Immunotherap. with immune checkpoint inhibitors (ICI) has become a cornerstone of the clinical management of some tumor types, particularly those with high PD-L1 expression, an unstable genome, or high mutational burden. By contrast to ICI monotherapy, few biomarkers exist to identify patients who may respond better to combination therapy with ICI and other targeted agents. In this study, Lee and colleagues report clinically effective stratification of renal cell carcinoma (RCC) patients who derived benefit from combination of lenvatinib, a multi-kinase inhibitor targeting VEGFR and FGFR, and the anti–PD-1 immunotherapeutic pembrolizumab. The authors found that patients with a diverse HLA-I genotype derived the most benefit from the combination. Specifically, HLA-I evolutionary divergence—a measure of the breadth of antigens and neoantigens that a patient's immune system can recognize—was a critical factor in determining outcomes in this phase Ib/II clinical trial, which was validated in an independent cohort that received ICI monotherapy. These...

You do not currently have access to this content.