Anlotinib plus everolimus as first-line treatment for advanced non–clear cell renal cell carcinoma: 1 year updated results from UC-001, a single-center, single-arm, phase II trial.

4525 Background: For patients (pts) with recurrent or stage IV non-clear cell renal cell carcinoma (nccRCC), the current guidelines recommend participation in clinical trials, or the use of tyrosine kinase inhibitors (TKIs), such as sunitinib, or mTOR inhibitors, such as everolimus. Anlotinib, a novel multi-target TKI, inhibits vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet-derived growth factor receptors, and c-kit. The ALTER-UC-001 study (NCT05124431) is a single-center, single-arm, phase II trial evaluating the efficacy and safety of anlotinib plus everolimus as first-line therapy in pts with advanced nccRCC. Data for 24 pts from Jan 2022 through Dec 2023 have been published in 2024 ASCO. Here, we present 1-year updated results. Methods: Eligible pts were those with advanced nccRCC and no prior systemic therapy for advanced disease, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Pts received anlotinib (12 mg orally once daily on days 1-14 of each 3-week cycle) and everolimus (5 mg orally once daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were graded according to CTCAE v5.0. Results: Between January 2022 and December 2024, 32 pts were enrolled and received treatment. The median age was 56 years old (range: 20-79 years), and 46.9% of pts had papillary renal cell carcinoma (pRCC). Most pts (81.3%; 26/32) had a ECOG PS score of 1. At the data cutoff in December 2024, with a median follow-up of 11.9 months (95% CI 9.3-14.5), the ORR was 54.5% (95% CI 32.2-75.6), and the DCR was 100% (95% CI 84.6-100.0). The median PFS was 20.8 months (95% CI 12.0-29.6). Adverse events (AEs) of any grade occurred in 90.6% of pts, with the most common being proteinuria (40.6%), mucositis and hypertension (37.5%), and anemia, increased creatinine, elevated transaminases (18.8%), glutamic-pyruvic transaminase increased and hematuria (15.6%), and hypercholesterolemia (12.5%). Grade 3 treatment-related AEs (TRAEs) occurred in 15.6% of pts, with no treatment-related deaths. Treatment was suspended in 18.8% (6/32) and 12.5% (4/32) of pts due to TRAEs associated with everolimus and anlotinib, respectively. Conclusions: This study demonstrates that anlotinib combined with everolimus is an effective and tolerable first-line therapy for advanced nccRCC, achieving a high ORR and prolonged PFS, with manageable toxicity. These findings provide critical evidence supporting the use of this novel combination in nccRCC. Survival follow-up is ongoing, and further validation in larger, multi-center randomized trials is warranted. Clinical trial information: NCT05124431 .