Faculty Bibliography

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 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.

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.

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.

OBJECTIVES/OBJECTIVE:Patients with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) associated with Lynch syndrome (LS) have an increased lifetime risk of endometrial cancer (EC). Multi-gene panel testing (MGPT) is a recent hereditary cancer risk tool enabling next-generation sequencing of numerous genes in parallel. We determined the prevalence of actionable cancer predisposition gene mutations identified through MGPT in an EC patient cohort. METHODS:A single center retrospective cohort study was conducted of patients with EC who had a clinical indication for genetic testing and who underwent MGPT as part of standard of care treatment between 2012 and 2021. Pathogenic mutations were identified and actionable mutations were defined as those with clinical management implications. Additionally, the number of individuals identified with LS was compared between MGPT and tumor-based screening. RESULTS:The study included a total of 224 patients. Thirty-three patients [14.7%, 95% confidence interval (CI) = 10.4-20.1] had actionable mutations. Twenty-one patients (9.4%, 95% CI = 5.9-14.0) had mutations in LS genes (4 MLH1, 5 MSH2, 7 MSH6, 4 PMS2, 1 Epcam-MSH2). MGPT revealed two patients with LS (9.5% of LS cases) not identified through routine tumor-based screening. Thirteen patients (5.8%, 95% CI = 3.1-9.7) had at least one actionable mutation in a non-Lynch syndrome gene (6 CHEK2, 2 BRCA2, 2 ATM, 2 APC, 1 RAD51C, 1 BRCA1). CONCLUSIONS:Germline MGPT is both feasible and informative as it identifies LS cases not found on tumor testing as well as additional actionable mutations in patients with EC.

OPINION STATEMENT/UNASSIGNED:Poly-ADP-ribose polymerase inhibitors (PARPi) are a class of anti-cancer drugs that target DNA repair pathways and have shown promising efficacy in patients with ovarian cancer in recent clinical trials. To date, there have been 9 FDA PARPi approvals/indications in ovarian cancer since 2014, highlighting the importance of this class of agents in the treatment of ovarian cancer. BRCA1/2-mutated tumors or other forms of homologous recombination deficient (HRD) tumors are particularly susceptible to PARP inhibition and have seen the greatest benefits of improvement in response rate and progression-free survival (PFS) in clinical trials. Patients with homologous recombination-proficient tumors also receive benefit, especially when a nice response to paltinum is noted, but to a lesser extent. PARP inhibitors now have FDA approval and indications in first-line and recurrent maintenance, and treatment. PARP inhibitor use as maintenance therapy in the front-line setting is now considered the standard of care in patients with BRCA1/2 mutations based on the SOLO-1/GOG-3004/ENGOT study. PARP inhibitors are also recommended per ASCO guidelines in all patients with ovarian cancer as front-line maintenance therapy based on the PRIMA/ENGOT-OV26/GOG-3012 trial. The combination of PARP inhibitor, olaparib, and the anti-angiogenesis inhibitor bevacizumab is also approved as maintenance therapy after front-line chemotherapy treatment in patients with HRD tumors and is an option for patients who have initiated bevacizumab with their chemotherapy treatment. PARPi are also FDA approved and can be utilized as a treatment in third-line and beyond in recurrent ovarian cancer patients with BRCA1/2 mutations and HRD tumors. In this review, we will cover in detail when PARP inhibitor use is appropriate in ovarian cancer, as well as the various clinical factors to take into consideration when selecting a PARP inhibitor regimen.