Clinical and Molecular Validation of the Very Favorable IMDC Risk Group in Metastatic Renal Cell Carcinoma

Importance: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria stratify metastatic renal cell carcinoma (mRCC) into favorable, intermediate, and poor risk groups, but heterogeneity within the favorable risk category remains poorly understood. Objective: To evaluate a proposed very favorable subgroup (tier 1: Karnofsky Performance Status ≥90%; diagnosis to treatment ≥3 years; and no brain, liver, and bone metastases) and characterize its molecular and clinical features. Design, Setting, and Participants: This retrospective cohort study analyzed IMDC data, from January 2015 to September 2024, of patients with favorable risk mRCC (tier 1 and tier 2 [favorable and not tier 1]). Molecular profiling leveraged IMmotion151 (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) trial data with whole-exome sequencing, RNA sequencing, and programmed cell death ligand 1 immunohistochemistry. Exposures: Systemic standard of care treatments for mRCC, which include vascular endothelial growth factor receptor targeted therapy (VEGF-TT [sunitinib or pazopanib]), immune-oncology-VEGF (IO-VE [pembrolizumab and axitinib, pembrolizumab and lenvatinib, nivolumab and cabozantinib, or avelumab and axitinib]), and 2 IO (IO-IO [ipilimumab and nivolumab]) regimens. Main Outcomes and Measures: The primary end point of this study was overall survival (OS) at 2 years of the favorable risk group and in the tier 1 and tier 2 subgroups with the different treatment options. Secondary end points included time to next treatment, treatment duration, and overall response rate. Outcomes were compared across treatment types: VEGF-TT, IO-VE, and IO-IO. Results: Among 641 patients with favorable risk mRCC (median [IQR] age, 65 [58-71] years; 475 males [74.1%]), 176 (27.5%) were in tier 1, and 465 (72.5%) were in tier 2. Those in tier 1 met criteria for a very favorable subgroup, characterized by similar age and treatment distribution but lower rates of sarcomatoid features; more patients with only 1 metastatic site; and an absence of brain, bone, and liver metastases compared with patients in tier 2 with favorable risk. Patients in tier 1 showed a median OS of 79.1 (95% CI, 73.7 to not reached) months vs 54.5 (95% CI 45.5-67.7) months in tier 2 (P < .001) and distinct molecular features: high polybromo-1 alterations (64.7%), low BRCA1-associated protein 1 alterations (8.8%), and programmed cell death ligand 1 positivity (21.9%); transcriptomics revealed less immune-infiltrated tumors (8.5% immunogenic clusters) than in the other subgroups. Clinically, IO-IO underperformed in tier 1, with a 2-year OS of 73.1% (95% CI, 49.1%-97.1%) vs 89.1% (95% CI, 79.0%-99.2%) with IO-VE and 92.4% (95% CI, 86.5%-98.3%) for VEGF-TT (IO-IO hazard ratio, 3.64 [95% CI, 1.49-9.06]; P = .005), and a lower overall response rate (26.3% vs 63.3% in IO-VE and 57.0% in VEGF-TT). Conclusions and Relevance: In this cohort study, the very favorable risk subgroup had a less immunogenic molecular profile and superior outcomes from VEGF-containing regimens (VEGF-TT and IO-VE) compared with the favorable risk group. The IO-IO combination showed significantly worse survival in this population, suggesting that VEGF inhibition remains essential for optimal outcomes.