Advancements in Endometrial Cancer Research in 2024

Endometrial cancer is one of the most common gynaecological cancers in developed countries, and the incidence is rising significantly. The staging of this disease is evolving from anatomic staging and risk stratification to a more molecular-based stratification. Treatment of endometrial cancer is also evolving. Paclitaxel plus carboplatin is the standard first-line chemotherapy for endometrial cancer; however, there is new evidence that the combination of chemotherapy and immunotherapy has synergistic effects in the treatment of this disease. This article discusses the latest advancements in endometrial cancer research in 2023, including highlights from the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancers 2023 in March, the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in June, the 24th European Gynaecological Oncology (ESGO) Congress in September and October, and the European Society for Medical Oncology (ESMO) Congress 2023 in October. The article highlights the unprecedented progression-free survival (PFS) data from two Phase III randomised controlled trials evaluating first-line immunotherapy in combination with chemotherapy in patients with advanced or recurrent endometrial cancer: RUBY with dostarlimab, and NRG-GY018 with pembrolizumab, which created a buzz at SGO 2023 in the spring, and stimulated discussion throughout the remainder of the year. The overall survival (OS) results, the clinically meaningful benefits regardless of mismatch repair status, and health-related quality of life (QOL) in these studies are also discussed. Further topics covered in this year-in-review article include the implications of the results from RUBY and NRG-GY018 on first-line treatment and recurrent settings, and the effect of adding a poly adenosine diphosphate ribose polymerase (PARP) inhibitor to immunotherapy–chemotherapy combinations in the Phase III trial, DUO-E. Disparities in endometrial cancer care, research on fertility-sparing, and the importance of the multidisciplinary team (MDT) in endometrial cancer management are also explored. Following the announcement of practice-changing findings from RUBY and NRG-GY018 in March, data presented and published throughout the remainder of 2023 show that research in endometrial cancer continues at a pace.

Decision-making preferences in patients with advanced and recurrent endometrial cancer (502)

Introduction: Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) has emerged as an actionable biomarker in endometrial cancer (EC) with the recent availability of MSI-directed therapies. Currently, there is no data on utilization of MSI/MMR testing for EC in Europe. This study aims to assess the real-world prevalence of MSI/MMR testing and related tumor status in women with recurrent or advanced EC (aEC) in Europe. Methodology: Endometrial Cancer Health Outcomes-Europe (ECHO-EU) is a multicenter retrospective chart review study in United Kingdom (UK), Germany (GE), Italy (IT) and Spain (SP). Physicians extracted de-identified data from medical records of women (≥18 years) diagnosed with aEC, who progressed after prior systemic therapy between July 2016 and July 2019. Patients’ demographics, clinical characteristics, and MSI/MMR testing data were collected. Women were categorized by MSI/MMR status. Results: Interim data from 81 physicians included 349 eligible women (UK=83, GE=64, IT=102, SP=100). More than 85% of physicians were medical oncologists and 91% had a hospital-based practice. At aEC diagnosis, eligible women were on average 68 years, 91% were Stage III/IV, and 56% had endometrioid carcinoma. Overall, 36% of patients were tested by either polymerase chain reaction (PCR) for MSI or immunohistochemistry (IHC) for MMR (UK=33%, GE=31%, IT=25%, SP=55%). Of those with ≥1 test, 54% were tested prior to systemic therapy initiation, with large inter-country differences (16-70%), 20% were MSI-high/deficient MMR (dMMR), 73% were non-MSI-high/proficient MMR (pMMR), and 7% had a mixed result. (Table) Conclusion: Overall MSI/MMR testing rates in Europe are low. Approximately 1 in 5 tested patients had MSI-high/dMMR tumors and three quarters had non-MSI-high/pMMR tumors. Knowledge regarding MSI/MMR testing and related tumor status may be helpful for optimal utilization of targeted therapies for aEC patients in Europe. Table - Patient characteristics and MSI/MMR testing/prevalence in women with aEC in Europe Variable All (N = 349) UK (N = 83) Germany (N = 64) Italy (N = 102) Spain (N = 100) Age at diagnosis of advanced or recurrent EC (years), Mean (SD) 67.5 (9.2) 69.0 (8.4) 68.5 (8.3) 66.1 (9.3) 67.1 (10.1) Stage III-IV at initial diagnosis, N (%) 318 (91.1) 78 (94) 58 (90.6) 96 (94.1) 86 (86) ECOG at recurrent or advanced diagnosis, N (%) 0-1 287 (82.2) 79 (95.2) 34 (53.1) 88 (86.3) 86 (86) Any MSI/MMR testing (IHC or PCR), N (%) Not tested 222 (63.6) 56 (67.5) 44 (68.8) 77 (75.5) 45 (45) Tested 127 (36.4) 27 (32.5) 20 (31.3) 25 (24.5) 55 (55) MSI/MMR status, N (%) MSI-High/dMMR 25 (19.7) 7 (25.9) 3 (15) 3 (12) 12 (21.8) Non-MSI-High/pMMR 93 (73.2) 20 (74.1) 14 (70) 19 (76) 40 (72.7) Mixed 9 (7.1) 0 (0) 3 (15) 3 (12) 3 (5.5) MSI/MMR testing administration, N (%) Before treatment initiation 68 (53.5) 19 (70.4) 10 (50) 4 (16) 35 (63.6) Citation Format: Jingchuan Zhang, Sneha S. Kelkar, Vimalanand S. Prabhu, Shelby Corman, Lucy Qiao, Véronique Grall, Nicola Miles. Real-world prevalence of MSI/MMR testing for patients with recurrent or advanced endometrial cancer in Europe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6276.

PURPOSEImmunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)–deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease.METHODSThis phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control.RESULTSSeven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1–positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents.CONCLUSIONCarboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

Introduction/Background*Dostarlimab is a humanized programmed death-1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands. GARNET (NCT02715284) is a phase 1 study assessing antitumor activity and safety of...

TPS5635 Background: Clinical trials have demonstrated antitumor activity of the immune checkpoint inhibitors in endometrial cancer patients. Two landmark phase III RCTs, NRG-GY018 and RUBY, proved that the addition of pembrolizumab or dostarlimab to standard chemotherapy resulted in significantly longer progression-free survival (PFS) than with chemotherapy alone in patients with advanced or recurrent endometrial cancer. Meanwhile, both two trials consistently showed that the effective size of adding an immune checkpoint inhibitor to combination chemotherapy on PFS was smaller in MMR-proficient (pMMR) cohort, compared to those in MMR-deficient (MMRd) cohort. As poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effects of immune checkpoint inhibitors when combined, improvement of PFS is expected by dual maintenance with pembrolizumab and a PARP inhibitor. Although the phase III DUO-E trial demonstrated elongated PFS from paclitaxel/carboplatin plus durvalumab followed by maintenance durvalumab with or without olaparib in patients with advanced or recurrent endometrial cancer, this trial is not designed to prove that addition of olaparib maintenance provides extra survival benefits. Nesuparib is a newly synthesized small-molecule chemical compound that inhibits both PARP-1&amp;2 and tankyrase. The PENELOPE trial will investigate whether the addition of nesuparib to pembrolizumab maintenance after paclitaxel/carboplatin plus pembrolizumab treatment further improves PFS in patients with advanced or recurrent pMMR endometrial cancer. Methods: In this multicenter, open-label phase II clinical trial, patients with pMMR, stage III/IV or recurrent endometrial cancer, naïve to first-line chemotherapy, will be enrolled. Six patients will be enrolled in Stage 1 (safety run-in) and treated with TCP (paclitaxel/carboplatin + pembrolizumab 200 mg; q3w for six cycles) followed by maintenance treatment with P (pembrolizumab 400 mg; q6w up to 14 cycles) + N (nesuparib 150mg PO once a day; up to 14 months). The study will proceed to Stage 2 (dose expansion) if less than 33% of patients in Stage 1 experience a dose-limiting toxicity. Otherwise, additional patients will be enrolled in Stage 1 at lower dose level. In Stage 2, 80 patients will be randomized (1:1) to: arm A) TCP followed by maintenance treatment with P; arm B) TCP followed by maintenance treatment with P + N (150mg or 100mg PO once a day; up to 14 months). Patients will receive maintenance treatment until disease progression. Primary endpoint is investigator-assessed PFS (RECIST 1.1) of arm B vs. arm A, and key secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and safety. Enrollment began in Q4 2024. Clinical trial information: NCT06502743 .

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Current Value Frameworks—What's New?

Assessment of Value Using the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) Frameworks for Novel Therapies for the Hematologic Malignancies

Simple SummaryPatients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment with unsatisfactory clinical outcomes. The combination of carboplatin + paclitaxel is the standard first-line chemotherapy, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with mTOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high/mismatch repair (MMR)-deficient EC.Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.

e17632 Background: Patients with advanced or recurrent endometrial cancer have a median progression-free survival (PFS) of 3-6 months and a 5-year survival rate of 17%, with limited therapeutic options. Recent studies indicate combination of chemotherapy and immunotherapy significantly increased PFS among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) population. Prior studies have shown reduced response to immunotherapy across different metastatic sites in various solid tumors, such as melanoma, colorectal and non-small cell lung cancer. This study explores the impact of metastatic sites on treatment outcomes in patients with advanced or recurrent endometrial cancer. Methods: In this single-center retrospective study of patients diagnosed with metastatic or recurrent endometrial cancer who received IO between 10/2019 and 12/2024, demographic characteristics, therapy received, site of metastatic disease (lung, liver, lymph node, brain), response to treatment were obtained from the medical records. Response was defined as partial or complete response and no response was defined as progression or stable disease. The association between site of metastatic disease and response was assessed using Fisher’s Exact Test. Results: We identified 21 patients with metastatic or recurrent endometrial cancer who received IO at MD Anderson Cancer Center. The majority identified as White (67%, n = 14) and Not Hispanic (60%, n = 12) with a median age of 68 (IQR: 61-71). Histologies include endometrioid (62%, n = 13), serous (33%, n = 7), clear cell (19%, n = 4) with 3 patients demonstrating multiple histologies. Patients received pembrolizumab and lenvatinib (67%, n = 14, median number of cycles 5.5) and pembrolizumab monotherapy (33%, n = 7, median number of cycles 9). The overall response to IO was stable disease (5%, n = 1), progression (38%, n = 8), partial response (38%, n = 8), and complete response (19%, n = 4). Patients received pembrolizumab and lenvatinib (67%, n = 14, median number of cycles 5.5) and pembrolizumab monotherapy (33%, n = 7, median number of cycles 9). The overall response to IO was stable disease (5%, n = 1), progression (38%, n = 8), partial response (38%, n = 8), and complete response (19%, n = 4). The odds ratios (OR) for overall response based on site of metastatic disease were liver (OR 1.77, p= 0.62), lung (OR 0.86, p= 1), lymph node (OR 1.04, p= 1), and bowel (OR not reported). Conclusions: This descriptive analysis identified patients with recurrent or advanced endometrial cancer with liver, lung, lymph node, and bowel metastases who received IO. Further retrospective data collection is underway to identify a possible role for site of disease, molecular signature, and response to IO.

ESMO/ASCO recommendations for a Global Curriculum (GC) in medical oncology—edition 2016

The off-label use of drugs in oncology: a position paper by the European Society for Medical Oncology (ESMO)

e17630 Background: Endometrial cancer (EC) is the second most prevalent gynecological cancer. After failure to first-line platinum-based chemotherapy, treatment options are sparse, but recent studies have investigated new approaches with promising results. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Lenvatinib plus Pembrolizumab in patients with advanced or recurrent EC. Methods: PubMed, Web of Science, Cochrane, Scopus, and LILACS databases, Central Register of Clinical Trials, and congresses publication websites were searched for studies using Lenvatinib plus Pembrolizumab in advanced or recurrent EC with progression after platinum-based chemotherapy. Outcomes of interest were best overall response rate (BORR) and disease control rate (DCR), on intention-to-treat (ITT) and per-protocol analyses, and according to mismatch repair status. Progression free-survival (PFS) and overall survival (OS) were also assessed. Heterogeneity was examined with the Cochran Q test and I2 statistics. We use a DerSimonian and Laird random-effects model. Results: Four studies, with 637 patients, were included: two clinical trials and two retrospective observational cohorts. Endometrioid EC was the predominant histology (53%), and most patients had mismatch repair-proficient tumors (pMMR, 86.5%). In a pooled analysis, with a medium follow-up of 12.2 months, BORR was 31% (95%CI 26, 37), and DCR was 74% (95%CI 65, 83) on ITT. CR, PR, and SD were documented in 37 (5.8%),168 (26.3%) and 284 (44.5%) patients, respectively. BORR was 48% in microsatellite unstable tumors compared to 31% in stable microsatellite disease (p = 0.07), while DCR was similar in both groups (p = 0.33). Median progression-free survival was 7.2 months (95%CI 3.2, 7.4), and median overall survival was 18.3 months (95%CI 8.6, 18.3) in patients receiving Lenvatinib and Pembrolizumab. The most common treatment-related adverse events (AE) included diarrhea 277/514 (53.8%), nausea 244/514 (47.4%), hypothyroidism 288/562 (39.1%), hypertension 338/632 (36.9%), fatigue 213/632 (31.0%), and vomiting 178/514 (34.6%). Grades 3 or 4 AE was reported in 436/514 (79.6%) patients. Overall, dose reductions, treatment interruptions, and discontinuation due to toxicities were required in 61%, 63%, and 27% of patients, respectively. Conclusions: This systematic review and meta-analysis reinforce the antitumor activity of the combination of Pembrolizumab and Lenvatinib in patients with advanced or recurrent EC, regardless of MMR status. Despite high rates of serious adverse events related to treatment, most were manageable.

For time-to-event endpoints, three additional benefit assessment methods have been developed aiming at an unbiased knowledge about the magnitude of clinical benefit of newly approved treatments. The American Society of Clinical Oncology (ASCO) defines a continuous score using the hazard ratio point estimate (HR-PE). The European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) developed methods with an ordinal outcome using lower and upper limits of the 95% HR confidence interval (HR-CI), respectively. We describe all three frameworks for additional benefit assessment aiming at a fair comparison across different stakeholders. Furthermore, we determine which ASCO score is consistent with which ESMO/IQWiG category. In a comprehensive simulation study with different failure time distributions and treatment effects, we compare all methods using Spearman's correlation and descriptive measures. For determination of ASCO values consistent with categories of ESMO/IQWiG, maximizing weighted Cohen's Kappa approach was used. Our research depicts a high positive relationship between ASCO/IQWiG and a low positive relationship between ASCO/ESMO. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 corresponds to ESMO categories. Using ASCO values of 21 and 38 as cutoffs represents IQWiG categories. We investigated the statistical aspects of the methods and hence implemented slightly reduced versions of all methods. IQWiG and ASCO are more conservative than ESMO, which often awards the maximal category independent of the true effect and is at risk of overcompensating with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and underpowered/overpowered studies influence all methods in some degree. Nevertheless, ESMO is the most liberal one. For the additional benefit assessment, the American Society of Clinical Oncology (ASCO) uses the hazard ratio point estimate (HR-PE) for their continuous score. In contrast, the European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) use the lower and upper 95% HR confidence interval (HR-CI) to specific thresholds, respectively. ESMO generously assigns maximal scores, while IQWiG is more conservative.This research provides the first comparison between IQWiG and ASCO and describes all three frameworks for additional benefit assessment aiming for a fair comparison across different stakeholders. Furthermore, thresholds for ASCO consistent with ESMO and IQWiG categories are determined, enabling a comparison of the methods in practice in a fair manner.IQWiG and ASCO are the more conservative methods, while ESMO awards high percentages of maximal categories, especially with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and under/-overpowered studies influence all methods. Nevertheless, ESMO is the most liberal one. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 correspond to the categories of ESMO. Using ASCO values of 21 and 38 as cutoffs represents categories of IQWiG.