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Renal cell carcinoma (RCC), a prominent genitourinary cancer, is rising in global incidence, with significant therapeutic advancements shaping its management. RCC was a common theme of ESMO 2024. In a study unrelated, researchers analyzed outcomes for 930 patients with metastatic RCC (mRCC) treated with first-line immunotherapy combinations or immunotherapy-tyrosine kinase inhibitors (ICI-TKI).
Immunotherapy, either alone or combined with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has transformed the treatment of mRCC. However, no direct comparisons of these combinations exist, making real-world data critical for informed decision-making. This retrospective study assessed outcomes the 930 patients treated with immune checkpoint inhibitor (ICI) combinations or ICI-TKI therapies across 58 centers in 20 countries, focusing on overall survival (OS) and progression-free survival (PFS) in intermediate- and poor-risk groups per International Metastatic RCC Database Consortium (IMDC) criteria.
The study’s median follow-up was 18.7 months. Among intermediate-risk patients, ICI-TKI combinations significantly improved median OS (55.7 vs. 40.2 months) and PFS (30.7 vs. 13.2 months) compared to dual-ICI therapy. Poor-risk patients, however, showed no significant differences in OS or PFS between the two regimens. These findings highlight the potential superiority of ICI-TKI combinations for intermediate-risk patients while suggesting limited benefits for poor-risk individuals.
Key clinical factors influenced outcomes. Intermediate-risk patients with higher body mass index (BMI ≥25 kg/m²), sarcomatoid differentiation, or metastases in bone, brain, or liver fared worse, aligning with previous findings. Conversely, poor-risk patients’ OS and PFS were predominantly affected by bone and brain metastases, with prior nephrectomy having no notable impact. These disparities suggest varying molecular and immunological pathways between risk groups, underscoring the complexity of tailored treatment strategies.
The study also references findings from the COSMIC 313 trial, which evaluated triple-combination therapy including cabozantinib, nivolumab, and ipilimumab. While effective for intermediate-risk patients, the trial revealed no benefit for poor-risk individuals, consistent with the study’s results. This aligns with hypotheses that intermediate-risk patients benefit from therapies targeting the hypoxia-inducible factor (HIF)-VEGF pathway, whereas poor-risk patients might rely more on immune-specific pathways.
Despite its contributions, the study had limitations. Its retrospective nature, lack of centralized radiological review, and insufficient data on comorbidities or concomitant medications constrain the findings. Additionally, the study’s reliance on investigator-reported radiological assessments and exclusion of non-assessable patients might introduce biases. These limitations underscore the need for prospective studies to validate these observations.
Overall, real-world evidence from this study suggests that ICI-TKI combinations may be optimal for intermediate-risk mRCC patients, offering superior OS and PFS compared to dual-ICI therapy. However, poor-risk patients did not demonstrate significant differences in outcomes between regimens, challenging the utility of TKI-containing combinations in this subgroup. These findings emphasize the importance of stratified treatment approaches based on patient risk profiles, paving the way for more personalized RCC management. Further research, including prospective trials, is necessary to confirm these results and refine therapeutic strategies for mRCC.
