Effectiveness and Safety of Anti-VEGF/VEGFR Monotherapy vs Combination with ICIs in Advanced RCC

Overview

This network meta-analysis compares anti-VEGF/VEGFR monotherapy with combination therapy including immune checkpoint inhibitors (ICIs) in advanced or metastatic renal cell carcinoma (RCC). Findings suggest that combination therapies improve progression-free and overall survival but may increase certain adverse events. Subgroup analyses highlight the importance of patient risk stratification and population-specific responses.

Background

Renal cell carcinoma (RCC) is a common kidney malignancy with poor prognosis in advanced stages, especially when metastasis is present at diagnosis or develops post-surgery. Targeting the VEGF pathway has been central to RCC treatment, with tyrosine kinase inhibitors (TKIs) improving outcomes but often limited by resistance and toxicity. Combining VEGF/VEGFR inhibitors with immune checkpoint inhibitors (ICIs) has shown promise in enhancing anticancer efficacy. However, safety profiles and optimal treatment selection remain complex due to varying adverse event incidences and inconsistent guideline recommendations.

Data Highlights

Phase III trials such as CLEAR, CheckMate 9ER, and KEYNOTE-426 demonstrated superior progression-free survival (PFS) and overall survival (OS) with ICI-based combinations compared to TKI monotherapy. However, grade ≥ 3 treatment-related adverse events were more frequent with some combinations, notably lenvatinib plus pembrolizumab. The RENOTORCH trial evaluated toripalimab plus axitinib in Asian populations, addressing previous data gaps. Meta-analyses report mixed safety outcomes, with some combinations showing higher toxicity profiles.

Key Findings

• Combination therapy of anti-VEGF/VEGFR agents with ICIs improves PFS and OS compared to monotherapy in advanced RCC.
• Grade ≥ 3 adverse events are more common with certain combination regimens, particularly lenvatinib plus pembrolizumab.
• Safety profiles vary among regimens, with specific anti-angiogenesis-related adverse events such as hypertension, fatigue, proteinuria, and hand-foot syndrome requiring careful monitoring.
• Subgroup analyses indicate that efficacy advantages of combination therapy may be less pronounced in low-risk patient groups.
• Asian population data, including from the RENOTORCH trial, provide important insights for treatment optimization in diverse ethnic groups.
• Current international guidelines differ on first-line treatment recommendations, reflecting ongoing uncertainty in optimal regimen selection.

Clinical Implications

Clinicians should weigh the improved survival benefits of combination anti-VEGF/VEGFR and ICI therapies against the increased risk of high-grade adverse events. Patient risk stratification and ethnic background are important considerations when selecting first-line treatments. Close monitoring for specific toxicities associated with anti-angiogenic agents is essential to optimize patient outcomes.

Conclusion

Combining VEGF/VEGFR inhibitors with immune checkpoint inhibitors offers enhanced efficacy in advanced RCC but introduces a distinct toxicity profile. Individualized treatment decisions informed by risk stratification and population-specific data are critical to maximizing therapeutic benefit.

References

1. Global Cancer Statistics 2025 -- Incidence and Mortality of RCC
2. Phase III Trials: CLEAR, CheckMate 9ER, KEYNOTE-426 -- Efficacy of ICI Combinations
3. RENOTORCH Trial -- Toripalimab Plus Axitinib in Asian Patients
4. NCCN, EAU, Chinese Guidelines -- RCC Treatment Recommendations
5. PRISMA-NMA Guidelines -- Network Meta-Analysis Methodology