Faculty Bibliography

Objectives With the National Cancer Institute (NCI) call-toaction to increase racial/ethnic diversity in clinical trial enrollment, we sought to evaluate minority patient enrollment in gynecologic cancer clinical trials as compared with disease prevalence estimates by race/ethnicity. Methods Enrollment data from endometrial and ovarian therapeutic clinical trials from January 2018-May 2022 at a NCI-designated Comprehensive Cancer Center in New York City was analyzed. Minority enrollment in ovarian and endometrial cancer trials was compared to SEER estimates of disease prevalence using chi-square analysis. Population estimates of NYC demographics were obtained from the U. S. Census. Results Over the study period, 129 patients were enrolled in ovarian cancer trials and 52 patients in endometrial cancer trials. Regarding total enrollment, the proportion of clinical trial participants identifying as racial/ethnic minorities (34.1%) was significantly higher than the SEER disease estimate of ovarian cancer in minority patients (25.7%, p<0.05). Likewise, total enrollment of minority patients in endometrial cancer trials (61.5%) exceeded their disease prevalence estimate of 28.5% (p<0.05). However, enrollment of Asian patients in endometrial cancer trials (1.9%) remained under disease prevalence estimates (7.7%) despite the NCI call-to-action (table 2). Conclusions In a diverse city population, enrollment of minority patients exceeded disease prevalence estimates for most underrepresented racial/ethnic groups in gynecologic cancer, with the exception of Asian patients in endometrial cancer. Further efforts are needed to increase enrollment of Asian patients in endometrial cancer clinical trials so that novel therapies can be tested in all patients

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)

Objectives Progression-free survival (PFS) is a rational surrogate primary endpoint in ovarian cancer (OC) trials. However, PFS is subject to biases, with validity dependent upon proper methodologic assessment. Therefore, blinded independent centralized radiologic review (BICR) is often recommended. We evaluated BICR and investigator-assessed evaluation of progressive disease (PD) in the PRIMA/ ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy in intent-to-treat (ITT) and homologous recombination deficient (HRd) populations. Methods In the randomized, double-blind, placebo-controlled phase 3 PRIMA/ENGOT-ov26/GOG-3012 trial, patients with newly diagnosed stage III/IV OC were assigned to receive either niraparib or placebo. The primary endpoint was PFS (per RECIST v.1.1) by BICR. Discordance between BICR and investigator assessments of PD ([#BICR reviews with unconfirmed PD assessment]/[total# investigator-triggered reviews]) was monitored throughout the study. A training intervention was developed for BICR reviewers based on PD determination in OC. Results In an initial patient subset (n=80), a 39% discordance rate was identified between BICR and investigator-assessed PD by the sponsor, most commonly due to peritoneal carcinomatosis or fluid collections arising from new non-target lesions. After reviewer intervention, final discordance rate between BICR and investigator improved to 12% and 13% for ITT (N=733) and HRd (n=373) populations, respectively (figure 1). Across the entire study population, median PFS and hazard ratios for the ITT and HRd populations were comparable between BICR and investigator (table 1). Conclusions PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize BICR and investigator concordance using early, specialized OC-specific training to maximize trial validity. (Figure Presented)

Objectives Perioperative management varies for patients with bleeding disorders. We sought to determine the association between bleeding disorders and perioperative transfusions for hysterectomy patients. Methods We included patients undergoing non-emergent hysterectomy between 2014-2019 from the NSQIP, a validated, risk-adjusted database from 700 hospitals. We compared 30- day perioperative transfusions between patients with and without bleeding disorders (chronic, persistent, active hematologic disorders). Transfusions <=1day were immediate, and after >=2days were delayed. Covariates were age, race/ethnicity, preoperative anemia (hematocrit <=30%) and thrombocytopenia (platelet <100,000/mL), fibroids, endometriosis, cancer, and surgical route. Results Of 290,642 patients, 10,705 (3.7%) received perioperative transfusions (8,679 ,2.9%, immediate; 2,026, 0.7%, delayed). Of 2,687 patients with bleeding disorders, 283 (10.5%) received transfusions, compared to 10,422/287,995 (3.6%) of those without (p<0.001). For gynecologic cancer patients, 17.1% (121/707) with bleeding disorders received transfusions compared to 8.4% (3,261/38,379) of those without (p<0.001). 999 (0.3%) underwent reoperation for bleeding, and this was more likely with bleeding disorders (27/2,687, 1.0% vs. 972/287,955, 0.3%, p<0.001). Anemia (OR 11.7, CI 11.1-12.4) and bleeding disorders (OR 2.0, CI 1.7-2.3) were associated with transfusions when adjusting for age, race/ethnicity, fibroids, endometriosis, cancer, and surgical approach. The effect of bleeding disorders on transfusions persisted in the laparoscopic group (OR 2.5, CI 1.9-3.3). Bleeding disorders were associated with immediate transfusions (OR 1.7, CI 1.5-2.0) and delayed transfusions (OR 2.1, CI 1.6- 2.7). Conclusions Patients with bleeding disorders are twice as likely to receive immediate and delayed transfusions for hysterectomies, even with a laparoscopic approach. Data are needed to optimize bleeding disorders to decrease transfusion risk

Objectives 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) tumors can respond to anti-programmed death 1 (PD-1) therapy. We report on a post-hoc analysis of ORR with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab. Methods GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg 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 IHC. MMR gene mutation was determined by Foundation One. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation. Results Cohort A1 included 143 patients; MMR gene mutation data was available for 101 (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. Conclusions 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 route to MMR deficiency does not influence response to dostarlimab

Objectives Universal mismatch repair (MMR) immunohistochemistry (IHC) in endometrial cancer began at our institution in July 2015. In April 2017, genetic counselors (GC) obtained IHC data and contacted physicians to approve genetic counseling for Lynch Syndrome (LS) in eligible patients. We assessed if this protocol increased frequency of genetic counseling referrals (GCRs) and genetic testing (GT) in patients with abnormal MMR IHC. Methods We retrospectively (7/2015-6/2021) identified patients with abnormal MMR IHC at a large urban hospital. GCR and GT rates were compared between cases from 7/2015-4/ 2017 (pre-protocol) and 5/2017-6/2021 (post-protocol) with Fisher's exact test. Results Of 717 patients with IHC testing, 156 (21.8%) had abnormal MMR results: MLH1/PMS2, 123; MSH2/MSH6, 10; MSH2/PMS2, 1; MSH6, 13; MLH1, 2; PMS2, 7. MLH1 hypermethylation was identified in 114 (73.1%) patients; 42 (26.9%) patients met criteria for LS screening with GT based on IHC results. Of 42 patients, 16 (38.1%) were identified before and 26 (61.9%) after protocol initiation. GCRs significantly increased from 11/16 (68.8%) to 25/26 (96.2%) in the pre-protocol versus post-protocol groups, p=0.02. There was no statistically significant difference in GT frequency between groups (10/16, 62.5% vs 23/26, 88.5%, p=0.06). Of 33 patients undergoing GT, 16 (48.5%) had LS: MSH6, 9; MSH2, 4; PMS2, 2; MLH1, 1. Conclusions Increased frequency of GCRs was observed following the protocol change, which is important as LS screening has clinical implications for patients and their families. Reflex protocols can maximize identification of patients for germline GT; alternatively universal GT can be considered in endometrial cancer (Levine et al. 2021)

Objectives Patterns of recurrence on PARP inhibitor maintenance therapy are unclear and may affect treatment choices for subsequent therapy, including secondary cytoreductive surgery (SCS). This analysis of PRIMA/ENGOT-OV26/GOG-3012 evaluated patterns of recurrence on niraparib maintenance therapy. Methods This post hoc subgroup analysis included 314 patients treated with niraparib maintenance monotherapy following first-line chemotherapy and who had no lesions identified by CT/MRI (or by investigator assessment) at baseline. Number and site(s) of initial recurrent lesions at the time of investigator-assessed RECIST-defined progressive disease (PD) were evaluated. Results As of the primary data cut, May 17, 2019, with a median follow-up of 13.8 months (range <1-28), 141/ 314 (45%) patients developed investigator-assessed PD, with an average 1.9 (standard deviation 0.9) lesions at PD. At the time of recurrence, 62 patients (44%) had 1 lesion, 46 (33%) had 2 lesions, 24 (17%) had 3 lesions, and 9 (6%) had 4-5 lesions. The five most common sites with >=1 lesion at PD were the peritoneum (n=45), lymph nodes (n=36), liver (n=34), other (n=26), and pelvis (n=20). Conclusions For patients who received niraparib maintenance monotherapy after first-line chemotherapy and had no lesions at baseline, <50% had recurrent disease after a median 13.8 months of follow-up and >75% of patients with recurrence progressed in 1-2 sites. Prospective evaluation is required to determine whether patients with oligoprogressive disease have improved outcomes with local therapies, like SCS, in addition to systemic therapy

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

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 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