e16546 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of all kidney cancers, includes papillary RCC, chromophobe RCC, unclassified RCC, and rare entities. Because nccRCC has different molecular characteristics from clear cell carcinoma, drug regimens routinely used for clear cell carcinoma are not very effective in controlling the growth of nccRCC cells. Novel combination regimen of angiogenic inhibitors and immune checkpoint inhibitors has demonstrated significant anti-tumor activity in certain subtypes. The purpose of this trial (NCT05220267) is to evaluate the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor that effectively inhibit VEGFR, FGFR, PDGFR, c-KIT, c-MET and RET) combined with sintilimab (a monoclonal antibody against programmed cell death protein 1) as first-line treatment in patients with advanced nccRCC. Methods: This study is a prospective, single-arm, open-label, phase II clinical trial. Patients aged 18 years or older, without prior systematic treatment, with histologically confirmed advanced nccRCC (defined as TNM staging IV, unresectable locally recurrent or metastatic disease), and ECOG PS 0-1 were considered eligible for enrollment. Patients were treated with oral anlotinib (12 mg once daily on days 1-14, repeated every 21 days) plus intravenous sintilimab (200 mg, once every 3 weeks) till disease progression or intolerant toxicity. The primary endpoint is progression-free survival (PFS) and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: Between April 2022 and January 2023, 18 patients (of 13 patients were male) were enrolled (successfully screened and treated with therapeutic regimen at least one time) with a median age of 46 years (range, 18–79). 72.2% of patients had received prior radical nephrectomy and 6% of patients received radiotherapy. PD-L1 expression was determined in 11 patients, of which 5/11(45.5%) had CPS > 1 and 3/11 (27.3%) had CPS > 10. At data cutoff (31 January 2023), 9 patients were evaluable and median (95% CI) follow-up time was 3.7 (0.6-6.8) months, the ORR and DCR were 22.2% (95% CI, 2.8-60.0) and 100% (95% CI, 66.4-100.0), respectively. The median PFS was not reached. The most frequently reported treatment-related adverse events were grade 1 and grade 2 included hand-foot syndrome 55.6%, hyperuricemia 38.9%, proteinuria 33.3%, hoarseness 33.3%, diarrhea 27.8%, hyperthyroidism 27.8%, pharyngitis 27.8%, hypercholesterolemia 27.8%, hyperglycemia 27.8%. Only 4 patients (22.2%) happened grade 2 AEs. No higher grade AEs were observed. Conclusions: Anlotinib combined with sintilimab were preliminary shown promising efficacy with a favourable toxicity profile for patients with advanced nccRCC. Clinical trial information: NCT05220267 .