Faculty Bibliography

OBJECTIVE:KEYNOTE-775 defined lenvatinib/pembrolizumab as the new standard-of-care for patients with proficient mismatch repair (pMMR) recurrent EC. However, the regimen required dose reductions in 66.5 % of participants and the generalizability of these results was uncertain. We conducted an observational study to determine the prescribing patterns, outcomes and side effects in a real-world setting. METHODS:A national multidisciplinary consortium was utilized to study treatment patterns of patients with advanced/recurrent EC treated with lenvatinib/pembrolizumab from 2019 through 2022. Treatment decisions were based on the physician's recommendation. RESULTS:188 patients across 14 institutions were included. Histologic subtypes were 33 % endometrioid, 41 % serous, 9.6 % mixed, 10.1 % carcinosarcoma, and 2.1 % clear cell. 85.6 % were pMMR and 5.3 % were dMMR. Lenvatinib starting dose was 20 mg in 19.7 %, 18 mg in 14.9 %, 14 mg in 47.3 %, and 10 mg in 18.1 %. Median dose intensity of lenvatinib was 14 mg. Pembrolizumab dosing was 200 mg Q3W in 94.1 %. Grade ≥ 3 adverse events (AE) rates related to lenvatinib were similar across starting doses: 20 mg (13.5 %), 18 mg (17.9 %), 14 mg (7.9 %), 10 mg (17.6 %) (p = 0.31). Response rates in relation to lenvatinib starting dose were 20 mg (27 %), 18 mg (35.7 %), 14 mg (39.3 %), 10 mg (44.1 %) (p = 0.50). In relation to lenvatinib starting dose, PFS, OS and duration of therapy were not statistically different. Response rates (p = 0.24), PFS (p = 0.66) & OS (p = 0.22) were similar in White and Black patients. CONCLUSIONS:In a real-world analysis, the predominant starting dose was 14 mg lenvatinib and 200 mg pembrolizumab. Starting at varying doses does not appear to compromise response rates or survival and no new severe adverse events emerged.

OBJECTIVE:Trastuzumab deruxtecan, a HER2 antibody drug conjugate (ADC), is active in HER2 expressing gynecologic cancers. This study aims to determine the proportion of endometrial cancers (EC) that are HER2 expressing and eligible for these ADCs. METHODS:This was a retrospective, single-institution study of patients who underwent surgery for EC over 18 months. Clinical HER2 testing consisted of HER2 IHC and reflex FISH for select 2+ IHC. The outcome of interest was the proportion of patients with HER2 expressing tumors by IHC (1+, 2+, 3+). Chi-square tests of independence were performed to examine relationships between categorical variables and HER2 expression. RESULTS:(2, N = 217) = 6.7, p = 0.035) than HER2 0 tumors. CONCLUSION/CONCLUSIONS:In this retrospective study, 60 % of newly diagnosed EC patients were HER2 expressing by IHC. One-third of unselected EC were HER2 2+ or 3+ and would potentially qualify for current NCCN listed HER2 directed ADCs. HER2 expression was distributed across all histologic and molecular EC subtype suggesting that all endometrial tumors should undergo HER2 IHC testing.

PURPOSE/OBJECTIVE:Tumor next generation sequencing (NGS) may identify potential germline DNA mutations associated with cancer susceptibility. We describe the frequency of tumor NGS results in patients meeting ESMO 2019 recommendations for germline genetic testing (GT) and reasons for not undergoing germline GT. METHODS:A retrospective study (Sept. 2019-Feb. 2022) in a large, urban healthcare system identified patients meeting ESMO guidelines for potentially actionable germline mutations on NGS. RESULTS:Of 3470 patients who underwent tumor NGS, 326 (9.4 %) had at least one potential actionable germline mutation. Of eligible patients, 189 (58.0 %) did not receive germline GT. Reasons for not undergoing GT include: 127 (67.2 %), not referred for GT; 30 (15.9 %), referred but did not attend genetic counseling; 32 (16.9 %), declined, died before GT, had insufficient samples, lacked insurance or lost to follow-up. Among 127 patients not referred for germline GT (39.0 % of the total eligible cohort), the most common cancer types were lung (33.0 %), colorectal (9.4 %), and cancer of unknown primary (9.4 %). Overall, 64 (50.4 %) patients not referred for germline GT had mutations in BRCA1/2 and/or Lynch syndrome genes. Of 137 patients who underwent germline GT, 86 (62.8 %) had positive GT. CONCLUSIONS:In this cohort, 60 % of the eligible population by ESMO criteria did not receive GT, most commonly due to lack of referral (over 2/3 of patients). Further, 50 % of patients not referred for GT had mutations in commonly known genes (i.e., BRCA1/2). Education on germline eligibility and reflex clinical protocols are needed to ensure patients receive germline GT.

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.

BACKGROUND/UNASSIGNED:Significant disparities exist in the care of patients with gynecologic malignancies. Higher incidences of gynecologic malignancies among underrepresented subpopulations (eg, racial, ethnic, and/or LGBTQAI+) and lack of representative enrollment within clinical trials have highlighted the need to improve healthcare equity. We aimed to identify barriers to equitable health care and clinical trial participation for specific diverse populations of patients with gynecologic malignancies and to identify potential solutions for overcoming these barriers. METHODS/UNASSIGNED:A series of 4 live and 3 asynchronous advisory boards facilitated by GSK was conducted between January 2023 and July 2024; live advisory boards were population specific. Gynecologic oncologists, health researchers, advanced practice providers, patients, and patient advocacy group representatives who worked with and/or were themselves members of the focus population participated. Insights were compiled and analyzed to identify barriers and potential solutions across and within populations. RESULTS/UNASSIGNED:Common barriers to equitable health care across all populations included cost, transportation, level of health literacy, and provider biases; 11 population-specific barriers were noted, with LGBTQAI+ patients described as facing the most barriers. Patient navigator involvement was identified as a feasible and highly impactful solution for breaking multiple barriers across various diverse populations. CONCLUSIONS/UNASSIGNED:Most barriers to equitable health care were population specific, affirming the need for continued consultation and discussions with members of communities and with individuals to address specific barriers and enact effective solutions. Engagement of patient navigators was identified as an important way to improve disparities within the care of gynecologic malignancies across all underrepresented patients.

OBJECTIVE:Mismatch repair deficiency (dMMR), high microsatellite instability (MSI-H), and high tumor mutation burden (TMB-H) are predictive and prognostic biomarkers in endometrial cancer. We aimed to characterize the racial/ethnic distribution of molecular markers and the clinical characteristics among endometrial cancer patients with TMB-H and MSI-H/dMMR. METHODS:The Endometrial Cancer Molecularly Targeted Therapy Consortium is a centrally verified clinical and molecular repository. Patients with endometrial cancer who underwent tumor profiling were included. TMB-H was defined as ≥10-12 mutations per megabase. MSI-H was determined by next-generation sequencing or polymerase chain reaction, and dMMR by loss of MLH1, MSH2, MSH6, or PMS2 on immunohistochemistry. Tumor biomarker positivity was defined as TMB-H and/or MSI-H/dMMR. Overall survival was assessed using Kaplan-Meier and Cox proportional hazard models. RESULTS:Among 742 patients, 22 % (n = 164) were biomarker positive: 12 % (n = 87) had both TMB-H and MSI-H/dMMR, 8 % (n = 63) had MSI-H/dMMR alone, and 2 % (n = 14) had 14 TMB-H alone. Only 9 % of non-Hispanic Black patients had biomarker positive tumors compared to 26 % of patients from other racial/ethnic groups. Pathogenic POLE mutations were rare (<1 %, n = 5). Patients with TMB-H had a higher proportion of high-risk histologies (43 %) than those with MSI-H/dMMR (24 %). Biomarker positive tumors were associated with a lower risk of death compared to biomarker negative tumors (aHR 0.63, 95 % CI: 0.46, 0.88). CONCLUSION/CONCLUSIONS:Less than 10 % of non-Hispanic Black patients with endometrial cancer had TMB-H and/or MSI-H/dMMR, and biomarker positivity was associated with improved survival. Prospective studies are necessary to elucidate how these molecular differences impact treatment and outcomes.

Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic option for the treatment of gynecologic malignancies and have become a key component of treatment strategies for recurrent ovarian, endometrial, and cervical cancers. These agents offer targeted tumor cell specificity while delivering potent cytotoxic agents. Despite their selectivity, ADCs are associated with unique treatment-related adverse events. Oral mucositis (stomatitis) has become a notable on-target, off-tumor toxicity among gynecologic cancer patients receiving certain trophoblast cell surface antigen 2 targeting ADCs. Though often acute and self-limiting, oral mucositis can significantly impact patient quality of life, hinder nutritional intake, increase infection risk, and result in dose delays or discontinuation, ultimately affecting cancer treatment outcomes. This review focuses on prevention and management strategies for ADC-associated oral mucositis in the gynecologic oncology setting. We outline practical, evidence-based approaches including routine symptom monitoring, basic oral care, prophylactic interventions, and graded treatment strategies to address established mucositis. Integrating these strategies can reduce the incidence and severity of oral mucositis, thus preserving both treatment efficacy and quality of life for patients with gynecologic malignancies.

The collaborative efforts between GOG and LACOG are aimed at advancing clinical oncology research through strategic global partnerships, particularly related to the conduct of clinical trials. Herein, we provide the framework of this relationship addressing key operational components including establishing a shared Publication Policy. In addition, this initiative seeks to standardize contributions, recognize authorship fairly, and ensure compliance with agreed protocols. Emphasis is placed on critical practices like study design, data interpretation, manuscript development, and intellectual review. The Policy considers the roles of individual scientists, institutional sponsors, and contributors while ensuring transparency and authenticity in scientific communication. This collaborative approach underscores the importance of collective expertise in addressing global challenges in oncology and fostering innovation through multi-institutional cooperation. The manuscript outlines the processes for critical review, approval, and publication, ensuring credibility in the dissemination of scientific findings to the community. These frameworks aim to promote inclusivity, equitable representation, and the advancement of oncology knowledge.

OBJECTIVE:OVATION-2, a randomized, controlled, open label phase 1/2 study, evaluated the safety and efficacy of IMNN-001, an IL-12 immune gene therapy, with neo/adjuvant chemotherapy (N/ACT) compared to N/ACT in newly-diagnosed advanced epithelial ovarian cancer (EOC). METHODS:IMNN-001 is an immunotherapeutic nanoparticle comprising a DNA plasmid encoding the IL-12 gene encased in a lipopolymer. High-grade EOC patients were randomized 1:1 to carboplatin/paclitaxel IV every 21 days for 3 cycles, before and after interval debulking surgery (IDS) or to intraperitoneal (IP) IMNN-001, given weekly concurrently with chemotherapy for 8 weeks before and 9 weeks after IDS. RESULTS:54 and 58 patients with predominantly Stage IIIC/IV EOC were evaluated in the control and experimental arm, respectively. Primary endpoints were safety and PFS. Overall, the experimental arm was well tolerated with gastrointestinal and cytopenias as the most common TEAEs with no CRS or elevated risk of immune events. PFS was 14.9 months (mo) for the experimental arm vs 11.9 mo; HR 0.79 (95 % CI: 0.51-1.23). Secondary endpoints included OS (46.0 mo for experimental arm vs 33.0 mo; HR 0.69 (CI: 0.40-1.19)) and surgical response R0 rate (64.6 % experimental arm vs 52.1 %). For patients who received PARPi maintenance, PFS was 33.8 mo vs 22.1 mo; HR 0.80 (CI: 0.31-2.12) and OS was NE vs 37.1 mo with a HR of 0.38 (CI: 0.13-1.06) both favoring the experimental arm. CONCLUSION/CONCLUSIONS:The addition of IMNN-001 to N/ACT shows a promising numerical 13-mo benefit on survival with an acceptable safety profile in patients with newly-diagnosed advanced EOC.

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.