Phase 2, Two-Group, Two-Stage, Open-Label Study Of Avelumab In Patients With Microsatellite Stable, Microsatellite Instable And Pole-Mutated Recurrent Or Persistent Endometrial Cancer.

TPS5615 Background: The Cancer Genome Atlas project identified 2 groups of hypermutated endometrial cancers (ECs): an ultramutated group that harbored mutations in the exonuclease domain of polymerase e ( POLE), and a hypermutated group with microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation. We (Howitt, JAMA Onc 2015) and others have shown that POLE and MSI ECs are associated with higher number of predicted neoepitopes and tumor infiltrating lymphocytes, which is counterbalanced by overexpression of PD-1/PD-L1, suggesting that they may be excellent candidates for PD-1/PD-L1 blockade. Anti-PD-1 therapy has also demonstrated promising activity in mismatch repair deficient colorectal cancers and collectively in non-colorectal cancers (Le, NEJM 2015). Methods: This is an open-label, two-cohort, two-stage, phase 2 trial, of avelumab, a fully human IgG1 antibody directed against PD-L1, in two cohorts: i) a MSI/ POLE cohort including ECs with immunohistochemical (IHC) complete loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) a MSS cohort including ECs with normal IHC expression of all MMR proteins. Key eligibility criteria include measurable disease, no upper limit of prior therapies, and any EC histology. Co-primary objectives include objective response rate and rate of progression-free survival at 6 months. Avelumab is administered at 10 mg/kg as 1-hour IV infusion every 2 weeks until disease progression or unacceptable toxicity; therapy may continue at the investigator’s discretion while awaiting radiologic confirmation of disease progression 4 weeks later. Maximum target enrollment is 70 patients (35 for each cohort). In the first stage, 16 patients will be enrolled in each cohort; if there are at least two objective responses or two patients progression-free at 6 months, accrual will continue to the second stage where 19 more patients will be enrolled for each cohort. Thus far, 16 patients have been enrolled, 13 on the MSS cohort and 3 on the MSI/ POLE cohort. Clinical trial information: NCT02912572.