Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma

Endometrial cancer can be characterized by high instability of microsatellites (MSI-H), a biomarker indicative of sensibility to immune checkpoint inhibitors (ICIs). The results of the KEYNOTE-158 trial led to the approval of pembrolizumab - a monoclonal, humanized IgG4 kappa anti-PD-1 antibody able to prevent T-cell PD-1/tumor cell PD-L1/2 interaction, thus restoring T-cell-mediated anti-tumor immunity - in MSI-H endometrial cancer relapsing after at least one line of chemotherapy (CT).

Ongoing trials, such as KEYNOTE-B21/ENGOT-en11, KEYNOTE-C93/ENGOT-en15/GOG-3064, and NRG/GY018, aim to move this option earlier in the algorithm, whether adjuvant or first-line, even CT-free. Combinatorial approaches associating ICIs with other target therapies blocking immunosuppressive pathways are also being studied.

The ICI overall response rates in MSI-H patients are encouraging, but over 50% do not respond to treatment. A more thorough definition of the MSI status regarding specific missing proteins could allow better use of this biomarker and explain why specific populations may not respond to immunotherapy regardless of widely accepted predictive biomarkers. Future developments should focus on identifying who can benefit from a CT-free treatment and translational research on primary resistant MSI-H EC.