{"doi":"10.1002/cncr.34025","title":"A phase 2 evaluation of pembrolizumab for recurrent Lynch‐like versus sporadic endometrial cancers with microsatellite instability","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.","journal":"Cancer","year":2021,"id":151832,"datarank":2.440470518866964,"base_score":4.394449154672439,"endowment":4.394449154672439,"self_citation_contribution":0.6591673732008659,"citation_network_contribution":1.781303145666098,"self_endowment_contribution":0.6591673732008659,"citer_contribution":1.781303145666098,"corpus_percentile":null,"corpus_rank":null,"citation_count":80,"citer_count":74,"citers_with_citation_signal":57,"citers_with_endowment":57,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02899793"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":627749,"name":"Dana M. Roque","orcid":"0000-0002-7098-6376","position":1,"is_corresponding":false},{"id":308652,"name":"Eric R. Siegel","orcid":"0000-0001-9824-6612","position":2,"is_corresponding":false},{"id":256631,"name":"Natália Buza","orcid":"0000-0002-0008-334X","position":3,"is_corresponding":false},{"id":316314,"name":"Pei Hui","orcid":null,"position":4,"is_corresponding":false},{"id":315589,"name":"Elena Bonazzoli","orcid":"0000-0003-2024-8102","position":5,"is_corresponding":false},{"id":393622,"name":"Adele Guglielmi","orcid":null,"position":6,"is_corresponding":false},{"id":315591,"name":"Luca Zammataro","orcid":"0000-0002-4348-6341","position":7,"is_corresponding":false},{"id":391969,"name":"Nupur Nagarkatti","orcid":"0000-0002-5736-4214","position":8,"is_corresponding":false},{"id":645689,"name":"Samir Zaidi","orcid":null,"position":9,"is_corresponding":false},{"id":645025,"name":"Jungsoo Lee","orcid":"0000-0002-3807-4377","position":10,"is_corresponding":false},{"id":316313,"name":"Dan‐Arin Silasi","orcid":null,"position":11,"is_corresponding":false},{"id":391970,"name":"Gloria S. Huang","orcid":"0000-0002-0001-888X","position":12,"is_corresponding":false},{"id":391971,"name":"Vaagn Andikyan","orcid":"0000-0001-9326-0255","position":13,"is_corresponding":false},{"id":292554,"name":"Shari Damast","orcid":"0000-0001-9030-0872","position":14,"is_corresponding":false},{"id":645026,"name":"Mitchell Clark","orcid":"0000-0003-1118-9585","position":15,"is_corresponding":false},{"id":315597,"name":"Masoud Azodi","orcid":"0000-0002-0570-8089","position":16,"is_corresponding":false},{"id":315598,"name":"Peter E. Schwartz","orcid":"0000-0002-0845-3624","position":17,"is_corresponding":false},{"id":574758,"name":"Joan Tymon‐Rosario","orcid":"0000-0003-0198-4761","position":18,"is_corresponding":false},{"id":645027,"name":"Justin Harold","orcid":"0000-0002-9117-6946","position":19,"is_corresponding":false},{"id":645028,"name":"Dennis Mauricio","orcid":"0000-0002-1511-9544","position":20,"is_corresponding":false},{"id":315588,"name":"Burak Zeybek","orcid":"0000-0003-4146-8614","position":21,"is_corresponding":false},{"id":315596,"name":"Gulden Menderes","orcid":"0000-0002-3140-3860","position":22,"is_corresponding":false},{"id":315594,"name":"Gary Altwerger","orcid":"0000-0002-2252-947X","position":23,"is_corresponding":false},{"id":256635,"name":"Elena Ratner","orcid":"0000-0002-6277-6002","position":24,"is_corresponding":false},{"id":13201,"name":"Ludmil B. Alexandrov","orcid":"0000-0003-3596-4515","position":25,"is_corresponding":false},{"id":105840,"name":"Akiko Iwasaki","orcid":"0000-0002-7824-9856","position":26,"is_corresponding":false},{"id":51180,"name":"Yong Kong","orcid":"0000-0002-2881-5274","position":27,"is_corresponding":false},{"id":105822,"name":"Eric Song","orcid":"0000-0001-5448-5865","position":28,"is_corresponding":false},{"id":333790,"name":"Weilai Dong","orcid":"0000-0002-8376-1758","position":29,"is_corresponding":false},{"id":86396,"name":"Julia A. Elvin","orcid":"0000-0001-9476-9563","position":30,"is_corresponding":false},{"id":333799,"name":"Jungmin Choi","orcid":"0000-0002-8614-0973","position":31,"is_corresponding":false},{"id":256628,"name":"Alessandro D. Santin","orcid":"0000-0003-4724-9738","position":32,"is_corresponding":false},{"id":256632,"name":"Stefania Bellone","orcid":"0000-0001-5909-5292","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:43:16.823357Z","pmid":"34875107","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}