Data from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Abstract

<div>Abstract<p>Missense mutations in the polymerase epsilon (<i>POLE</i>) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many <i>POLE</i>-mutated tumors do not respond to such treatment. To better understand the link between <i>POLE</i> mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient <i>POLE</i>-mutated solid tumors. We found that only tumors harboring selective <i>POLE</i> pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy.</p>Significance:<p>POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring <i>POLE</i> mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy.</p><p><i>See related video: <a href="https://vimeo.com/720727355" target="_blank">https://vimeo.com/720727355</a></i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-6-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 1397</a></i></p></div>