Clinical Use of Dostarlimab in Advanced Stage and Recurrent Endometrial Cancer: Patient Selection and Perspectives

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Abstract

Endometrial cancer (EC) is the most common gynecologic cancer in developed nations with reported 420,368 new cases worldwide in 2022 and resulting in 97,723 deaths that year; it is also one of the few cancers with expected increases in incidence and mortality, which are expected to increase by 50% and 70%, respectively, by 2045. The mortality from EC can largely be attributed to the advanced stage and recurrent cases. Over the past decade, the standard of care for treatment of primary advanced stage and recurrent EC has been chemotherapy, resulting in a median overall survival (OS) of less than 3 years. Advances in molecular tumor profiling have highlighted that a portion of EC tumors release high levels of neoantigens, indicating an opportunity to harness the immune system in therapeutic strategies. On August 1 ^st, 2024, the United States Food and Drug Administration expanded the indication of the immunologic anti-PD-1 checkpoint inhibitor, dostarlimab, and chemotherapy in endometrial cancer. This review summarizes the rationale, evidence, and indications for the use of dostarlimab in advanced and recurrent endometrial cancer.

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Integrated Genomic Characterization of Endometrial Carcinoma

Nikolaus Schultz (2014)

Summary We performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors.

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Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Aurélien Marabelle, Dung Le, Paolo Ascierto … (2019)

Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

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Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors.

Kristian Hargadon, Coleman E Johnson, Corey Williams (2018)

Although T lymphocytes have long been appreciated for their role in the immunosurveillance of cancer, it has been the realization that cancer cells may ultimately escape a response from tumor-reactive T cells that has ignited efforts to enhance the efficacy of anti-tumor immune responses. Recent advances in our understanding of T cell immunobiology have been particularly instrumental in informing therapeutic strategies to overcome mechanisms of tumor immune escape, and immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment. Designed to interfere with inhibitory pathways that naturally constrain T cell reactivity, immune checkpoint blockade releases inherent limits on the activation and maintenance of T cell effector function. In the context of cancer, where negative T cell regulatory pathways are often overactive, immune checkpoint blockade has proven to be an effective strategy for enhancing the effector activity and clinical impact of anti-tumor T cells. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have yielded unprecedented and durable responses in a significant percentage of cancer patients in recent years, leading to U.S. FDA approval of six checkpoint inhibitors for numerous cancer indications since 2011. In this review, we highlight the clinical success of these FDA-approved immune checkpoint inhibitors and discuss current challenges and future strategies that must be considered going forward to maximize the efficacy of immune checkpoint blockade therapy for cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Manag Res

Journal ID (iso-abbrev): Cancer Manag Res

Journal ID (publisher-id): cmar

Title: Cancer Management and Research

Publisher: Dove

ISSN (Electronic): 1179-1322

Publication date (Electronic): 25 January 2025

Publication date Collection: 2025

Volume: 17

Pages: 161-170

Affiliations

[1 ]Department of Gynecologic Oncology, University of California, Irvine-Medical Center , Orange, California, USA

[2 ]Department of Obstetrics and Gynecology, University of California, Irvine-Medical Center , Orange, California, USA

Author notes

Correspondence: Alyssa C Bujnak, University of California, Irvine-Medical Center , 3800 West Chapman Avenue, Suite 3400, Orange, CA, USA, Tel +1 714 456-8888, 92868, Fax +1 714 509-2257, Email abujnak@hs.uci.edu

Article

Publisher ID: 341469

DOI: 10.2147/CMAR.S341469

PMC ID: 11776397

PubMed ID: 39881947

SO-VID: b06766f2-920d-4ace-a288-f55d57bf2d89

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 19 April 2024

Date accepted : 09 January 2025

Page count

Figures: 2, Tables: 2, References: 35, Pages: 10

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Clinical Use of Dostarlimab in Advanced Stage and Recurrent Endometrial Cancer: Patient Selection and Perspectives

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Karger: Oncology

Most cited references 27

Integrated Genomic Characterization of Endometrial Carcinoma

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors.

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Most referenced authors 752