Genomic Determinants of De Novo Resistance to Immune Checkpoint Blockade in Mismatch Repair–Deficient Endometrial Cancer

Abstract

INTRODUCTION : Despite the success of programmed death 1 (PD-1)/PD ligand 1 (PD-L1) inhibitors in mismatch repair-deficient (MMRD) endometrial cancer (EC), many patients exhibit de novo resistance.1,2 To identify determinants of resistance to immune checkpoint blockade (ICB) in MMRD EC, we evaluated genomic data from patients who were enrolled in an investigator- initiated clinical trial of avelumab.3 In that study, avelumab met the prespecified criteria to be considered worthy of additional investigation in MMRD EC with an objective response rate of 26.7%. Responses to avelumab were observed regardless of PD-L1 expression, the presence or absence of tumor-infiltrating lymphocytes, multiple prior lines of therapy, and somatic or germline origin of MMRD, which suggests that baseline clinical and pathologic characteristics could not predict response. Here, we report Janus kinase 1 (JAK1) and β2- microglobulin (B2M) mutations and a higher number of insertions and deletions (indels) and exposure to an MMRD-associated mutational signature—Signature 20 in the Catalogue Of Somatic Mutations In Cancer—as candidate genomic determinants of de novo resistance to ICB in MMRD EC. PATIENTS