First-Line Treatment Strategies in IMDC Favourable-Risk Metastatic Clear Cell Renal Cell Carcinoma

Area of Science:

• Oncology
• Genitourinary Cancers
• Renal Cell Carcinoma

Background:

• Immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are standard for advanced clear cell renal cell carcinoma (ccRCC).
• Current guidelines recommend ICI plus VEGF-TKI (IO+TKI) for favorable-risk ccRCC (IMDC score 0) based on response rates and progression-free survival.
• However, overall survival (OS) benefits for IO+TKI in this subgroup remain unproven.

Purpose of the Study:

• To evaluate the efficacy and safety of IO+TKI combinations versus sunitinib in favorable-risk advanced ccRCC.
• To investigate the role of molecular subtypes in treatment response within the favorable-risk ccRCC population.
• To assess the potential for overtreatment with current standard-of-care in specific favorable-risk ccRCC patient groups.

Main Methods:

• Pooled analysis of four pivotal phase III trials including 839 favorable-risk patients.
• Comparison of overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and toxicity between IO+TKI and sunitinib monotherapy.
• Exploration of molecular classifications, including transcriptomic subgroups and gene expression (e.g., HIF pathway), in relation to treatment outcomes.

Main Results:

• No statistically significant OS advantage was observed for IO+TKI compared to sunitinib (HR 1.24; 95% CI 0.86-1.78).
• IO+TKI combinations were associated with higher rates of Grade ≥ 3 adverse events (71-82%) compared to sunitinib (63-72%) and substantially greater cost.
• Favorable-risk ccRCC exhibits molecular heterogeneity, with an angiogenic subtype showing high VEGF-TKI responsiveness and less benefit from immunotherapy.

Conclusions:

• Universal application of IO+TKI in favorable-risk ccRCC may lead to overtreatment due to lack of OS benefit, increased toxicity, and higher costs.
• VEGF-TKI monotherapy and active surveillance are viable alternatives for selected favorable-risk patients, especially those with indolent disease.
• Development of predictive biomarkers and molecular risk stratification is crucial for personalizing treatment and identifying candidates for de-escalation strategies, such as HIF-2α inhibitors.