Faculty Bibliography

Objectives We evaluated the feasibility of a facilitated referral pathway for cascade genetic testing (GT) for patients with mutations associated with gynecologic cancers. Methods This is a prospective cohort study of patients with BRCA1, BRCA2, BRIP1, MSH2, MLH1, MSH6, PMS2, EPCAM, RAD51C, and RAD51D mutations from March 2019-March 2022. Eligible patients were offered a facilitated referral pathway for GT for first and second-degree relatives (figure 1). Decision Regret Scale and Impact of Events Scale assessed psychological impact at 3-months. The primary outcome was the proportion of patients with a relative who successfully completed GT. Results Of 583 eligible patients, 73 (13%) enrolled in our study. Reasons for declining participation were: no eligible relatives or previously tested (235, 40%), lost to follow-up (105, 18%), does not want to discuss GT with family (55, 9%), relatives not interested (50, 9%), language (38, 7%), and other (27, 5%). Of 73 enrolled patients, 45 (62%) contacted at least one relative to discuss GT within two months of enrollment. Twelve patients had at least one relative who participated in our facilitated referral pathway, but only 2 (3%) relatives completed GT through our pathway. Two additional relatives underwent GT separately. Of 20 patients who completed 3-month psychological impact questionnaires, 13 (65%) had no regret, and 19 (95%) had none to subclinical range stress. Conclusions Although over 50% of patients contacted family members regarding GT, only 3% had a relative undergo GT via our facilitated referral pathway. Comprehensive novel efforts to simplify access to GT for relatives are desperately needed. (Figure Presented)

Introduction/Background Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as monotherapy in patients with mismatch repair deficient (dMMR) advanced/ recurrent endometrial cancer (EC) that has progressed on or after platinum-based chemotherapy or dMMR solid tumours that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the EU as monotherapy in patients with dMMR/microsatellite instability-high (MSI-H) advanced/recurrent EC that has progressed on or after platinum-based chemotherapy. We report efficacy endpoints by immune-related RECIST (irRECIST) per investigator assessment (IA) for the EC cohorts of the GARNET trial. Methodology GARNET is a multicentre, open-label, singlearm phase 1 study. Assignment to cohort A1 (dMMR/MSIH EC) or A2 (mismatch repair proficient [MMRp]/microsatellite stable [MSS] EC) was based on local assessment. Patients received 500 mg of dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. Immune-related endpoints (irORR, irDOR, and irPFS) were prespecified secondary endpoints. Results The irRECIST efficacy-evaluable population included 152 patients with dMMR/MSI-H EC and 160 patients with MMRp/MSS EC with measurable disease at baseline and >=6 months' follow-up per IA. irORR and irDOR were similar to the primary endpoints of ORR and DOR by BICR per RECIST v1.1 (table 1). For dMMR/MSI-H, median irPFS was 11.2 mo versus median PFS of 6.0 mo, although the probability of remaining progression free at 6, 12, or 18 mo was similar. Safety was previously reported. Conclusion In line with the study primary endpoints, secondary efficacy endpoints by irRECIST demonstrate the benefit of dostarlimab in patients with EC

Introduction/Background Mismatch repair (MMR) deficiency is caused by loss of expression of MMR proteins, MLH1, PMS2, MSH2, and/or MSH6, that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to mediate DNA repair. Loss of function caused by mutation or epigenetic methylation leads to defective MMR and genomic instability. MMR deficient (dMMR) tumours can respond to anti-programmed death 1 (anti-PD-1) therapy. We report a post hoc analysis of objective response rate (ORR) with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab. Methodology GARNET is a multicentre, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg of dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. MMR protein status (presence or loss) was determined by local immunohistochemistry. MMR gene mutation was determined by FoundationOne. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation. Results Cohort A1 included 143 patients; MMR gene mutation data were available for 101 patients (table 1). Cohort A1 ORR was 45.5%. 66% of patients had loss of MLH1/PMS2; ORR was 48.9%. 11.2% of patients had loss of MSH2/ MSH6; ORR was 56.2%. ORR was 41.7% for MLH1 loss with MMR gene mutation and 39.4% for MLH1 loss without MMR gene mutation. Conclusion Patients with dMMR advanced/recurrent EC benefitted from dostarlimab, with no noticeable difference by dimer-pair loss or MMR gene methylation/mutation status. These data suggest the route to MMR deficiency does not influence response to dostarlimab

Introduction/Background LIO-1 (NCT04042116) assesses the combination of lucitanib, an oral anti-angiogenic, multikinase inhibitor administered using safety-based dose titration, and nivolumab, an inhibitor of programmed cell death receptor 1 (PD-1). Here, we present phase 2 study results of this combination in 4 advanced gynaecological malignancies. Methodology LIO-1 enrolled patients with advanced, recurrent or metastatic endometrial cancer (EC), cervical cancer (CC), high-grade ovarian cancer (OC) or EC/OC with clear-cell histology (EOCC). Patients with EC, CC or EOCC received >=1 prior platinum-based chemotherapies (CC, +/- bevacizumab; EOCC, + taxane); patients with OC received >=2 prior chemotherapies (including >=1 platinum doublet). Patients received lucitanib at a starting dose of 6 mg QD plus intravenous nivolumab 480 mg every 28 days. Lucitanib dose could be escalated to 8 mg then 10 mg QD. The data cutoff was 14 April 2022. Results Total treated was 124 patients; 31 (25.0%) patients are ongoing. At data cutoff, 32 (25.8%) patients escalated to lucitanib 8 mg and 20 (16.1%) to 10 mg. The confirmed best overall response rates at data cutoff were: EC cohort, 5/22 (22.7%); CC cohort, 12/46 (26.1%); OC cohort, 4/33 (12.1%); EOCC cohort, 6/23 (26.1%). Among EC-cohort patients, confirmed responses were reported for 2/5 patients who received prior PD-1 inhibitor (both were non-responders to prior PD-1 inhibitor). Among EC-cohort patients with known microsatellite status, confirmed responses were observed in 3/14 with microsatellite stability and 2/3 with high instability. Grade >=3 treatment-emergent adverse events (TEAEs) considered study-treatment related were reported in 55 (44.4%) patients, with the most frequent being hypertension (n=30 [24.2%]). TEAEs leading to lucitanib dose reduction or discontinuation occurred in 21 (16.9%) and 20 (16.1%) patients, respectively. Conclusion Lucitanib + nivolumab displays anti-tumour activity in patients with advanced gynaecological malignancies, including clear-cell cancer. Effective dose titration resulted in manageable safety, similar to previous reports

Introduction/Background Biomarkers are used to classify endometrial cancer (EC) into molecular subtypes such as TCGA and/or a surrogate classification (POL mutated [mut], mismatch repair/microsatellite instability [MMR/MSI], TP53mut, and no specific mutation profile [NSMP]) or by estrogen receptor (ER) status. Here, we report on a post hoc analysis of objective response rate (ORR) by a surrogate classification for EC in patients receiving dostarlimab monotherapy. Methodology GARNET is a multicentre, open-label, single-arm phase 1 study. Patients were assigned to cohort A1 (MMR deficient/MSI-high [dMMR/MSI-H EC]) or A2 (MMR proficient/microsatellite stable [MMRp/MSS] EC) based on local assessment. Patients received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints were ORR and duration of response by blinded independent central review. Molecular subtype was determined by POL and TP53 mutation status by Foundation Medicine, and MMR/MSI status was determined by local immunohistochemistry or next-generation sequencing; all others were assigned as NSMP. The hierarchy for classification was POLmut MMR/MSI TP53 status NSMP. ER status was determined by local immunohistochemistry testing. Only patients with samples available for additional biomarker testing were included in the biomarker assessment. Results 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS were included in the efficacy-evaluable population. ORRs were determined for molecular subtypes and ER expression (table 1). Safety has been previously reported. Conclusion The observed ORRs in each molecular subgroup were consistent with the overall ORR in each cohort. Differences by ER expression status were not observed. These findings support the importance of testing patients with EC for MMR/MSI biomarker status as a predictor of response. Additionally, data suggest that TP53 mutation or ER expression should not modify treatment approach. The data are of interest for hypothesis generation

Introduction/Background Clinical characteristics of patients have demonstrated that there may be independent predictors of response to cancer drug therapies. In this analysis, we evaluated objective response rate (ORR) by subgroups of clinical characteristics in patients with advanced or recurrent endometrial cancer who were treated with the anti-PD-1 dostarlimab. Methodology GARNET is a multicentre, open-label, single-arm phase 1 study. Patients were assigned to cohort A1 (mismatch repair deficient [dMMR]/microsatellite instability-high [MSI-H EC]) or A2 (mismatch repair proficient [MMRp]/microsatellite stable [MSS] EC) based on immunohistochemistry assessment. Patients received 500 mg of dostarlimab IV every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. Patient baseline demographics (age and BMI), histology, and prior lines of therapies were collected for enrolled patients. ORR by BICR per RECIST v1.1 for prior lines of therapy and histology were pre-specified exploratory subgroup analyses, whereas age and BMI were post hoc subgroup analyses. Results 153 patients with dMMR/MSI-H and 161 patients with MMRp/MSS EC were enrolled and treated. The efficacyevaluable population included 143 patients with dMMR/MSIH EC and 156 patients with MMRp/MSS EC with measurable disease at baseline and the opportunity for at least 6 months of follow-up. ORR for each subgroup (age, BMI, prior lines of therapy, and histology) in each cohort were similar to that of the ORR for each overall cohort (see table 1). Overlapping 95% CIs are observed for all the subgroups assessed. Conclusion The treatment benefit of dostarlimab was consistent across clinical characteristic subgroups on a per-cohort basis (dMMR/MSI-H response rates were consistently >=40%, whereas MMRp/MSS response rates were between 8% and 20%). No correlation could be made between response rate and individual clinical characteristics. Given the small sample size of the subgroups, caution should be used when interpreting the results

OBJECTIVES/OBJECTIVE:Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States. METHODS:The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis. RESULTS:Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis. CONCLUSIONS:Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.

Background/UNASSIGNED:placebo. Methods/UNASSIGNED: = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019). Results/UNASSIGNED:placebo (mean gains of 5.9 [95% CI, 3.5-8.6] and 3.5 [95% CI, 1.7-5.6] months, respectively) in the HRd and ITT populations. Conclusions/UNASSIGNED:placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure. Trial registration/UNASSIGNED:ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016. Plain language summary/UNASSIGNED:

Background: Lynch syndrome accounts for 3% of newly diagnosed endometrial cancers and colon cancers. Identifying patients with Lynch syndrome is fundamental to enable proper screening and prevention of at-risk malignancies, along with encouraging cascade testing of family members. We aimed to assess medical students' knowledge of Lynch syndrome-associated cancers and screening and prevention measures to decrease malignancy risk in patients with Lynch syn-drome. Methods: An anonymous, voluntary, multiple-choice survey was emailed to 14 medical schools throughout the US to evaluate medical students"™ knowledge of Lynch syndrome. Results: We surveyed 342 medical students, and 65% were third or fourth-year medical students. Ninety-three percent knew that colon cancer is one of two most commonly diagnosed cancers in Lynch syndrome; however, only 37% knew endometrial cancer was the other most common malignancy in Lynch syndrome patients. Fifty-nine percent of students recognized that 2-5% of all newly diagnosed endometrial and colon cancers are due to Lynch syndrome. Ninety-one percent recognized a family history that would indicate evaluation for Lynch syndrome, but only 49% knew that all patients diagnosed with endometrial cancer prior to age 50 should be evaluated for Lynch syndrome as per the National Comprehensive Cancer Network guidelines regardless of other risk fac-tors. Conclusion: Almost two-thirds of medical students did not recognize endometrial cancer as a common Lynch syndrome malignancy and less than 50% were aware of when to evaluate patients with endometrial cancer for Lynch syndrome; comparatively almost all students recognized the link between colon cancer and Lynch syndrome. Curriculum change with targeted education regarding en-dometrial cancer and Lynch syndrome during medical school obstetrics and gynecology clinical ro-tations should be implemented. This call to action is critical in improving the diagnosis of Lynch syndrome, evaluation, screening, and prevention of cancers in both patients and family members to reduce mortality.

OBJECTIVE:Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS:The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS:This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS:Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL.