherapy. To observe and evaluate the safety and tolerance of anlotinib hydrochloride combined with cisplatin plus etoposide or pemetrexed in the treatment of locally advanced NSCLC patients. To determine the maximum tolerable dose of (MTD) and / or stage II clinical recommended dose (RP2D) and evaluate its preliminary efficacy. In the first stage of this study, 12 patients with locally advanced NSCLC were divided into 3 experimental groups. After taking three different doses of anlotinib combined with platinum simultaneous radiotherapy, the dose limited toxicity was observed, and the maximum tolerable dose was determined in the second stage. 78 patients were enrolled according to RP2D, and the indexes such as ORR were evaluated. To evaluate the safety and efficacy of anlotinib combined with platinum-containing simultaneous radiotherapy in the treatment of locally advanced NSCLC.

1. Administration regimen: anlotinib (21 days as a cycle, 2 weeks, 1 week). Group 1: 8mg po qd, Group 2: 10mg po qd, Group 3: 12mg po qd;

Combined chemotherapy:

Cisplatin 50 mg 2, ivgt, D1, 8, 29, 36, etoposide 50 mg 2, ivgt, D1-5, 29-33; Or PC: carboplatin AUC2, paclitaxel 45-50 mg 2 per week; Cisplatin 25 mg 2, ivgt, D1-3, 22-24, pemetrexed ivgtt,500 mg/m2,ivgtt,d1, d22; (non-squamous cell carcinoma).