Immuno-molecular features and therapeutic implications of brain metastases in clear cell renal cell carcinoma...

Area of Science:

• Oncology
• Translational Research
• Genomics

Background:

• Brain metastases (BrM) in metastatic clear-cell renal cell carcinoma (m-ccRCC) present a therapeutic challenge due to resistance to standard systemic therapies.
• Cabozantinib has shown improved response rates in patients with BrM compared to other treatments.

Purpose of the Study:

• To evaluate the intracranial response of various systemic therapies in m-ccRCC patients with BrM.
• To elucidate the molecular mechanisms associated with treatment efficacy and resistance in BrM.
• To identify the optimal systemic therapy for m-ccRCC patients with BrM.

Main Methods:

• Retrospective analysis of 30 m-ccRCC patients with BrM treated with 39 systemic therapy lines.
• Documentation of intracranial response rates and time-to-intracranial-progression for each therapy.
• Whole transcriptome sequencing of primary ccRCC tumors and metastatic lesions, including brain metastases.

Main Results:

• Cabozantinib (alone or with nivolumab) demonstrated the highest partial response rates (64% and 50%, respectively) and longest median time-to-intracranial-progression (not reached).
• Ipilimumab/nivolumab and pazopanib showed no partial responses, while nivolumab, sunitinib, axitinib, and axitinib/pembrolizumab had lower response rates.
• Molecular analysis revealed higher cMET and AXL expression in BrM, with decreased angiogenesis and immune scores, fewer CD8+ T-cells, and more M2-like macrophages.

Conclusions:

• Cabozantinib is the optimal systemic therapy for m-ccRCC patients with BrM.
• Baseline screening for BrM is crucial for guiding first-line treatment decisions in m-ccRCC patients, including those without symptoms.