Biomarker-defined outcomes in metastatic clear cell renal cell carcinoma (mccRCC) receiving first-line (1L) immune checkpoint inhibitor-based therapy

Adults with mccRCC diagnosed through 2/4/2025 were identified in ConcertAI’s Patient360, a U.S. de-identified database integrating health records, claims, genomics, and mortality data. Patients initiating 1L IO-IO (ipilimumab + nivolumab) or IO-TKI (cabozantinib + nivolumab, pembrolizumab + axitinib, or lenvatinib + pembrolizumab) were included. Molecular testing performed prior to or during 1L therapy was collected. PD-L1 positivity was defined as ≥1% tumor cell staining. Overall survival (OS) and progression-free survival (PFS) were estimated via Kaplan-Meier methods; associations by treatment and biomarker status were assessed using Cox models.

Among 4,845 patients with mccRCC, 3,225 patients had 1L treatment data, of whom 1,007 (31.2%) received IO-based therapy. IO-based therapy included IO-IO (508 patients; 50.4%) and IO-TKI (499 patients; 49.6%). Among patients receiving IO-based therapy, median age was 62 years, and 63.6% had de novo metastatic disease. Tumor genomic alterations were identified in 125 patients, including VHL (77.6%), PBRM1 (50.4%), BAP1 (28.8%), and SETD2 (4.8%). Patients with any alterations in VHL, PBRM1, or BAP1 demonstrated significantly longer median PFS with IO-TKI compared with IO-IO (37.9 vs. 18.4 months, respectively; p=0.04). In gene-specific analyses, similarly large numerical differences in PFS were observed with IO-TKI vs. IO-IO amongst patients with VHL (38.0 vs. 18.4 months) and PBRM1 (34.4 vs. 18.4 months) alterations. In the overall cohort, median PFS was 32.2 vs. 20.8 months (p=0.06), and median OS was 58.4 vs. 56.7 months (p=0.60) for IO–TKI and IO–IO, respectively. Among 102 patients with available PD-L1 status, 25.5% were PD-L1-positive and 74.5% were PD-L1-negative. Among PD-L1-positive patients, OS and PFS did not significantly differ between regimens.

Among patients with mccRCC receiving 1L IO-based therapy, those harboring VHL, PBRM1, or BAP1 alterations were collectively associated with numerically longer PFS when treated with IO-TKI. These findings represent one of the first and largest biomarker-stratified comparisons of outcomes between IO-TKI and IO-IO regimens.