Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC), the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. This a single-center, single-arm, phase II trial which will evaluate the efficacy and tolerability of anlotinib hydrochloride plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Key inclusion criteria are: age ≥18 years; histologically confirmed advanced nccRCC, advanced disease is defined as TNM stage IV, not available for surgery, locally recurrent or metastatic renal cell carcinoma; no prior systemic drug therapy for advanced disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Approximately 30 pts will be assigned to receive anlotinib hydrochloride: 12 mg every 21 days (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21) by oral, and everolimus 5mg qd, continued for up to 1 year (∼17 cycles ) or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Radiographic imaging will be performed every 6 weeks. Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Recruitment have begun in Jan. 2022. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT05124431.