Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of all kidney cancers, however, the effect of systemic chemotherapy is limited. We report the first results of a single-arm, phase 2 study (NCT05220267) evaluating the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor) combined with sintilimab (a monoclonal antibody against programmed cell death protein 1) as first-line treatment in patients with advanced nccRCC. Methods: Patients with histologically confirmed advanced nccRCC and measurable disease per RECIST v1.1 who had not previously received systemic therapy were received anlotinib (12 mg qd, d1-14, repeated every 21 days) plus sintilimab (200 mg IV Q3W) till disease progression or intolerant toxicity. The primary endpoint is progression-free survival (PFS); secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From April 2022 to December 2023, 43 patients were enrolled with a median age of 43 years (range: 18-79), 10 (23.3%) had papillary histology, 10 (23.3%) had FH-RCC histology, 8 (18.6%) had TFE3-RCC histology and 15 (34.9%) were unclassified. Among these participants, 34 patients were evaluable. 62.8% were IMDC intermediate- or poor-risk, 74.4% had prior nephrectomy and 100% had synchronous metastatic disease. ORR and DCR were 52.9%(95%CI 0.35-0.70)and 94.1%(95%CI 0.80-0.99), respectively.≥1 and <1 Combined Positive Score of PD-L1 expression were observed in 50.0% (17/34) and 32.4% (11/34) patients respectively, and the ORR was 52.9% (95%CI: 0.278-0.770) and 45.5% (95%CI: 0.167-0.766) in the two groups. The median time of the first response was 3.7 months (range, 3.3-9.5). As of January 7, 2024, median follow-up time was 8.5m (95%CI 4.8-12.3). The median PFS was 15.1m (95%CI 13.2-15.9). Treatment-related grade 3/4 adverse events were observed in 20.9% (9/43) of the patients, encompassed hyponatremia (3 patients, 7%), proteinuria (1 patients, 2%), anemia (1 patients, 2%), Hand-foot syndrome (4 patients, 9.1%). Neither unexpected safety signals nor treatment-related death occurred. Conclusions: Our results showed promising efficacy and acceptable toxicity of anlotinib plus sintilimab for patients with advanced nccRCC. Complete results are awaited in 2024 after follow-up completion of the entire cohort. Clinical trial information: NCT05220267.