Faculty Bibliography

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

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 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 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

Purpose: Locally advanced cervical cancer was defined by an international consensus panel as a high priority malignancy during the COVID-19 pandemic, recommending prompt initiation of definitive treatment and completion of treatment (PMID 32563593). The objective of this study was to study the clinical outcomes of patients (pts) with cervical cancer treated with definitive chemoradiation (CRT) and brachytherapy (BT) at our institution in 2019 (pre-COVID) and in 2020 (peri-COVID).
Material(s) and Method(s): This was a retrospective cohort study of pts with FIGO Stage IB2-IVA cervical cancer at our institutions from 1/1/2019 to 12/31/2020. Pts received CRT followed by intracavitary brachytherapy (IC) with two operative insertions one week apart, or interstitial (IS) BT with one operative insertion. BT treatment was planned using image-guided CT or MR delineation. Pre-COVID was defined by initiation of CRT in 1/2019-12/2019, and peri-COVID was defined by initiation in 1/2020-10/2020. Process changes peri-COVID included limited on-site staff (e.g., minimal OR staff, no trainees, remote physics team), universal implementation of COVID-19 testing prior to surgery, and CT instead of MR-delineation based treatment. Outcomes of interest were time to treatment initiation and completion and differences in treatment planning modality or dosimetry. Fisher's exact and Mann Whitney U tests were used with significance p<0.05.
Result(s): Thirty-one pts were included, with 18 patients undergoing treatment pre-COVID and 13 peri-COVID. The median age at diagnosis pre-COVID was 57.7 (range 23-77) and for peri-COVID, 45.5 (range 28-62, p=0.06). There were no differences in non-English speaking pts (44% vs 59%, p=0.71) or uninsured pts (11% vs 33%, p=0.184) between the two cohorts. Median time to initiation of treatment from biopsy diagnosis was 52 days (range 13-209) in 2019 and for peri-COVID, 55.5 (range 20-173, p=0.71). During COVID, four pts had delayed initiation to treatment >100 days: two related to fertility, and one due to fear of COVID-19. For this pt, tumor size progressed from 2.3 cm to 4.2 cm maximal dimension. One pt treated in 2020 tested positive following treatment and did not require hospital admission. All pts except one completed CRT with RT: 25 pts pelvic RT (45 Gy), 3 pelvic and para-aortic RT (45 Gy with 57.5 Gy concomitant boost to nodes), 8 pts pelvic RT (45Gy) with sequential parametrial boost (50.4-59.4 Gy) using IMRT with no dose differences between pre and peri-COVID (Table 1). No pts required treatment breaks and the median overall treatment time was 50 days (range 31-85) in 2019 vs 50 days (range 43-63) in 2020 (p=0.710).
Conclusion(s): Despite the significant burden of the COVID-19 pandemic on our health care system, all cervical cancer pts receiving CRT met standard of care including CRT and BT within the recommended time frame with no significant differences in dosimetric treatment parameters pre- and peri-COVID. Delays in treatment initiation of treatment initiation were seen in 30% of pts in the peri-COVID period, suggesting that patients may have had increased barriers to access care. More follow-up is needed to determine how the Covid pandemic impacted cervical cancer outcome measures.
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Background: Median age of EC diagnosis is 62 y, yet most EC deaths occur in pts >65 y (median 70 y). Unmet need in older pts is not addressed by current standard of care. Dostarlimab is an anti-programmed death receptor 1 (PD-1) antibody. We report a post-hoc analysis of dostarlimab antitumor activity and safety by age in pts with dMMR/microsatellite instability high (MSI-H) EC and MMR proficient (MMRp)/MS stable (MSS) EC.
Method(s): GARNET (NCT02715284) is a Phase I, single-arm study of dostarlimab in pts with advanced/recurrent (A/R) solid tumors. Pts with dMMR/MSI-H EC were enrolled in Cohort A1 and pts with MMRp/MSS EC in Cohort A2. Pts were stratified: <65 y, >=65 to <75 y, or >=75 y at baseline. Antitumor activity and safety were assessed. Data cut was March 1, 2020.
Result(s): In Cohort A1 (n=129), 51.2% of pts were <65 y, 39.5% were >=65 to <75 y, and 9.3% were >=75 y. In Cohort A2 (n=161), 43.5% were <65 y, 44.7% were >=65 to <75 y, and 11.8% were >=75 y. In the efficacy-evaluable population (measurable disease at baseline; >=24 w follow up), objective response rates (ORRs) (95% confidence interval [CI]) per RECIST v1.1 assessed by BICR were similar across age groups for pts with dMMR/ MSI-H EC (<65 y: 45.3% [31.6-59.6] vs >=65 to <75 y: 43.9% [28.5-60.3] vs >=75 y: 45.5% [16.7-76.6]) and for pts with MMRp/MSS EC (<65 y: 9.1% [3.4-18.7] vs >=65 to <75 y: 16.9% [9.0-27.7] vs >=75 y: 21.1% [6.1-45.6]). There were few Grade >=3 treatment-related adverse events (TRAEs) (for pts with dMMR/MSI-H EC [n=129]: 13.6% vs 13.7% vs 8.3%, respectively) and for MMRp/MSS EC [n=161]: 22.9% vs 19.4% vs 5.3%, respectively); observed TRAEs were similar between groups.
Conclusion(s): Dostarlimab antitumor activity and safety for pts with dMMR/MSI-H EC and MMRp/MSS EC were comparable across age groups, with low Grade >=3 TRAE incidence. Older pts with A/R dMMR/ MSI-H EC experienced broadly similar treatment benefits as younger pts

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 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 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