Immune checkpoint inhibitors for recurrent endometrial cancer

ABSTRACT

Introduction

Endometrial cancer (EC) is the most common gynecologic malignancy. Outcomes for patients with advanced and/or recurrent disease have been modest with the use of chemotherapy. The approval of immune checkpoint inhibitors targeting PD-1 has recently revolutionized human cancer treatment. Recent trials with immune checkpoint inhibitors used alone or in combination with other agents, have demonstrated remarkable efficacy in the treatment of the all-comers EC patient population.

Areas covered

In this article, we review major clinical trials on PD-1/PD-L1 inhibitors in advanced and recurrent EC and discuss the response rates of these agents in the context of their genomic background.

Expert opinion

Immune checkpoint inhibitors have significantly changed our approach to the treatment of advanced/recurrent EC. Single agent anti-PD-1 regimens are highly effective in MMRd/MSI-H patients, but their clinical efficacy remains modest in MMR proficient/TMB low EC patients. Combination regimens that can decrease the tumor microenvironments immunosuppression and increase tumor immunogenicity represent a viable treatment option to broaden the activity of immune checkpoint inhibitors in advanced/recurrent EC patients. An increased understanding of the biomarkers of response and the molecular mechanisms of resistance to immune checkpoint inhibitors remains key for the next advancement of the field.

KEYWORDS:

• Endometrial cancer
• immune checkpoint inhibitors
• immunotherapy
• PD-1 inhibitor
• PD-L1 inhibitor
• targeted therapy

Article highlights

• Endometrial carcinoma is classified into four clusters with different mutational signatures and mutational load: POLE ultra-mutated, MMR deficient/MSI-H, Copy Number Low, and Copy Number High

• PD-1 and PD-L1 interaction results in decreased T-cell response to tumor cells; accordingly, the targeting of this pathway with immune checkpoint inhibitors has emerged as an efficacious strategy for treatment of recurrent or advanced endometrial carcinoma

• POLE ultra-mutated and MMRd/MSI-H endometrial carcinomas have a high mutational load, increased tumor infiltrating lymphocytes and an excellent response rates to single agent anti-PD-1 regimens

• Combination regimens, such as pembolizumab and lenvatinib, have shown significant efficacy not only in MSI-H, but also in MMR proficient endometrial carcinoma as reported in KEYNOTE-775.

• Resistance to immune checkpoint inhibitors include mutations in antigen presentation and cytokine pathways and the upregulation of other immune checkpoints.

Declaration of interest

No funding was used for the preparation of this manuscript. Dr. Alessandro Santin reports grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO, grants and personal fees from EISAI. Other authors do not have grants to report.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have no funding to report.