Faculty Bibliography

BACKGROUND:Despite significant increase in COVID-19 publications, characterization of COVID-19 infection in patients with gynecologic cancer remains limited. Here we present an update of COVID-19 outcomes among people with gynecologic cancer in New York City (NYC) during the initial surge of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]). METHODS:Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 NYC area hospital systems between March and June 2020. Multivariable logistic regression was utilized to estimate associations between factors and COVID-19 related hospitalization and mortality. RESULTS:Of 193 patients with gynecologic cancer and COVID-19, the median age at diagnosis was 65.0 years (interquartile range (IQR), 53.0-73.0 years). One hundred six of the 193 patients (54.9%) required hospitalization; among the hospitalized patients, 13 (12.3%) required invasive mechanical ventilation, 39 (36.8%) required ICU admission. Half of the cohort (49.2%) had not received anti-cancer treatment prior to COVID-19 diagnosis. No patients requiring mechanical ventilation survived. Thirty-four of 193 (17.6%) patients died of COVID-19 complications. In multivariable analysis, hospitalization was associated with an age ≥ 65 years (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.11, 4.07), Black race (OR 2.53, CI 1.24, 5.32), performance status ≥2 (OR 3.67, CI 1.25, 13.55) and ≥ 3 comorbidities (OR 2.00, CI 1.05, 3.84). Only former or current history of smoking (OR 2.75, CI 1.21, 6.22) was associated with death due to COVID-19 in multivariable analysis. Administration of cytotoxic chemotherapy within 90 days of COVID-19 diagnosis was not predictive of COVID-19 hospitalization (OR 0.83, CI 0.41, 1.68) or mortality (OR 1.56, CI 0.67, 3.53). CONCLUSIONS:The case fatality rate among patients with gynecologic malignancy with COVID-19 infection was 17.6%. Cancer-directed therapy was not associated with an increased risk of mortality related to COVID-19 infection.

BACKGROUND:Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab. METHODS:GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review. RESULTS:Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab. CONCLUSION:Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile. TRIAL REGISTRATION NUMBER:NCT02715284.

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:

STUDY OBJECTIVE/OBJECTIVE:Obesity is a growing worldwide epidemic, and obese patients undergoing gynecologic robotic surgery are at increased risk for surgical complications. This study aimed to evaluate the feasibility and outcomes of a surgical safety protocol known as the High BMI pathway (HBP) for patients with a body mass index (BMI) of 40 or greater undergoing planned robotic hysterectomy. Our primary outcome was rate of all-cause perioperative complications in patients undergoing surgery with the utilization of the HBP. DESIGN/METHODS:A retrospective cohort study. SETTING/METHODS:An academic teaching hospital. PATIENTS/METHODS:) undergoing robotic hysterectomy. INTERVENTIONS/METHODS:The HBP was developed by a multidisciplinary team and was instituted January 1, 2016 as a quality improvement project. Morbidly obese patients undergoing robotic hysterectomy after this date were compared to consecutive historic controls. MEASUREMENTS AND MAIN RESULTS/RESULTS:Seventy-two patients underwent robotic hysterectomies on the HBP and were compared to 66 controls. There were no differences in age, BMI, blood loss, number of comorbidities, or cancer diagnosis. Since the implementation of HBP, there has been a decrease in anesthesia time (-57.0 min; p=.001), total operating room time (-47.0 min; p=.020), lower estimated blood loss (median 150 cc [IQR 100-200] vs 200 cc [IQR 100-300]; p=.002), and overnight hospital admissions (33.3% vs 63.6%; p < 0.001). There were fewer all-cause complications seen in HBP (19.4% vs 37.9%; p=.023) and infectious complications (8.3% vs 33.3%; p=.001) and no increase in readmission rates (p=.400). In multivariable analysis, the HBP reduced all-cause complications (odds ratio [OR] 0.353; p=.010) after controlling for covariate (total time in OR). CONCLUSION/CONCLUSIONS:HBP is a feasible method of optimizing outcome for morbidly obese patients undergoing major gynecologic surgery. Initiation of HBP can lead to decreased all-cause complications and overnight hospital admissions without increasing readmission rates.

Background Dostarlimab is a humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the ligands PD-L1 and PD-L2. Dostarlimab is approved as a monotherapy in adult patients (pts) with mismatch repair deficient (dMMR; US) or dMMR/microsatellite-instability high (EU) recurrent or advanced endometrial cancer that has progressed progressing on or following prior treatment with a platinum-containing regimen. GARNET is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in pts with solid tumors. Methods Pts with dMMR solid tumors, mismatch repair proficient endometrial cancer, and non-small cell lung cancer that progressed on or after prior therapy received 500 mg of dostarlimab IV every 3 weeks (Q3W) for 4 cycles, then 1000 mg IV every 6 weeks (Q6W) for up to 2 years or until disease progression or discontinuation. Here, we report TRAEs by cycle. Results A total of 515 pts were included. Of these pts, 60 (11.7%) experienced TRAEs leading to treatment interruption, and 25 (4.9%) experienced TRAEs leading to discontinuation. TRAEs of any grade with overall incidence of >=10% of pts are shown (table 1). The majority of TRAEs occurred during cycles 1-3, with highest incidence during cycle 1. Grade 3 or 4 TRAEs were rare; those seen in >=1% of pts are shown. Immune-related (ir) TRAEs of any grade with overall incidence of >=2% of pts are shown. Most cases (96.9%) of irTRAEs occurred during cycles 1-8. The peak incidence of hypothyroidism occurred during cycle 4; in addition, frequency was increased during cycles 5-8, compared with cycles 1-4. No deaths were attributed to dostarlimab. Abstract 370 Table 1 Time course of adverse events in the GARNET trial Conclusions No new safety signals were detected with dostarlimab compared to other anti-PD-1 inhibitors. Most TRAEs were low grade. The majority of TRAEs and grade >=3 TRAEs occurred in the first 3 cycles (first 12 weeks), but some cases occurred later, suggesting a need for ongoing monitoring. Few increases in the incidence of TRAEs were seen during cycle 5 following the transition to the 1000-mg Q6W dosing schedule; the TRAEs with increased incidence after the transition were fatigue and lipase increased. An increase in the frequency of the irTRAE hypothyroidism was seen after transitioning to the 1000-mg Q6W schedule

BACKGROUND:In women with BRCA mutations, risk-reducing bilateral salpingo-oophorectomy (RRSO) has been shown to decrease gynecologic cancer-specific and overall mortality. The National Comprehensive Cancer Network (NCCN) recommends that patients with BRCA mutations undergo RRSO between the ages of 35-40 years for BRCA1 mutation carriers and between the ages of 40-45 years for BRCA2 mutation carriers, or after childbearing is complete. Currently, uptake and timing of RRSO and reasons for delays in RRSO are not well understood. OBJECTIVE:We sought to evaluate uptake and timing of RRSO among women with BRCA1/2 mutations in relation to NCCN guidelines, and reasons for delays in RRSO. STUDY DESIGN/METHODS:In this retrospective chart review, we identified women with BRCA1/2 mutations who discussed RRSO with a provider between 2012 and 2021. Uptake of RRSO was documented, and patients were classified as having timely or delay in RRSO based on NCCN guidelines. For those with delay in RRSO, reasons cited for delay were collected. Comparative statistical analyses were performed to evaluate characteristics of those with timely vs delayed RRSO. A multivariable logistic regression model was used to evaluate the associations between factors related to timing of RRSO. RESULTS:We identified 638 BRCA1/2 mutation carriers seen between 2012 and 2021. Of these patients, 306 (48.0%) had undergone RRSO and 332 (52.0%) had not. When evaluating timing of RRSO, 136 (21.3%) underwent timely RRSO, 239 (37.5%) had delay in RRSO, and 263 (41.2%) had not undergone RRSO but were younger than NCCN age guidelines so were neither timely nor delayed. Patients with delay in RRSO were significantly older at the time of genetic testing compared to those with timely RRSO (mean 49.8 vs 36.3 years; p < 0.001). Of the 306 patients who underwent RRSO, those with delayed RRSO had a significantly shorter interval between BRCA identification and RRSO compared to those with timely RRSO (median 8.7 vs 17.6 months; p < 0.001). Patients with delay in RRSO were more likely to have a personal history of cancer than those with timely RRSO (49.8% vs 37.5%; p=0.028). Of the 239 women with delay in RRSO, reasons included: 188 (78.7%) for delayed BRCA mutation identification; 29 (12.1%) for menopausal concerns; 17 (7.1%) for ongoing cancer treatment; 12 (5.0%) for coordination with breast surgery; 20 (8.4%) for miscellaneous reasons; and 19 (7.9%) with no reasons documented. In the multivariate model, older age at BRCA diagnosis (OR 0.73; 95%CI [0.68-0.78]; p<0.001) was significantly associated with delayed RRSO timing; those with BRCA2 mutation type were 7.54 times as likely to have timely RRSO compared to BRCA1 mutation carriers (OR 7.54; 95%CI [3.70-16.42]; p<0.001). CONCLUSION/CONCLUSIONS:Nearly 38% of BRCA1/2 mutation carriers undergo or have yet to undergo RRSO beyond the NCCN recommended age. The most common reason for delay in RRSO was delayed identification of BRCA mutation, noted in 79% of patients with delayed RRSO. Timely genetic testing for eligible patients can increase appropriately timed RRSO for prevention of ovarian cancer and reduction of mortality in BRCA mutation carriers.

Objectives Dostarlimab is a humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interactions with PD-1 ligands. GARNET is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in patients with advanced solid tumors. Methods This multicenter, open-label, single-arm study is conducted in 2 parts: dose escalation and expansion. Patients with advanced or recurrent mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) endometrial cancer (EC) or mismatch repair-proficient (MMRp) EC that progressed on or after a platinum regimen received dostarlimab 500 mg intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression or discontinuation. Primary endpoints were objective response rate (ORR) and duration of response by BICR using RECIST v1.1. Here we report ORR in dMMR/ MSI-H and MMRp EC by prior lines of therapy (LOTs). Results Efficacy analyses included 108 dMMR/MSI-H and 142 MMRp patients. ORR was 43.5% in dMMR/MSI-H and 13.4% in MMRp. ORR was slightly higher (47.8%) in patients with dMMR/MSI-H with 1 prior LOT but lower (35.9%) in those who received >=2 prior LOTs. In the MMRp population, ORR was similar, regardless of prior LOTs. Safety has been previously reported.1 Conclusions Dostarlimab demonstrated antitumor activity in recurrent or advanced dMMR/MSI-H and MMRp EC regardless of number of prior LOTs. Patients with dMMR/MSI-H EC who received 1 prior LOT had slightly higher ORR than those who received >=2 prior LOTs. 1. Oaknin A, et al. Ann Oncol 2020;31(suppl 4):S1142-S1215

ABSTRACT/UNASSIGNED:The emergence of clinical trial data for poly(ADP-ribose) polymerase inhibitors (PARPi), in BRCA-associated ovarian cancer (epithelial ovarian cancer [EOC]) in 2009 (Lancet 2010;376:245-251) unleashed a rapid series of additional asset development and clinical trial activation across all lines of EOC treatment, ultimately leading to 8 new approvals of 3 different PARPi in EOC since 2014. Monotherapy iPARPi were approved as frontline maintenance treatment for all patients with EOC who respond to platinum-based chemotherapy irrespective of biomarker (niraparib) and for BRCA-associated cancers (olaparib) (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf). Combination of olaparib and bevacizumab was approved as maintenance for patients in response to platinum-based and bevacizumab containing frontline therapy whose tumor is characterized as homologous recombination deficient and as approved test by the Food and Drug Administration, inclusive of BRCA-associated cancers (N Engl J Med 2019;381:2416-2428). Niraparib, olaparib, and rucaparib were also approved as maintenance treatment following response to platinum-based therapy in the recurrent setting irrespective of biomarker (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf). All 3 PARPi were also approved as treatment in lieu of chemotherapy for patients with BRCA-associated cancers in third line and beyond (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1;https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf) and platinum-sensitive homologous recombination deficient in the fourth line and beyond (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf), as well as the National Comprehensive Cancer Network listed in combination with bevacizumab for treatment of patients with platinum-sensitive recurrent disease (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf). Ongoing clinical trials in all lines of treatment are evaluating combinations of therapies to improve efficacy among biomarker negative tumors as well as overcome acquired PARPi resistance due to prior use.

OBJECTIVES/OBJECTIVE:We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. METHODS:Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. RESULTS:The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9-90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11-168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. CONCLUSION/CONCLUSIONS:The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Background/UNASSIGNED:Medical marijuana (MM) use is common among cancer patients, but relatively little is known about the usage patterns and efficacy of MM used by gynecologic cancer patients. Methods/UNASSIGNED:Demographic and clinical data were collected for gynecologic cancer patients prescribed MM between May 2016 and February 2019. The electronic medical record was used to query formulation prescribed, usage patterns, length of use, symptom relief, and side effect profile. Descriptive statistics were calculated. Results/UNASSIGNED:Of 45 gynecologic cancer patients prescribed MM, 89% were receiving chemotherapy; 56% were undergoing primary treatment. MM was used for a median of 5.2 months (range 0.6-25.4). Over 70% of patients reported improvement in nausea/vomiting, compared to 36% of patients using MM for pain relief (p = 0.02). Of 41 patients with follow-up information, 71% found MM improved at least one symptom. Conclusions/UNASSIGNED:Among a small sample of gynecologic cancer patients prescribed MM for symptom management, self-reported follow-up indicated symptom relief for the majority of patients and minimal therapy-related side effects. This data can prove useful for counseling gynecologic cancer patients on the efficacy and side effects of MM.