Matthew Wagar, MD, is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology at the University of Wisconsin School of Medicine and Public Health. 

Dr Wagar on the Evolution of Advanced/Recurrent Endometrial Cancer Management

"In the past couple of years, the management of advanced/recurrent endometrial cancer has changed dramatically. We have seen an integration of immunotherapy with chemotherapy, as well as new ADCs that have found a home and have thrived for some of our patients with endometrial cancer."

Matthew Wagar, MD, a gynecologic oncology fellow in the Department of Obstetrics and Gynecology at the University of Wisconsin School of Medicine and Public Health, discusses the evolving management of advanced and recurrent endometrial cancer.

The management of advanced or recurrent endometrial cancer has evolved significantly in recent years, with the integration of immunotherapy into chemotherapy-based regimens and the emergence of ADCs as viable treatment options, Wagar begins. During a recent 

 State of the Science Summit™ on gynecologic cancers, Wagar and colleagues reviewed 2 case studies that were emblematic of these advancements.

The first case focused on the incorporation of immunotherapy with chemotherapy in a patient with recurrent endometrial cancer who had not previously received chemotherapy, Wagar details. The discussion included an evaluation of eligibility criteria and the clinical data supporting the use of carboplatin plus paclitaxel in patients with this disease, he recounts. Historically, this regimen was the standard of care; however, the publications of the phase 3 NRG-GY018 (NCT03914612) and RUBY (NCT03981796) trials led to a paradigm shift, he says. These studies demonstrated the efficacy of adding immunotherapy—pembrolizumab (Keytruda) in NRG-GY018 and dostarlimab-gxly (Jemperli) in RUBY—to chemotherapy in patients with advanced or recurrent disease. Key considerations for integrating these agents—including patient selection, adverse effect monitoring, and optimal sequencing—were also discussed at the meeting, he adds.

The second case highlighted the role of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in endometrial cancer, Wagar continues.

As immunotherapies continue to gain traction in the endometrial cancer treatment paradigm, their efficacy and safety profiles are being further explored, he says. Overall, these discussions underscored the rapid advancements in endometrial cancer management and the importance of personalized approaches in optimizing patient outcomes, he concludes.

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Matthew Wagar, MD, discusses how the management of advanced and recurrent endometrial cancer has evolved in recent years.

Dr Wagar on Lenvatinib Plus Pembrolizumab vs Chemo in First-Line Advanced Endometrial Cancer

“There wasn't really a difference in overall survival [OS] outcomes between the lenvatinib [plus] pembrolizumab up-front group vs the chemotherapy up-front group. [Data] didn't meet a specific prespecified criterion for progression-free survival [PFS] or OS. [Therefore,] chemotherapy remains the standard of care, particularly for [patients with pMMR] endometrial cancer. [However], in the dMMR group, there was quite a bit of a signal [favoring] the lenvatinib plus pembrolizumab arm."

Matthew Wagar, MD, a gynecologic oncology fellow in the Department of Obstetrics and Gynecology at the University of Wisconsin School of Medicine and Public Health, discusses findings from the phase 3 LEAP-001 trial (NCT03884101) evaluating lenvatinib (Lenvima) plus pembrolizumab (Keytruda) vs chemotherapy as first-line treatment for patients with advanced endometrial cancer.

Findings demonstrated that lenvatinib plus pembrolizumab did not meet prespecified statistical criteria for progression-free survival (PFS) or overall survival (OS) superiority over chemotherapy in the mismatch repair–proficient (pMMR) population, Wagar begins. In this subgroup, the median PFS was 9.6 months (95% CI, 8.2-11.9) in the lenvatinib plus pembrolizumab arm (n = 320) vs 10.2 months (95% CI, 8.4-10.5) in the chemotherapy arm (n = 322; HR, 0.99; 95% CI, 0.82-1.21). Among all-comers, the median PFS was 12.5 months (95% CI, 10.3-15.1) with lenvatinib plus pembrolizumab (n = 420) vs 10.2 months (95% CI, 8.4-10.4) with chemotherapy (n = 422; HR, 0.91; 95% CI, 0.76-1.09).

Additionally, median OS in the pMMR population was 30.9 months (95% CI, 25.4-37.7) with lenvatinib plus pembrolizumab vs 29.4 months (95% CI, 26.2-35.4) with chemotherapy (HR, 1.02; 95% CI, 0.83-1.26). Among all-comers, the median OS was 37.7 months (95% CI, 32.2-43.6) in the lenvatinib plus pembrolizumab arm vs 32.1 months (95% CI, 27.2-35.7) in the chemotherapy arm (HR, 0.93; 95% CI, 0.77-1.12).

Notably, exploratory analysis in the mismatch repair–deficient (dMMR) population suggested a potential signal favoring lenvatinib plus pembrolizumab, leading to interest in future immunotherapy-first strategies for dMMR advanced endometrial cancer, Wagar explains. This approach may offer a means to delay chemotherapy and preserve platinum-based treatments for later disease progression, he adds.

These findings confirm that chemotherapy remains the standard of care for pMMR advanced endometrial cancer, and further investigation into immunotherapy-based strategies for dMMR patients is warranted, Wagar concludes.

Matthew Wagar, MD, discusses lenvatinib plus pembrolizumab vs chemotherapy as first-line treatment for advanced endometrial cancer.

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“The integration of immunotherapy into the adjuvant treatment realm really drives home the importance of staging and having access to someone who’s capable [of performing] these staging procedures for these patients. There [are] some mixed data for using immunotherapy in patients that have early-stage disease or disease that is not necessarily very high risk for recurrence, [suggesting that] maybe [immunotherapy is] not as efficacious [in that population] as [it is for] some of these more high-risk patients.”

Matthew Wagar, MD, gynecologic oncology fellow, Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, discusses the role of immunotherapy in the adjuvant treatment of patients with endometrial cancer and underscores the importance of accurate staging in optimizing therapeutic outcomes.

The integration of immune checkpoint inhibitors into the adjuvant setting has shown clinical benefit in patients with endometrial cancer, particularly in those with high-risk disease. However, Wagar notes that data on the efficacy of immunotherapy in early-stage or lower-risk endometrial cancer remain mixed. This underscores the need for comprehensive risk stratification, facilitated by precise staging techniques such as sentinel lymph node mapping and, when indicated, full lymphadenectomy with pelvic and para-aortic lymph node dissection.

Accurate staging provides essential prognostic information that can guide treatment selection, particularly given the significant survival benefit associated with immunotherapy in patients with adequately staged, high-risk disease. Additionally, molecular characterization, including mismatch repair (MMR) status, further refines patient selection. Wagar notes that patients with MMR-deficient tumors have demonstrated substantial responses to immune checkpoint inhibitors, reinforcing the need for early biomarker identification.

Beyond staging, Wagar also explains that patient-specific factors including medical comorbidities, surgical risk, and overall functional status must be carefully considered when incorporating immunotherapy into adjuvant treatment strategies. Collaboration with pathologists to obtain comprehensive molecular data is critical, particularly for patients who are not surgical candidates or who present with advanced or recurrent disease.

Wagar also notes that although immunotherapy is indicated for a broad range of patients, its effect is most pronounced in those with MMR-deficient tumors and high-risk features. Ensuring optimal staging and molecular characterization at diagnosis is critical for maximizing therapeutic benefit. He concludes that continued research and refinement of treatment algorithms will further clarify the role of immunotherapy in early-stage disease while reinforcing its established efficacy in high-risk endometrial cancer.

Matthew Wagar, MD, discusses the use of adjuvant immunotherapy in endometrial cancer and the importance of accurate staging in optimizing outcomes. 

Matthew Wagar, MD

Articles

Dr Wagar on the Evolution of Advanced/Recurrent Endometrial Cancer Management

Dr Wagar on Lenvatinib Plus Pembrolizumab vs Chemo in First-Line Advanced Endometrial Cancer

Dr Wagar on the Role of Adjuvant Immunotherapy in Endometrial Cancer