In a phase II trial reported in the Journal of Clinical Oncology, Panagiotis A. Konstantinopoulos, MD, PhD, and colleagues found evidence of promising activity of the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in mismatch repair–deficient (MMRD) recurrent or persistent endometrial cancer, but not in MMR-proficient (MMRP) disease without a POLE (polymerase ε) mutation.
Panagiotis A. Konstantinopoulos, MD, PhD
Study Details
The study was intended to evaluate avelumab in two cohorts: an MMRD/POLE cohort, defined by immunohistochemical (IHC) loss of expression of one or more MMR proteins and/or documented mutation in the exonuclease domain of POLE; and an MMRP cohort with normal IHC expression of all MMR proteins.
Avelumab was given at 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The coprimary endpoints were objective response and progression-free survival at 6 months.
Responses
All 16 patients enrolled in the MMRD/POLE cohort had MMRD on IHC; none had a documented POLE mutation, with the cohort thus being referred to as the MMRD cohort. All 17 patients in the MMRP cohort were subsequently assessed for POLE mutations, with none being identified; this cohort was thus referred to as the MMRP/non–POLE-mutated cohort.
The MMRP/non–POLE-mutated cohort was closed after a first study stage due to futility; objective response and progression-free survival at 6 months was observed in only 1 of 16 patients. The MMRD cohort met the predefined primary endpoint of 4 patients experiencing objective response after accrual of only 17 patients; among the 15 patients who initiated avelumab in this cohort, 4 (26.7%) had an objective response (one complete and three partial responses) and 6 (40.0%), including the 4 patients with a response, achieved progression-free survival at 6 months; four patients with progression-free survival at 6 months had responses ongoing at the time of analysis. Responses were observed irrespective of PD-L1 expression status.
KEY POINTS
- Avelumab exhibited promising activity in mismatch repair–deficient endometrial cancer irrespective of PD-L1 expression status.
- Little evidence of activity was seen in patients with mismatch repair–proficient/non-POLE mutant disease.
The investigators noted that IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or via genomic targeted sequencing. They concluded, “Avelumab exhibited promising activity in MMRD [endometrial cancer] 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 [endometrial cancers] was low.”
Panagiotis A. Konstantinopoulos, MD, PhD, of Dana-Farber Cancer Institute, Harvard Medical School, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck KGaA/Pfizer Alliance. For full disclosures of the study authors, visit jco.ascopubs.org.
