Journal Article

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

Church, David, Loiero, Dominik, Nijman, Hans W., Haan, Floris-Jan, Koelzer, Viktor Hendrik, Paijens, Sterre T., Wardenaar, René, Bosse, Tjalling, Klomp, Rie, van Rooij, Nienke, Foijer, Floris, de Lange, Natascha M., Vledder, Annegé, Klok, Patty, Jalving, Mathilde, de Bruyn, Marco, Spierings, Diana, Brummel, Koen, Plat, Annechien, Bart, Joost, Eerkens, Anneke L., Roelofsen, Thijs, Yigit, Refika, Reyners, Anna K. L., Requesens, Marta, ter Elst, Arja

2024

Overview

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment. Immune checkpoint blockade (ICB) has shown promising activity in patients with advanced endometrial cancer, however its potential in the context of loco-regional disease remains unclear. Here the authors report the results of a phase I trial of neoadjuvant pembrolizumab (anti-PD1) in patients with mismatch repair deficient resectable endometrial cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/51 / 38/91 / 42 / 45 / 45/90 / 692/308/575 / 692/4028/67/1059/2325 / 692/4028/67/1517/1931 / 692/4028/67/580/1884 / Adult / Aged / Antibodies, Monoclonal, Humanized - therapeutic use / Cancer / Colorectal cancer / DNA Mismatch Repair / Effectiveness / Endometrial cancer / Endometrial Neoplasms - diagnostic imaging / Endometrial Neoplasms - drug therapy / Endometrial Neoplasms - genetics / Endometrial Neoplasms - immunology / Endometrial Neoplasms - pathology / Endometrium / Feasibility studies / Female / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - therapeutic use / Immune response / Immune system / Immunotherapy / Lymph nodes / Lymphatic drainage / Lymphocytes / Lymphocytes T / Magnetic resonance imaging / Middle Aged / Mismatch repair / Monoclonal antibodies / multidisciplinary / Neoadjuvant Therapy / Patients / PD-1 protein / Pembrolizumab / Regional analysis / Science / Science (multidisciplinary) / Toxic diseases / Toxicity / Treatment Outcome / Uterine cancer / Yeast