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

Anneke L. Eerkens, Koen Brummel, Annegé Vledder, Sterre T. Paijens, Marta Requesens, Dominik Loiero, Nienke Rooij, Annechien Plat, Floris-Jan Haan, Patty Klok, Refika Yigit, Thijs Roelofsen, Natascha M. Lange, Rie Klomp, David Church, Arja Elst, René Wardenaar, Diana Spierings, Floris Foijer, Viktor Hendrik Koelzer, Tjalling Bosse, Joost Bart, Mathilde Jalving, Anna K. L. Reyners, Marco Bruyn () and Hans W. Nijman ()
Additional contact information
Anneke L. Eerkens: University Medical Centre Groningen
Koen Brummel: University Medical Centre Groningen
Annegé Vledder: University Medical Centre Groningen
Sterre T. Paijens: Erasmus University Medical Centre
Marta Requesens: University Medical Centre Groningen
Dominik Loiero: University of Zurich
Nienke Rooij: University Medical Centre Groningen
Annechien Plat: University Medical Centre Groningen
Floris-Jan Haan: University Medical Centre Groningen
Patty Klok: University Medical Centre Groningen
Refika Yigit: University Medical Centre Groningen
Thijs Roelofsen: University Medical Centre Groningen
Natascha M. Lange: Isala
Rie Klomp: Treant
David Church: University of Oxford
Arja Elst: University Medical Centre Groningen
René Wardenaar: University Medical Centre Groningen
Diana Spierings: University Medical Centre Groningen
Floris Foijer: University Medical Centre Groningen
Viktor Hendrik Koelzer: University of Zurich
Tjalling Bosse: Leiden University Medical Centre
Joost Bart: University Medical Centre Groningen
Mathilde Jalving: University Medical Centre Groningen
Anna K. L. Reyners: University Medical Centre Groningen
Marco Bruyn: University Medical Centre Groningen
Hans W. Nijman: University Medical Centre Groningen

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52098-8

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