A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability
- Authors
- Bellone, Stefania; Roque, Dana M.; Siegel, Eric R.; Buza, Natalia; Hui, Pei; Bonazzoli, Elena; Guglielmi, Adele; Zammataro, Luca; Nagarkatti, Nupur; Zaidi, Samir; Lee, Jungsoo; Silasi, Dan-Arin; Huang, Gloria S.; Andikyan, Vaagn; Damast, Shari; Clark, Mitchell; Azodi, Masoud; Schwartz, Peter E.; Tymon-Rosario, Joan R.; Harold, Justin A.; Mauricio, Dennis; Zeybek, Burak; Menderes, Gulden; Altwerger, Gary; Ratner, Elena; Alexandrov, Ludmil B.; Iwasaki, Akiko; Kong, Yong; Song, Eric; Dong, Weilai; Elvin, Julia A.; Choi, Jungmin; Santin, Alessandro D.
- Issue Date
- Mar-2022
- Publisher
- WILEY
- Keywords
- clinical trial results; endometrial cancer; gynecologic cancers; gynecologic oncology; immunotherapy; checkpoint blockade; phase 2 clinical trial
- Citation
- CANCER, v.128, no.6, pp.1206 - 1218
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCER
- Volume
- 128
- Number
- 6
- Start Page
- 1206
- End Page
- 1218
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/139458
- DOI
- 10.1002/cncr.34025
- ISSN
- 0008-543X
- Abstract
- Background Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). Methods Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for <= 2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). Results Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. Conclusions This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.
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