Faculty Bibliography

OBJECTIVE:Next-generation sequencing and tumor testing to direct therapy in advanced/recurrent endometrial cancer are frequently used, but the impact of this approach is unclear. We sought to confirm the proportion of patients with at least 1 actionable alteration and whether the use of molecularly targeted therapy was associated with improved survival in metastatic endometrial cancer. METHODS:A multidisciplinary consortium was formed to study tumor testing and treatment with targeted therapies in advanced/recurrent endometrial cancer. Tumor testing and therapeutic decisions were physician's recommendations. The abstracted data included age, stage, grade, histology, race, ethnicity, treatment, genomic alterations, protein expression for Her2, p53, mismatch repair, estrogen and progesterone receptors, and survival. Statistical analyses were performed using SAS v9.4. RESULTS:A total of 967 patients from 12 centers were included. The median age was 64 years (range; 22-93 years). Of the participants, 68.5% were White, 24.0% were Black, 2.0% were Asian, and 92.7% were non-Hispanic. A total of 656 (67.8%) patients had recurrent/persistent disease and received a median of two (range; 0-9) therapies. 902 (93.3%) underwent tumor testing. Overall, 576 (94.0%) patients with next-generation sequencing testing had at least 1 genomic alteration in 11 pre-specified genes. The most frequent alterations were PI3K (35.8%), TP53 (34.7%), and PTEN (26.5%) mutations, respectively. A subset of 233 patients received 292 matched biologic therapies, and the median follow-up was 29.7 months, while the median progression-free survival and overall survival were 6.9 and 20.5 months, respectively. CONCLUSIONS:The consortium facilitated the development of real-world data on the patterns of genomic testing and molecularly targeted therapy used in a racially and geographically diverse patient cohort with advanced/recurrent endometrial cancer. Survival improved for those receiving matched biologic therapies compared to chemotherapy.

This article highlights the gender data gaps in clinical trial inclusion and funding, with a particular focus on gynecologic oncology. Female patients have historically been excluded from clinical trials across all medical domains. Despite recent improvements, female patients remain underrepresented in key diseases, including several cancer types, despite experiencing increased burden of disease. Lack of representation is particularly stark for patients in racial, ethnic, and gender minoritized populations, including in gynecologic cancer trials. Furthermore, female health conditions receive disproportionately small amounts of funding relative to their disease burden. Despite their high lethality, gynecologic cancers, including ovarian, cervical, and uterine malignancies, rank among the lowest funded cancer sites from the National Cancer Institute. Likewise, there is significant bias against female investigators with regard to funding, publication, and academic advancement, which affects the prioritization of women's health. In combination, gender disparities at multiple steps along the research pathway from investigator and disease funding to trial inclusion to publication and dissemination of research perpetuate a significant data gap in the diagnosis, treatment, and prevention of diseases affecting female patients, including gynecologic cancers. Strategies to improve this gender gap and prioritize women's health funding include increasing female representation in clinical trials with a specific focus on inclusion of patients from historically marginalized backgrounds, considering disease burden-based funding policies, and prioritizing female academic leadership opportunities.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .

AIMS/OBJECTIVE:Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships. METHODS:A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS). RESULTS:For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships. CONCLUSIONS:The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships.

OBJECTIVE:We sought to determine the association between platinum-free interval (PFI) and response to retreatment with platinum-based chemotherapy vs lenvatinib/pembrolizumab in patients with recurrent endometrial cancer. METHODS:Endometrial Cancer Molecularly Targeted Therapy (ECMT2) Consortium patients with recurrent disease were included in this retrospective analysis if they received first-line treatment with platinum-based chemotherapy (adjuvant or first recurrence), followed by second-line re-treatment with platinum or lenvatinib/pembrolizumab. PFI was defined as time between date of last platinum to start date of second-line therapy. Patients were stratified according to PFI ≤12 months or > 12 months. Overall response rate (ORR) to second-line treatment was estimated after stratification by PFI. RESULTS:Of 217 patients, 146 (67 %) underwent retreatment with platinum and 71 (33 %) were treated with lenvatinib/pembrolizumab. 127 (59 %) had PFI ≤12 months, and 84 (39 %) patients had PFI >12 months. Patients treated with platinum had longer PFI than those treated with lenvatinib/pembrolizumab (median PFI 12.9 vs 4.6 months; p < 0.001). ORR was 58 % vs 49 % for platinum vs lenvatinib/pembrolizumab (p = 0.27). For all patients, ORR was 68 % vs 47 % with PFI >12 months and ≤ 12 months, respectively (p = 0.002). At each PFI, ORR was similar regardless of treatment with platinum or lenvatinib/pembrolizumab (PFI ≤12 months ORR 49 % vs 44 % respectively, p = 0.75; PFI >12 months ORR 67 % vs 75 % respectively, p = 0.74). CONCLUSION/CONCLUSIONS:Longer PFI is associated with improved response to second-line treatment in patients with recurrent endometrial cancer. Despite utilization of PFI for real-world treatment decisions, it was not found to predict response between regimens at any given PFI.

PURPOSE OF REVIEW/OBJECTIVE:The Cancer Genome Atlas identified four distinct molecular subtypes of endometrial cancer (EC): POLE mutated, mismatch repair deficient (dMMR), copy number low, and copy number high. The goal of this review is to summarize the profound clinical implications of molecular subtyping, particularly in guiding treatment decisions for dMMR and microsatellite instability high (MSI-H) EC. RECENT FINDINGS/RESULTS:Clinical trials have demonstrated the remarkable efficacy of immunotherapy in dMMR/MSI-H EC tumors. Trials including GARNET, KEYNOTE-158, NRG GY-018, and RUBY have shown significant improvements in clinical outcomes for patients with advanced and recurrent disease, leading to FDA approvals for immunotherapy in both frontline and recurrent EC treatment settings.Building on these successes, recent studies, including DUO-E, are exploring combination therapies to enhance the efficacy of immunotherapy in EC. Simultaneously, trials including NRG GY-020, are investigating the potential benefits of immunotherapy in early-stage disease. SUMMARY/CONCLUSIONS:Immunotherapy therapy has revolutionized the treatment of endometrial cancer in both upfront and recurrent settings, with molecular subtyping identifying patients most likely to benefit, especially those with dMMR/MSI-H tumors.

BACKGROUND:Compared to White women, Black women and other minority groups have a higher age-adjusted incidence risk of cervical and endometrial cancer. However, the extent of racial and ethnic disparities in clinical trial enrollment among studies performed mainly in North America and Europe for gynecologic malignancy is unknown. OBJECTIVE:This study analyzed enrollment rates by race/ethnicity in trials that led to Food and Drug Administration approvals for gynecological cancers from 2010 to 2024. STUDY DESIGN/METHODS:This cross-sectional study examined clinical trials registered with ClinicalTrials.gov that resulted in new Food and Drug Administration approvals for gynecologic malignancies between 2010 and 2024. Exclusion criteria were studies not conducted in North America or Europe. Enrollment fractions were obtained by dividing the number of trial participants segregated by the racial/ethnic group by the corresponding U.S. cancer prevalence (uterine, ovarian, and cervical cancer) for 2016 to 2020 for each racial/ethnic group. Odds ratios and 95% confidence intervals were calculated to compare enrollment fractions of minority groups to non-Hispanic Whites. RESULTS:A total of 31 studies met the inclusion criteria, with 21 reporting race/ethnicity data. Three (3/21) studies dichotomized race as non-Hispanic White and non-White and 7 (7/21) reported ethnicity. The median number of participants was 494 [interquartile range 150-674]. Fifteen studies were phase III, and 6 were phase IB/II trials. Treatments included immune checkpoint inhibitors (7 studies), poly (ADP-ribose) polymerase inhibitors (5), vascular endothelial growth factor inhibitors (4), antibody-drug conjugates (4), and an imaging marker (1). Across all studies, 11,258 patients were included, 5563 (49.4%) in ovarian cancer studies, 2963 (26.3%) in endometrial cancer studies, and 2732 (24.3%) in cervical cancer studies. Three studies (n=1734) dichotomized participants into non-Hispanic White and non-White; non-Hispanic White 1291 [74.4%] and non-White 443 [25.6%], and enrollment fractions were 0.51% for non-Hispanic White and 0.43% for no-White, with non-White being underrepresented odds ratio 0.85, 95% confidence interval [0.76-0.95], P=.004. In an Analysis of 18 studies reporting race categories, non-Hispanic Black patients were significantly underrepresented (odds ratio 0.50, 95% confidence interval [0.45-0.54], P<.001), while Asian patients were overrepresented (odds ratio 2.81, 95% confidence interval [2.64-2.99], P<.001). In the 4 studies reporting ethnicity, Hispanic patients were also significantly underrepresented (odds ratio 0.69, 95% confidence interval [0.61-0.78], P<.001). CONCLUSION/CONCLUSIONS:In clinical trials, performed in North America and Europe mainly, leading to Food and Drug Administration approvals for gynecologic malignancies, non-Hispanic Black and Hispanic patients are significantly underrepresented compared to non-Hispanic White participants when enrollment is benchmarked to the U.S. female population with gynecological cancer. These trials do not adequately reflect the U.S. populations diagnosed with these malignancies. Enrollment strategies to increase diversity are urgently needed to ensure clinical trial results are equitable and applicable across all populations. Efforts from the American Society of Clinical Oncology, the Association of Community Cancer Centers, and the Gynecologic Oncologic Group/Society of Gynecologic Oncology Inclusion, Diversity, Equity, and Access initiative provide a comprehensive framework for achieving this goal.

OBJECTIVE:In the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin-paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin-paclitaxel, with manageable toxicity, in patients with primary advanced or recurrent endometrial cancer. Here we report on patient-reported outcomes in the mismatch repair-deficient/microsatellite instability-high population, a secondary endpoint in the trial. METHODS:Patients were randomized 1:1 to dostarlimab+carboplatin-paclitaxel or placebo+carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo monotherapy every 6 weeks for ≤3 years or until disease progression. Patient-reported outcomes, assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Endometrial Cancer Module, were prespecified secondary endpoints. A mixed model for repeated measures analysis, a prespecified exploratory analysis, was conducted to generate least-squares means to compare between-treatment differences while adjusting for correlations across multiple time points within a patient and controlling for the baseline value. Results are provided with 2-sided, nominal p values. RESULTS:Of 494 patients enrolled, 118 were mismatch repair-deficient/microsatellite instability-high. In this population, mean change from baseline to end of treatment showed visual improvements in global quality of life (QoL), emotional and social function, pain, and back/pelvis pain for dostarlimab+carboplatin-paclitaxel. Meaningful differences (least-squares mean [standard error]) favoring the dostarlimab arm were reported for change from baseline to end of treatment for QoL (14.7 [5.45]; p=0.01), role function (12.7 [5.92]); p=0.03), emotional function (14.3 [4.92]; p<0.01), social function (13.5 [5.43]; p=0.01), and fatigue (-13.3 [5.84]; p=0.03). CONCLUSIONS:Patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin-paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin-paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin-paclitaxel as a standard of care in this setting. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT03981796.

The presented retrospective analysis suggests, to the best of our knowledge for the first time, a potential significant interaction between statins and niraparib in clinical settings. Nevertheless, further investigations are required to gain a better understanding of the potential clinical benefit.

BACKGROUND:Evidence is limited in gynecologic cancers on best practices for clinical trial screening, but the risk of ineffective screening processes and subsequent under-enrollment introduces significant cost to patient, healthcare systems, and scientific advancement. Absence of a defined screening process makes determination of who and when to screen potential patients inconsistent allowing inefficiency and potential introduction of biases. This is especially germane as generative artificial intelligence (AI), and electronic health record (EHR) integration is applied to trial screening. Though often a requirement of cooperative groups such as the Cancer therapy Evaluation Program (CTEP), and/or the Commission on Cancer (CoC), there are no standard practice guidelines on best practices regarding screening and how best to track screening data. DEVELOPMENT OF MANUSCRIPT/UNASSIGNED:The authors provided a review of current clinical trial screening practices and the effect on enrollment and trial activation across a variety of disease and practice sites. Established clinical trial screening practices and evidence supporting emerging strategies were reviewed and reported. Due to lack of published literature in gynecologic oncology, authors sought to survey the members of current rostered GOG sites to provide perspectives on clinical trial screening practices. Survey results showed a variety of screening practices. Most respondents participate in some type of manual screening process, where approximately 13 % also report incorporating AI or EHR integration. Over half (60 %) of sites track screening data to use for feasibility when opening new trials. The rapid increase in generative AI, EHR integration, and site agnostic screening initiatives could provide a significant opportunity to improve screening efficiency, translating to improved enrollment, but limitations and barriers remain.