Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer

J Clin Oncol. 2019 Oct 20;37(30):2786-2794. doi: 10.1200/JCO.19.01021. Epub 2019 Aug 28.

Abstract

Purpose: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).

Methods: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.

Results: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.

Conclusion: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Cohort Studies
  • DNA Mismatch Repair / genetics*
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / genetics
  • Female
  • Humans
  • Progression-Free Survival

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • avelumab