Immunotherapy in MMR-d/MSI-H recurrent/metastatic endometrial cancer

ABSTRACT

Introduction

The advent of immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the management of mismatch repair deficient (MMR-d)/microsatellite instability-high (MSI-H) endometrial cancer (EC). Initially investigated as monotherapy in phase I-II clinical trials for recurrent disease, immunotherapy demonstrated remarkable activity, yielding overall response rates (ORR) ranging from 27% to 58%. Based on these promising findings, phase III trials have explored the integration of immunotherapy into first-line treatment regimens for advanced/recurrent EC in combination with chemotherapy or other agents such as tyrosine kinase inhibitors (TKIs), resulting in improved ORR, progression-free survival, and overall survival compared to the standard chemotherapy regimen of paclitaxel and carboplatin. As a result, the incorporation of ICIs with standard platinum-based chemotherapy is becoming a new standard of care in MMR-d/MSI-H EC.

Areas covered

This review synthesizes literature from PubMed, Embase databases, and recent congress abstracts on gynecological cancers. It covers MMR-d/MSI-H EC incidence, molecular diagnostics, clinical trial outcomes, predictive biomarkers for ICIs, patient profiles likely to benefit, resistance mechanisms, and the future of immunotherapy in this setting.

Expert opinion

By offering a comprehensive overview, this review delineates the pivotal role of ICIs in the management of MMR-d/MSI-H EC.

KEYWORDS:

• Endometrial cancer
• immunotherapy
• microsatellite instability
• molecular diagnostics
• predictive biomarkers
• resistance mechanisms

Article highlights

• Immune checkpoint inhibitors (ICIs) therapy is based on the biological rationale of immune dysregulation in mismatch repair deficient (MMR-d)/microsatellite instability-high (MSI-H) endometrial cancer (EC), characterized by a high mutation load (TMB), tumor-infiltrating lymphocytes, and expression of the programmed death-1 receptor (PD-1) and programmed death-1 ligand (PD-L1).

• Monotherapy with ICIs in the second-line setting has played a pivotal role in the treatment of MMR-d/MSI-H EC and currently is the standard of care.

• Combining ICIs with chemotherapy in the first-line setting for MMR-d/MSI-H EC has led to significant improvements in progression-free survival and overall survival compared to standard chemotherapy, with medians yet to be reached.

• Administering ICIs to patients with a good performance status, and endometrioid histology, at an earlier stage of the disease, with high TMB, and positive expression of PD-L1 appears to yield better treatment outcomes.

• Ongoing studies will explore novel contexts for administering ICIs in MMR-d/MSI-H EC.

Declaration of interest

R Pacholczak-Madej reports having received lectures fees and travel grants from MSD, BMS, Roche, GSK. M. Bartoletti is on the advisory board for GSK, MSD, EISAI, Roche, lectures fees form GSK, AstraZeneca, MSD, and has received a travel grant from Pharmamar outside the submitted work. M Püsküllüoglu reports having received lectures fees and travel grants from Gilead, AstraZeneca, Novartis, Roche, Amgen and Janssen. P Blecharz reports having received lectures fees and travel grants from AstraZeneca, MSD, GSK. D. Lorusso is on the advisory Board, Personal, Participation in Advisory Boards and Invited Speakers: Astra Zeneca, Clovis Oncology, Corcept, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Novocure, Seagen, Sutro; Funding, Institutional, Financial interest, Clinical trial/contracted research: Astra Zeneca, Clovis Oncology, Pharmaand, Genmab,

GSK, Immunogen, Incyte, MSD, Novartis, Pharmamar, Roche, Seagen, Alkermes, Corcept. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.