User login
Gynecologic Oncology Consult: Update on Endometrial Cancer Treatment
While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.1 The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis.
In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.
PD-1 inhibitors
Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.
Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.2
Additionally, in 2022, Makker et al. published results from a phase 3 trial3 evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population.
With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,4 comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.
In the similar randomized, international, phase 3 RUBY trial,5 Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.
The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.
Takeaway
Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.
Anti-HER2 therapies
HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.7 These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.
Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,8 which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.
The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
Takeaway
Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.
2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.
3. Makker V et al. N Engl J Med. 2022;386(5):437-48.
4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.
5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.
6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.
7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.
8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.
While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.1 The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis.
In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.
PD-1 inhibitors
Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.
Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.2
Additionally, in 2022, Makker et al. published results from a phase 3 trial3 evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population.
With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,4 comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.
In the similar randomized, international, phase 3 RUBY trial,5 Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.
The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.
Takeaway
Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.
Anti-HER2 therapies
HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.7 These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.
Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,8 which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.
The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
Takeaway
Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.
2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.
3. Makker V et al. N Engl J Med. 2022;386(5):437-48.
4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.
5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.
6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.
7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.
8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.
While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.1 The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis.
In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.
PD-1 inhibitors
Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.
Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.2
Additionally, in 2022, Makker et al. published results from a phase 3 trial3 evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population.
With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,4 comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.
In the similar randomized, international, phase 3 RUBY trial,5 Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.
The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.
Takeaway
Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.
Anti-HER2 therapies
HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.7 These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.
Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,8 which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.
The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
Takeaway
Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.
2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.
3. Makker V et al. N Engl J Med. 2022;386(5):437-48.
4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.
5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.
6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.
7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.
8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.
<!--$RCSfile: InCopy_agile.xsl,v $ $Revision: 1.35 $-->
<!--$RCSfile: drupal.xsl,v $ $Revision: 1.7 $-->
<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>168407</fileName> <TBEID>0C0508A3.SIG</TBEID> <TBUniqueIdentifier>MD_0C0508A3</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname/> <articleType>353</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20240617T170116</QCDate> <firstPublished>20240618T094017</firstPublished> <LastPublished>20240618T094017</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240618T094016</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline>Haag and Tucker</byline> <bylineText>JENNIFER HAAG, MD, PHD, AND KATHERINE TUCKER, MD</bylineText> <bylineFull>JENNIFER HAAG, MD, PHD, AND KATHERINE TUCKER, MD</bylineFull> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.1 The landscape of endomet</metaDescription> <articlePDF/> <teaserImage>301446</teaserImage> <teaser>Checkpoint inhibitors improve outcomes in women with advanced endometrial cancer and an immunotherapy and antivascular endothelial growth factor combination is useful in certain tumors lacking biomarker expression.</teaser> <title>Gynecologic Oncology Consult: Update on Endometrial Cancer Treatment</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>ob</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term>31</term> <term canonical="true">23</term> </publications> <sections> <term canonical="true">76</term> <term>52</term> </sections> <topics> <term canonical="true">217</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012937.jpg</altRep> <description role="drol:caption">Dr. Jennifer Haag</description> <description role="drol:credit">UNC Chapel Hill</description> </link> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24010c86.jpg</altRep> <description role="drol:caption">Dr. Katherine Tucker</description> <description role="drol:credit">UNC Chapel Hill</description> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Gynecologic Oncology Consult: Update on Endometrial Cancer Treatment</title> <deck/> </itemMeta> <itemContent> <p>While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.<sup>1</sup> The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis. </p> <p>[[{"fid":"301446","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals","field_file_image_credit[und][0][value]":"UNC Chapel Hill","field_file_image_caption[und][0][value]":"Dr. Jennifer Haag"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.<br/><br/></p> <h2>PD-1 inhibitors</h2> <p>Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.</p> <p>[[{"fid":"286503","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Katherine Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. ","field_file_image_credit[und][0][value]":"UNC Chapel Hill","field_file_image_caption[und][0][value]":"Dr. Katherine Tucker"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.<sup>2</sup> <br/><br/>Additionally, in 2022, Makker et al. published results from a phase 3 trial<sup>3</sup> evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population. <br/><br/>With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,<sup>4</sup> comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.<br/><br/>In the similar randomized, international, phase 3 RUBY trial,<sup>5</sup> Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.<br/><br/>The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.<br/><br/></p> <h2>Takeaway</h2> <p>Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.</p> <h2>Anti-HER2 therapies</h2> <p>HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.<sup>7</sup> These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.</p> <p>Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,<sup>8</sup> which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd. <br/><br/>The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.<br/><br/></p> <h2>Takeaway</h2> <p>Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.<span class="end"/></p> <p> <em>Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest. </em> </p> <h2>References</h2> <p>1. Siegel R et al. <span class="Hyperlink"><a href="https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21820">CA Cancer J. 2024;74(1):12-49</a></span>.<br/><br/>2. Marabelle A et al. <span class="Hyperlink"><a href="https://ascopubs.org/doi/10.1200/JCO.19.02105"> J Clin Oncol. 2020;38(1):1-10</a></span>.<br/><br/>3. Makker V et al. <span class="Hyperlink"><a href="https://www.nejm.org/doi/10.1056/NEJMoa2108330">N Engl J Med. 2022;386(5):437-48</a></span>.<br/><br/>4. Eskander RN et al. <span class="Hyperlink"><a href="https://www.nejm.org/doi/10.1056/NEJMoa2302312">N Engl J Med. 2023;388(23):2159-70</a></span>.<br/><br/>5. Mirza MR et al. <span class="Hyperlink"><a href="https://www.nejm.org/doi/10.1056/NEJMoa2216334">N Engl J Med. 2023;388(23):2145-58</a></span>.<br/><br/>6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.<br/><br/>7. Fader AN et al. <span class="Hyperlink"><a href="https://ascopubs.org/doi/10.1200/JCO.2017.76.5966">J Clin Oncol. 2018;36(20):2044-51</a></span>.<br/><br/>8. Meric-Bernstam F et al. <span class="Hyperlink"><a href="https://ascopubs.org/doi/10.1200/JCO.23.02005">J Clin Oncol. 2024;42(1):47-58</a></span>.</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
