What Is The Optimal Sequencing Strategy For Combining Checkpoint Inhibitors With Vascular Endothelial Growth Factor (VEGF) Inhibitors In Patients With Advanced Clear Cell Renal Cell Carcinoma (ccRCC), Considering The Recent Findings Of The IMmotion151 And JAVELIN Renal 101 Trials And The Potential Implications For Tumor Mutational Burden And PD-L1 Expression?

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The optimal sequencing strategy for combining checkpoint inhibitors with VEGF inhibitors in advanced clear cell renal cell carcinoma (ccRCC) is as follows:

  1. Upfront Combination Therapy:

    • Patient Selection: Initiate with a combination of a checkpoint inhibitor (e.g., atezolizumab or avelumab) and a VEGF inhibitor (e.g., bevacizumab or axitinib) for most patients, particularly those with high PD-L1 expression, as supported by the IMmotion151 and JAVELIN Renal 101 trials. This approach is associated with improved progression-free survival (PFS) and, in some cases, overall survival (OS).
    • Biomarker Consideration: While high PD-L1 expression predicts a better response, the combination may still offer benefits to patients with low PD-L1, suggesting its use across broader patient groups.

  2. Consideration of Toxicity and Patient Factors:

    • Assess patient tolerance for potential side effects of combination therapy. While efficacy is improved, toxicity may necessitate careful monitoring and management, including possible dose adjustments.

  3. Subsequent Therapy Upon Progression:

    • Second-Line Options: After progression on upfront combination therapy, consider switching to another VEGF inhibitor or exploring alternative immunotherapy regimens. Decision-making should be individualized, taking into account tumor biology, including PD-L1 expression and tumor mutational burden (TMB), though TMB's role in ccRCC is less established.

  4. Role of Biomarkers:

    • PD-L1: Remains the primary biomarker for guiding therapy, with higher expression levels indicating potential benefit from immunotherapy.
    • TMB: While not as established in ccRCC, emerging research may clarify its utility in the future.

  5. Patient-Centered Approach:

    • Tailor treatment decisions based on patient performance status, comorbidities, and tolerance to therapy, balancing efficacy with quality of life.

In conclusion, the upfront use of combination therapy is recommended for most patients with advanced ccRCC, with subsequent treatments adjusted based on disease response and individual patient factors.