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Cervical cancer continues to affect women in the United States and throughout the world despite an effective vaccine against human papillomavirus and cancer screening programs. For the women who develop cervical cancer, surgery, radiation, and chemotherapy have been the mainstays of treatment for years. Recently, novel therapeutics have been developed that offer new treatment opportunities for women living with advanced and/or recurrent disease. Immunotherapy has become an important tool against cervical cancer with the approval of pembrolizumab in the second line for advanced or recurrent disease. Checkpoint inhibitors have recently been approved in the front line for advanced and/or recurrent disease in combination with chemotherapy, and they are being studied in the front line in combination with chemoradiation. Antibody-drug conjugates-specifically tisotumab vedotin (TV)-also have recently received Food and Drug Administration (FDA) approval, and TV is currently being studied in combination with checkpoint inhibitors and with carboplatin. Tumor-infiltrating lymphocytes have been studied in early-phase trials and have shown promise in small patient series. Despite these new therapies, there continue to be racial, ethnic, and socioeconomic inequities with respect to access to care, access to and participation in clinical trials, and survival in the United States as well as globally. New FDA guidance requires researchers to work to reduce disparities by including women of more diverse backgrounds in clinical trials. Finally, as progress continues to be made in the treatment of established disease, prevention through vaccination and screening remains paramount. PLAIN LANGUAGE SUMMARY: The treatment of cervical cancer remains a significant problem in the United States and especially worldwide. Although early cases can be cured, cervical cancer that has spread remains difficult to treat. The past few years have seen significant advances in new therapies and combinations of therapies for women with advanced or recurrent disease. Although this is excellent news for these women, cervical cancer is a preventable disease through screening with Papanicolaou smears and vaccination with the human papillomavirus vaccine. By improving access to and acceptance of screening and vaccination, we can eradicate cervical cancer in the United States and the world.

This study explored the feasibility of cetuximab with chemoradiation in women with cervical carcinoma and evaluated fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) to assess early response to cetuximab (NCT00292955).Eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVB invasive carcinoma of the uterine cervix were treated on 1 of 3 dose levels (DL). DL1 consisted of neoadjuvant cetuximab, then concurrent radiotherapy with cetuximab 250 mg/m2/cisplatin 40 mg/m2, followed by weekly cetuximab. DL2 consisted of radiotherapy with cetuximab 200 mg/m2 and cisplatin 30 mg/m2. DL3 consisted of radiotherapy with cetuximab 250 mg/m2 and cisplatin 30 mg/m2. Patients underwent 18F-FDG-PET/CT before treatment, after neoadjuvant cetuximab, and at the end of treatment.Of the 21 patients enrolled, 9, 3, and 9 were treated in DL1, DL2, and DL3, respectively. DL1 required dose reductions due to gastrointestinal toxicities. DL2 and 3 were tolerated with 1 dose-limiting toxicity (grade 4 renal failure) at DL3. Following 3 weekly treatments of neoadjuvant cetuximab in DL1, 7 patients had maximum standardized uptake value changes on 18F-FDG-PET/CT consistent with response to cetuximab. Of the 12 patients with locally advanced disease, eleven evaluable patients had no evidence of disease on 18F-FDG-PET/CT at treatment end. Five-year progression-free survival and overall survival rates for all patients were 57.5% and 58.5%, respectively.Cetuximab with cisplatin 30 mg/m2 and radiotherapy was tolerated. 18F-FDG-PET/CT demonstrated early evidence of response to neoadjuvant cetuximab. With advances in precision oncology and the recent approval of pembrolizumab in metastatic cervical cancer, dual-target inhibition with an epidermal growth factor receptor inhibitor may be a promising treatment in the future.

Objective To evaluate how women with epithelial ovarian cancer (EOC), dichotomized by BRCA status, tolerate intravenous (IV) or intraperitoneal (IP) chemotherapy given with veliparib and bevacizumab (bev) on a GOG phase I study (GOG 9923, NCT00989651). Methods This is an unplanned, post hoc analysis of an IRB approved, multi-institutional, prospective study (GOG 9923). Clinical characteristics and toxicity data based on BRCA status were evaluated and descriptive statistics were used to summarize baseline patient characteristics and toxicities. The Kaplan Meier method was used to generate survival estimates. Results Four hundred twenty-four patients were evaluable. Patients were treated with IV carboplatin, paclitaxel, and bev every 21 days (regimen 1), weekly IV paclitaxel with carboplatin and bev (regimen 2) or IV paclitaxel and bev with IP cisplatin (regimen 3). Bev was continued as maintenance in all arms. Within each of these regimens, veliparib was given either twice daily for the entirety of each cycle (continuous) or on days −2 to 5 (intermittent). Ten percent of patients treated on regimen 1, 12% on regimen 2, and 19.8% on regimen 3 had BRCA-associated tumors. Patients with BRCA-associated tumors, when compared to wild type, experienced similar rates of anemia, febrile neutropenia (, abdominal pain, colonic perforation, nausea, vomiting, and peripheral sensory neuropathy. Median progression free survival (PFS) was not significantly different between BRCA-associated and wild type cancers (HR 0.96, CI 0.65–1.42), though this study's primary aim was not to evaluate outcomes. Conclusions Germline BRCA mutations positively affect chemosensitivity in EOC, but whether differences in toxicities among BRCA-associated and BRCA wild type tumors existed was previously not reported. In this population with newly diagnosed ovarian cancer no differences in reported toxicity between the two groups was observed.

Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. Results: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed > 1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words

The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all 4 BET family members (BRD2, BRD3, BRD4, and BRDT). PLX2853 development is continuing at Opna Bio as OPN-2853. Clinical experience with PLX2853 monotherapy in subjects with heavily pretreated solid tumors and lymphoma showed signs of activity. The current study (NCT04493619) was designed as a multicenter, open-label trial with two parallel arms: (1) a phase 2a study of PLX2853 monotherapy in advanced gynecological malignancies with a known ARID1A mutation and (2) a phase Ib/2a combination study of PLX2853 plus carboplatin in platinum resistant OC. The primary objective of the Ib portion of the study was safety and tolerability, with the primary objective of both phase 2a portions being efficacy. In the monotherapy arm, up to 6 patients were treated at 80 mg PLX2853 daily in a safety lead-in, with progression to phase 2a using a Simon 2-stage design if dose limiting toxicities (DLTs) were observed in fewer than 33% subjects. In Stage 1, 6 additional subjects (N=12 total) were planned, with progression to stage 2 if two or more patients responded in stage 1. The combination arm included an escalation phase Ib. Three to six evaluable subjects were planned for each group, with dose escalation pending less than 33% DLT rate. The combination arm defined by the phase 1b portion of the study continued to a planned phase 2a Simon 2 stage design similar to that described for the monotherapy arm. 34 of 37 enrolled patients were evaluable with data from at least 1 post-baseline response (14 monotherapy, 20 combination therapy). Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a partial response (PR) with progression-free survival of 278 days, 5 (35.7%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable OC patients on the PLX2843 + carboplatin combination, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study in a larger cohort of gynecologic cancer patients confirmed the safety profile of the agent and demonstrated the feasibility of combination with carboplatin. While these results did not meet the pre-specified response criteria, evidence of clinical activity nevertheless highlights the rationale for further exploration of BRD4 inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway, frequently activated in these cancers. Citation Format: Elizabeth M. Swisher, Linda R. Duska, Erika P. Hamilton, Amit M. Oza, Gini Fleming, Oladapo O. Yeku, Alexander I. Spira, Debra L. Richardson, Robin Guo, Jackie Walling, Kerry Inokuchi, Dmitriy Zamarin. Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT160.

Background Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements. Methods Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion. Results As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab. Conclusions Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially. Lay summary Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy. Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer. Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy.

Summary Background High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. Methods In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov , NCT02595892 , and is active but closed to enrolment. Findings Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6–81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2–69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9–72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7–36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33–0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. Interpretation To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. Funding US National Cancer Institute.

Objective The “surprise question” (“Would you be surprised if this patient died in the next year?”) has been shown to be predictive of 12-month mortality in multiple populations, but has not been studied in gynecologic oncology (GO) patients. We sought to evaluate the prognostic performance of the surprise question in GO patients among physician and non-physician providers. Methods GO providers at two tertiary care centers were asked the surprise question about a cohort of their patients undergoing chemotherapy or radiation. Demographic and clinical information was chart abstracted. Mortality data were collected at one year; relative risk of death at one year based on response to the surprise question was then calculated. Results 32 providers (12 MDs, 7 APPs, 13 RNs) provided 942 surprise question assessments for 358 patients. Fifty-seven % had ovarian cancer and 54% had recurrent disease. Eighty-three (24%) patients died within a year. Patients whose physician answered “No” to the surprise question had a 43% one-year mortality (compared to 10% for “Yes”). Overall RR of 12-month mortality for “No” was 3.76 (95% CI 2.75–5.48); this association remained significant in all provider types. Among statistically significant predictors of 12-month mortality (including recurrent disease and >2 prior lines of chemotherapy), the surprise question had the highest RR. Conclusions The surprise question is a simple, one question tool that effectively identifies GO patients increased risk of 12-month mortality. The surprise question could be used to identify patients for early referral to palliative care and initiation advance care planning.

Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC.An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%).The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Objectives Given the disparity that exists in enrollment of minorities to oncology clinical trials, the objective of our study was to assess whether race is associated with willingness to participate in gynecologic oncology clinical trials in a rural Southern academic medicine setting. Our secondary aim was to determine whether willingness to participate is impacted by an educational intervention. Methods A single institution prospective survey study was performed at an academic medical center. Women presenting to the gynecologic oncology clinic with a current or prior diagnosis of gynecologic malignancy were approached to participate. The validated Attitudes to Randomized Trials Questionnaire (ARTQ) assessed willingness to participate in clinical trials. Relevant demographic and clinical data were abstracted. Characteristics were compared between those willing and unwilling to participate in clinical trials with a chi-square test for categorical variables and Wilcoxon rank sum tests for continuous data. Results We enrolled 156 participants (50% White, 50% non-White) from May 2017 to January 2018. The minority group included 35% non-Hispanic Black, 9% Hispanic, 4% Asian, and 2% other. Median age was 63 years with endometrial cancer being the most common diagnosis (48%). On initial screen, only 35% were willing to participate in a clinical trial. Willingness to participate did not differ between race, age, marital status, education level, cancer type, stage, or mode of treatment. Rates improved to 82% after being provided additional educational information. Following education, White women and those with more education were significantly more willing to participate in clinical trials than their minority and less educated counterparts. Conclusions Willingness to participate improved among all sub-categories following an educational intervention. The increase in willingness was less robust among racial and ethnic minorities, suggesting that different tools are needed for recruitment of minorities to gynecologic oncology clinical trials.

At an academic institution in rural Virginia, we noticed a trend of increased re-admissions for postoperative pelvic abscesses. The primary study objective was to determine if intraoperative use of hemostatic agents (HA) was associated with postoperative abscess formation in patients undergoing hysterectomy.Retrospective chart review identified women who underwent hysterectomy by a Gynecologic Oncologist for any indication at a single institution from January 1, 2019 through December 31, 2019. Patient and surgical characteristics were abstracted and comparisons were made among those who received any HA and those that did not. The relationship between intraoperative HA use and postoperative pelvic abscess formation was determined using multivariate logistic regression. Secondary outcomes evaluated included the presence of other major post-operative adverse events.428 hysterectomies were identified with a postoperative pelvic abscess rate of 3.7 %. Abscesses were identified in 4 (2.2 %) of cases without vs 12 (4.9 %) of cases with HA use with a logistic regression model demonstrating no significant difference in the groups (OR = 2.10, p = 0.22). Data showed an increase in presentation to the Emergency Department (ED) (OR = 3.43, p = 0.002 adjusted) and higher odds of readmission within 30 days of surgery (OR = 3.19, p = 0.03) with HA use.No association was found between HA use and abscess formation; however, data showed HA use was associated with increased odds of presentation to the ED and readmission to the hospital within 30 days of surgery. Given the potential negative impact on patient outcomes, use of these products at time of hysterectomy should be made with careful consideration.

BackgroundCabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which might enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960), a multicenter phase 1b study, is evaluating the combination of cabozantinib with atezolizumab in advanced solid tumors; here we present efficacy and safety results in patients with triple negative breast cancer (TNBC), ovarian cancer (OC), and endometrial cancer (EC).MethodsEligible patients had locally advanced or metastatic TNBC, OC, or EC and had radiographically progressed on prior systemic anticancer therapy. One or two lines of prior therapy were permitted. Patients with OC were platinum resistant or refractory. Prior treatment with anti-PD-1 or anti-PD-L1 agents was allowed for patients with TNBC. Patients received cabozantinib, 40 mg PO QD, plus atezolizumab, 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 as assessed by investigator. Other endpoints included safety, duration of response (DOR), progression free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter.ResultsAs of February 19, 2021, 30–32 patients were enrolled in each of the cohorts. 47% of patients with TNBC, 47% with OC, and 40% with EC had received 2 lines of prior therapy. Median follow-up was 18.7 months, 20.8 months, and 19.0 months for the TNBC, OC, and EC cohorts, respectively. Grade 3/4 treatment-related adverse events occurred in 33% of patients with TNBC, 56% with OC, and 37% with EC. One Grade 5 treatment-related adverse event of pulmonary hemorrhage occurred in the TNBC cohort and one of encephalitis occurred in the OC cohort. Cabozantinib plus atezolizumab demonstrated clinical activity in all three tumor cohorts (table 1).Abstract 531 Table 1ConclusionsCabozantinib in combination with atezolizumab demonstrated encouraging clinical activity in patients with previously treated advanced cancers.AcknowledgementsMedical writing support provided by Suvajit Sen, PhD (Exelixis, Inc.)Trial RegistrationNCT03170960Ethics ApprovalYesConsentYes

Introduction/Background* Dostarlimab is a humanised programmed death (PD-1) receptor monoclonal antibody approved for patients with mismatch mutation repair-deficient/microsatellite instability-high (dMMR/MSI-H) recurrent or advanced endometrial cancer (EC) that progressed on or after a platinum-based chemotherapy regimen. GARNET is a phase 1 study assessing the antitumour activity and safety of dostarlimab monotherapy in patients with advanced solid tumours. Methodology GARNET is a multicentre, open-label, single-arm study. Here we report on 2 independent expansion cohorts of patients with recurrent or advanced EC that progressed on or after a platinum-based chemotherapy regimen. Patients were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (mismatch mutation repair-proficient/microsatellite-stable [MMRp/MSS] EC) based on immunohistochemistry testing. Patients received 500 mg of dostarlimab intravenously once every 3 weeks for 4 cycles, then 1000 mg once every 6 weeks until disease progression, discontinuation or withdrawal. The primary endpoints are objective response rate (ORR) and duration of response by blinded independent central review using RECIST version 1.1. Result(s)* In total, 129 dMMR/MSI-H and 161 MMRp/MSS patients were enrolled and dosed. Of these, 108 dMMR/MSI-H and 156 MMRp/MSS patients who had measurable disease at baseline and ≥6 months of follow-up were included for efficacy analyses. ORR and disease control rate (DCR) for dMMR/MSI-H EC was 43.5% and 55.6%, respectively; ORR and DCR for MMRp/MSS EC was 14.1% and 34.6%, respectively (table 1). Overall, 16 patients (5.5%) discontinued treatment due to a treatment-related adverse event (5 dMMR/MSI-H, 11 MMRp/MSS). Table 2 shows safety by cohort and overall. No deaths were attributed to dostarlimab. Conclusion* Dostarlimab demonstrated durable antitumour activity in both dMMR/MSI-H and MMRp/MSS advanced/recurrent EC. dMMR/MSI-H status was associated with a higher response rate. DCR achieved in MMRp/MSS EC was noteworthy, considering MMRp/MSS tumours are historically associated with a poor prognosis. The dostarlimab safety profile was manageable. Clinical trial registration NCT02715284

Introduction/Background* High-risk locally advanced cervical cancer has a poor prognosis, and more than half of patients recur in 2 years. External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer. The immunostimulatory activity of the PD-1 inhibitor pembrolizumab may be enhanced by concurrent chemoradiotherapy (CCRT). After the KEYNOTE-158 study, in which pembrolizumab showed durable antitumor activity, pembrolizumab monotherapy was approved for patients with PD-L1–positive recurrent or metastatic cervical cancer who progressed during or after chemotherapy. ENGOT-cx11/GOG 3047/KEYNOTE-A18 (NCT04221945) is a phase 3, randomized, placebo-controlled study evaluating pembrolizumab with CCRT for the treatment of high-risk, locally advanced cervical cancer. Methodology Approximately 980 patients with high-risk (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive either 5 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) + CCRT followed by 15 cycles of pembrolizumab 400 mg Q6W or 5 cycles of placebo Q3W + CCRT followed by 15 cycles of placebo Q6W. CCRT includes 5 cycles (optional 6th dose) of cisplatin 40 mg/m2 Q1W + EBRT followed by brachytherapy. Randomization is stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cancer stage at screening (stage IB2-IIB vs III-IVA), and planned total radiotherapy dose. Treatment will continue until the patient has received 20 cycles of pembrolizumab (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 years) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator and overall survival (OS). Secondary endpoints include PFS by blinded independent central review, PFS at 2 years, OS at 3 years, complete response at 12 weeks, objective response rate, PFS and OS by PD-L1 status, quality of life, and safety. Enrolment began May 2020 and is planned for 193 sites in 30 countries. Klikněte nebo klepněte sem a zadejte text.

Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer.This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured.27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03).Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.

One of the most prevalent potential therapeutic targets for women with endometrioid endometrial cancer (EC) is the estrogen receptor (ER)/progesterone receptor (PR) pathway. Despite a high proportion of endometrioid ECs being ER and/or PR positive, endocrine therapy is only effective in a minority of women with EC and ultimately patients progress with resistance developing to treatment. A variety of treatment approaches with progestins, selective ER modulators (SERMs) and aromatase inhibitors (AIs) are available. Exploration of these agents is desirable given their favorable toxicity profile. Greater understanding of ER and PR biology may help identify patient populations who will derive benefit and strategies for new therapeutic options. Here we review the clinical efficacy of endocrine therapy in EC, discuss the role of ER and/or PR as prognostic biomarkers, describe disease-specific mechanisms of resistance to endocrine therapy and explore potential strategies to enhance response for the "next generation" of endocrine therapy clinical trials. We also describe the use of endocrine therapy in younger women seeking to pursue fertility sparing options for management of EC.

Background Granulosa cell tumors (GCT) variably express estrogen receptors (ER) and progesterone receptors (PR). The goal of this study is to evaluate the relationship between ER and PR expression patterns and clinical outcomes in women with GCT. Methods A multicenter, retrospective analysis was performed of all cases of GCT diagnosed between 1989 and 2012. Immunohistochemical staining for ER and PR was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue and interpreted using a semiquantitative scoring system that incorporated tumor cell staining proportion and intensity. Demographics, disease status, and survival information were collected. Associations between ER and PR staining scores and recurrence-free and overall survival were assessed using univariate Cox proportional hazards models. Results FFPE tumor blocks were available for 149/186 GCT patients. The majority of the women had clinical stage I disease (76%). ER and PR expression was present in 52% and 98% of subjects, respectively. The median composite scores of ER and PR staining were 1 (range 0–8) and 9 (range 0–15), respectively. In univariate analysis, PR composite score >9 was strongly associated with decreased recurrence-free survival (HR = 2.9, 95% CI = 1.5–5.5) and decreased overall survival (HR = 3.7, CI 1.3–10.2). ER composite score was not a significant predictor of recurrence-free survival or overall survival (p = 0.7, HR = 1.1, 95% CI 0.6–2.0 and p = 0.06, HR = 1.1, 95% CI 0.4–2.9, respectively). Conclusions Our results reveal that high PR composite score (≥9) was associated with both decreased recurrence-free and overall survival in patients with GCT while ER expression was not associated with survival outcomes.

Microsatellite instability (MSI) due to defective DNA mismatch repair has emerged as an actionable biomarker in advanced endometrial cancer (aEC). Currently, there are no treatment patterns and outcomes data in non-MSI-high (non-MSI-H) or mismatch repair proficient (pMMR) aEC patients following prior systemic therapy (FPST). Our goal was to describe real-world data in this population in the US in 2019 and prior years.Endometrial Cancer Health Outcomes (ECHO) is a retrospective patient chart review study conducted in the US. Patients with non-MSI-H/pMMR aEC and progression between 06/01/2016-06/30/2019 FPST were eligible. Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS), and overall survival (OS), separately by treatment category.A total of 165 eligible patients initiated second-line therapy with chemotherapy ± bevacizumab (n = 140) or hormonal therapy (n = 25). Median age was 66.0 years at aEC diagnosis, 70.2% were Stage IIIB-IV, 40.0% had ECOG ≥ 2 at second-line therapy initiation. Median rwPFS was 5.0 months (95% CI: 4.0-6.0) for patients receiving chemotherapy ± bevacizumab and 5.5 months (95% CI: 3.0-29.0) for those receiving hormonal therapy. Median OS was 10.0 months (95% CI: 8.0-13.0) and 9.0 months (95% CI: 6.0-NA) in these groups, respectively.Non-MSI-H/pMMR patients who initiated second-line therapy with chemotherapy ± bevacizumab or hormonal therapy had poor clinical outcomes with a median survival less than 1 year and rwPFS less than 6 months. This was the first study to define the clinical unmet need in patients with non-MSI-H/pMMR aEC with conventional therapy.

5514 Background: Mesothelin and its binder, antigen-CA125, are highly expressed in high grade serous and endometrioid ovarian cancers (HGOC) and, can inhibit paclitaxel-induced cell death. Anetumab ravtansine (AR) is a fully-human antibody directed at the mesothelin antigen, conjugated to a tubulin polymerization inhibitor. We assessed the safety and activity of the combination AR/bevacizumab (ARB) versus weekly paclitaxel/bevacizumab (PB) in patients (pts) with platinum resistant HGOC. Methods: An initial run-in phase I assessed the safety of ARB. After determination of the recommended phase 2 dose (RP2D), a multicenter 1:1 randomized phase 2 trial was designed to evaluate the progression free survival (PFS) in pts with platinum resistant/refractory HGOC. Pts were stratified by platinum resistant or refractory and prior bevacizumab (bev). Eligibility required measurable disease and mesothelin tested positive centrally on archival tissue by IHC. No limitation on the number of prior lines of therapy. A futility analysis was planned at 35 PFS events. The control arm was weekly intravenous paclitaxel 80mg/m2 with bev 10mg/kg every 2 weeks. A CT was performed every 8 weeks for RECIST1.1 assessment. The toxicities were reported according to CTCAE version 5.1. NCT03587311. Results: 7 pts were enrolled in the run-in phase 1 and the RP2D determined as bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly on a 28 day-cycle. In the phase 2, 57 pts were enrolled, 28 pts in the ARB and 29 pts in the control group. The positivity rate for mesothelin screening was 88%. Pts were heavily pre-treated, median prior lines of 3 (range (1-9) with 24 pts received prior bev (42%) and 13 pts were platinum refractory (7 in ARB and 6 in PB). At the time of 35 PFS events, one CR and 4 PR were observed (ORR = 18%) in the ARB arm, versus no CR and 16 PR in the weekly PB (ORR = 55%). The estimated median PFS was 5.3 (95% CI: 3.7-7.4) months for ARB and 9.6 (95% CI: 7.4-17.4) months for PB (HR = 1.7(95% CI: 0.9-3.4)). The median number of cycles were 4 (1, 29) and 8 (1, 19) respectively. The most common treatment-related AEs in the ARB arm were mostly grade 1/2 increase AST (71%) and ALT (64%), thrombocytopenia (61%), fatigue (57%), and peripheral neuropathy (46%). In the PB arm, the most common treatment-related AE were anemia (66%), neutropenia (59%), epistaxis (48%), fatigue (45%) and peripheral neuropathy (45%). Conclusions: At the time of futility analysis, weekly PB had better outcome than weekly ARB leading to the study termination. Molecular and blood analyses are on-going to assess potential biomarkers of response. This study highlights the importance of randomization in assessment of novel therapies and potential for re-challenge with bevacizumab. These data show that weekly PB is an effective regimen and can be considered as the control arm in platinum resistant HGOC. Clinical trial information: NCT03587311.

In approximately ten months' time, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 34 million people and caused over one million deaths worldwide. The impact of this virus on our health, relationships, and careers is difficult to overstate. As the economic realities for academic medical centers come into focus, we must recommit to our core missions of patient care, education, and research. Fellowship education programs in gynecologic oncology have quickly adapted to the “new normal” of social distancing using video conferencing platforms to continue clinical and didactic teaching. United in a time of crisis, we have embraced systemic change by developing and delivering collaborative educational content, overcoming the limitations imposed by institutional silos. Additional innovations are needed in order to overcome the losses in program surgical volume and research opportunities. With the end of the viral pandemic nowhere in sight, program directors can rethink how education is best delivered and potentially overhaul aspects of fellowship curriculum and content. Similarly, restrictions on travel and the need for social distancing has transformed the 2020 fellowship interview season from an in-person to a virtual experience. During this time of unprecedented and rapid change, program directors should be particularly mindful of the needs and health of their trainees and consider tailoring their educational experiences accordingly., Highlights • The novel coronavirus pandemic has disrupted medical education at all levels. • Fellowship programs must adapt to the realities of social distancing, workforce redeployments, and laboratory closures. • The integration of teleconferencing into clinical practice and learning provides both challenges and growth opportunities. • Program directors should be aware of new stressors our fellows, particularly underrepresented minorities, are facing. • Programs should take advantage of the opportunity to rethink fellowship education and the needs of our recent graduates.

Objectives: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. Prior literature has reported an association of CTNNB1 mutations and an aggressive biology and shorter survival in endometrioid endometrial cancer. We previously demonstrated Wnt activating mutations were associated with higher DKK1 tumoral expression in advanced gynecologic malignancies. Methods: Pts with recurrent gynecologic cancers [endometrial (EEC), ovarian (EOC) and carcinosarcoma (MMMT)] were treated with D as monotherapy (mono) or in combination with paclitaxel (pac) in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on the subgroup of pts with Wnt activating mutations (CTNNB1, RNF43, APC). Clopper-Pearson confidence intervals were used to study the association of Wnt activating mutations with clinical benefit (CR, PR or SD); Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). Results: A total of 111 pts enrolled; 52 pts treated with D mono; 59 pts treated with D + pac. Mean number of prior therapies was 3.6 (range 1, 11) and 3.9 (range 1, 10) for D mono and D + pac, respectively. A total of 108 pts (97%) with available genetics; 23 pts (21%) had Wnt activating mutations [CTNNB1 (n=17), RNF43 (n=5), APC (n=3)]. Wnt activating mutations were more common in EEC (n=17/54, 31%) than EOC (n=2/33, 6%) and MMMT (n=4/24, 17%). Median duration of treatment with D was 6 cycles in pts with Wnt activating mutations compared with 3 cycles for pts without Wnt activating mutations. A total of 15 of 23 (65%) evaluable pts with Wnt activating mutations had clinical benefit [1 PR, 14 SD; durable SD (> 4 months) in 11 of 14 pts (48%)] compared with 34 of 76 (45%) evaluable pts [1 CR, 2 PR, 31 SD; durable SD (> 4 months) in 12 of 31 SD pts (16%)] without Wnt activating mutations. All 4 pts with an objective response had a PIK3CA mutation. Pts with Wnt activating mutations had longer PFS [median 5.5 mos; 95% CI (1.8, 6.0)] and OS [median 22.2 mos; 95% CI (7.3, NE)] compared with pts without Wnt activating mutations [median PFS 2.0 mos; 95% CI (1.8, 3.1)] and OS (median 9.9 mos; 95% CI (6.9, 12.5)]. Download : Download high-res image (65KB) Download : Download full-size image Conclusions: D has single agent activity in a subgroup of pts with Wnt activating mutations, historically identified as a poor prognostic group, whereby they experienced greater clinical benefit and longer survival compared with pts without Wnt activating mutations. A notable finding was that all responding pts had PIK3CA mutations. This study is ongoing and updated results will be presented.

Purpose: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma. Patients and Methods: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21–24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response. Results: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008). Conclusions: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.

Background High-risk locally advanced cervical cancer (CC) has a poor prognosis, and >50% of patients recur in 2 years. Concurrent chemoradiotherapy (CRT) may enhance the immunostimulatory activity of the PD-1 inhibitor pembrolizumab. After KEYNOTE-158, in which pembrolizumab demonstrated durable antitumor activity, pembrolizumab monotherapy was approved for patients with PD-L1–positive recurrent or metastatic CC who progressed during or after chemotherapy. ENGOT-cx11/KEYNOTE-A18 (NCT04221945) is a phase 3, randomized, placebo-controlled study evaluating pembrolizumab with concurrent CRT in locally advanced CC. Trial design Approximately 980 patients with high-risk, locally advanced, histologically confirmed CC who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive 5 cycles of pembrolizumab 200 mg Q3W + CRT (5 cycles [with optional 6th cycle] of cisplatin 40 mg/m2 Q1W + external beam radiotherapy [EBRT] followed by brachytherapy) followed by 15 cycles of pembrolizumab 400 mg Q6W or 5 cycles of placebo Q3W + CRT followed by 15 cycles of placebo Q6W. Randomization is stratified by planned EBRT type, cancer stage at screening, and planned total radiotherapy dose. Treatment will continue until patient receives ≤20 cycles of pembrolizumab (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 years) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints include PFS at 2 years, OS at 3 years, complete response at 12 weeks, ORR, PFS and OS in PD-L1–positive patients, and safety. Enrollment is ongoing.

Highlights • More than 25% of advanced endometrial cancer patients were treated with chemotherapy alone. • Omission of surgery for a majority (61%) of patients was due to bulk of disease or medical co-morbidities. • Median overall survival for the chemotherapy group was 9.8 months and 9.4 months for patients who had a suboptimal surgery., Objective To describe outcomes in patients with advanced endometrial cancer treated with chemotherapy only and compare them to patients treated with a combination of chemotherapy and surgery. Methods Retrospective chart review for all patients diagnosed with stage III and IV endometrial cancer from January 1, 2000 to December 31, 2015. We abstracted relevant demographic and clinical data. Kaplan-Meier analysis was used to create survival curves; Cox proportional hazards regression model was used to identify prognostic factors. Results Ninety-six patients met inclusion criteria; the median age was 64.5. Seventy patients were treated with combination therapy and 26 with chemotherapy alone. For the entire group, median overall survival (OS) was significantly different between groups (22.3 months surgery versus 9.8 months chemotherapy only, p = 0.0002). After multivariable analysis, having carcinosarcoma (HR 3.84 95% CI 2.64–5.03, p = 0.03), having grade 3 disease (HR 4.95 95% CI 3.70–6.18, p = 0.01), and having chemotherapy only (HR 4.13 95% CI 3.23–5.02, p = 0.002) were associated with increased mortality. When analysis was restricted to just patients who had a suboptimal debulking or chemotherapy alone, median OS was equivalent similar at 9.4 and 9.8 months (p = 0.46). Conclusion For advanced endometrial cancer patients, surgery in addition to chemotherapy confers a survival advantage except when optimal debulking cannot be achieved.

The incidence of endometrial cancer (EC) in the U.S. has been rising, from an estimated annual incidence of 49,560 in 2013 to 61,380 in 2017. Meanwhile, the SEER-based relative survival of women with EC in the U.S. has remained flat [82.3% from 1987 to 1989, 82.8% from 2007 to 2013] and our recent increased understanding of EC biology and subtypes has not been translated into therapeutic advances. The U.S. National Cancer Institute (NCI) therefore convened a Uterine Clinical Trials Planning Meeting in January 2016 to initiate and accelerate design of molecularly-targeted EC trials. Prior to the meeting a group of experts in this field summarized available data, emphasizing data on human samples, to identify potentially actionable alterations in EC, and the results of their work has been separately published. The Clinical Trials Meeting planners focused on discussion of (1) novel trial designs, including window-of opportunity trials and appropriate control groups for randomized trials, (2) targets specific to serous carcinoma and promises and pitfalls of separate trials for women with tumors of this histology (3) specific recommendations for future randomized trials.

Objectives: To determine safety, efficacy, and biomarkers of response to neoadjuvant therapy (NACT) with atezolizumab (atezo), weekly paclitaxel and carboplatin (wPC) followed by maintenance (maint) atezo±bevacizumab (bev) in women with advanced epithelial ovarian, tubal, and peritoneal cancer (EOC). Methods: Patients (pts) with high-grade EOC were eligible. Pts underwent pretreatment biopsy, received paclitaxel 80 mg/m2 IV D1/8/15 + carboplatin AUC6 IV D1 + atezo 1200 mg D1 every 3 weeks x 3 cycles followed by interval cytoreductive surgery (ICS). Post-surgery, pts received adjuvant atezo, wPC±bev followed by maint atezo±bev. Primary objective was to assess safety of the combination when given prior to ICS. Early stopping rules were built around the primary safety endpoint if patients were unable to proceed to planned ICS within the specified timeframe (≤6 weeks from last dose of NACT) due to atezo-related toxicities. Safety was assessed in all treated pts using frequency and severity of adverse events (AE). Objective response rate (ORR), pathologic complete response rate (pCR) at ICS, and progression free survival (PFS) were determined. Planned exploratory objectives included quantitation of changes in PD-L1 expression, tumor-infiltrating lymphocyte subpopulations, immune checkpoint receptor profile, and immune blood-based markers. Results: A total of 18 pts enrolled and received therapy between 05/15/2018 - 07/14/2020. Median age was 69 years (range 46-87). Key disease characteristics: 18 (100%) pts had high-grade serous EOC; 13 (72%) pts had Stage III and 5 (28%) had stage IV disease; BRCA status: 5 (28%) mutations, 13 (72%) wildtype. Grade (G) 3/4 atezo-related AEs included 1 (6%) G3 anemia, 2 (11%) G3 thrombocytopenia, 2 (11%) G4 hypokalemia, 2 (11%) G3 rash, 1 (6%) thrombotic event. Other AEs of special interest included pneumonitis (n=3, 2 G2, 1 G1), blurred vision (n=1, G1), and myositis (n=1, G1). A total of 3 pts withdrew prior to ICS; 1 to change to every 3 weeks therapy locally, 1 due to non-atezo related AEs, and 1 due to negative results of IMAGYN050. These 3 pts are not included in the response-evaluable population (n=15). Nine (60%) pts had a partial response (PR) after 3 cycles and 6 (40%) had stable disease. All 15 pts underwent ICS; 1 had delayed cytoreduction due to pulmonary embolism, possibly atezo-related. Cytoreduction status was optimal in 86% pts [R0 8 (53%), R1 (33%)], and suboptimal in 2 (13%) pts; no pCRs were observed. All response-evaluable pts completed chemotherapy. Pts opted for maint therapy as follows: 6 (40%) adjuvant/maint atezo+bev; 4 (27%) atezo alone; and 5 (33%) withdrew for PARP inhibitor maint. A total of 2 (20%) of 10 receiving atezo maint discontinued due to recurrence. Blood-based and tumor biomarker results will be presented. Download : Download high-res image (90KB) Download : Download full-size image Conclusions: NACT with atezo + wPC followed by maint atezo±bev was feasible with no new safety signals. Biomarker analysis is ongoing to identify potential candidates who may benefit from atezo front-line therapy.

Objectives: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone vs MPA plus histone deacetylase (HDAC) inhibitor entinostat regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma (EC). Methods: A multi-site, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth (PO) on days 1, 8 and 15 was randomly assigned with equal probability. Surgery followed on day 21-24. Pre- and post-treatment slides were assessed for PR H-scores, Ki-67 levels and histologic response. Results: A total of 50 patients were accrued in 4 months; 22 and 20 participants had PR evaluable pre- and post-treatment slides in the MPA and MPA/Entinostat arms respectively. The median post treatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs 27, MPA/Entinostat: 260 vs 23 respectively) p=0.87. Decreased Ki-67 was shown in 90% treated with MPA/Entinostat compared to 68% treated with MPA alone (p=0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) vs not decreased (45). The decrease in PR pre- vs post-treatment was associated with a loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (p Conclusions: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki67 as secondary. Despite no immediate effect of entinostat on PR in this short term study, lessons learned can inform future window and treatment trials.

Objective To characterize risk for opioid misuse among gynecologic oncology patients. Methods The Opioid Risk Tool (ORT), a validated screen for opioid misuse risk, was administered to a convenience sample of patients with gynecologic cancer receiving opioid prescriptions in gynecologic oncology or palliative care clinics from January 2012–June 2016. Demographic and clinical information was abstracted on chart review. The primary outcome was ORT risk level (low vs. moderate or high). Chi-square tests were performed for categorical variables. Results A total of 118 women were screened. Most women were Caucasian (79%) with a median age of 57years. Ovarian cancer patients comprised 46% of the cohort with fewer endometrial (25%), cervical (23%), vulvar (4%), and vaginal (2%) cancer patients. The median ORT score was 1.0 (range, 0–10) out of a possible 26. Overall, 87% of patients were categorized as low-risk for opioid misuse, 7% as moderate-risk, and 6% as high-risk. Patients who were at moderate or high-risk of opioid misuse were significantly younger (47 vs. 58years, p =0.02), more likely to have cervical cancer ( p =0.02), be smokers ( p =0.01) and be uninsured or on Medicare ( p =0.03). Conclusions Most gynecologic oncology patients in our cohort were low-risk for opioid misuse (87%). Cervical cancer patients were more likely to be moderate to high-risk for misuse. Future screening efforts for opioid misuse may have the highest utility in this subset of patients.

Objective Etirinotecan pegol (EP) is a novel polyethylene glycol conjugated form of irinotecan with documented activity in platinum-resistant ovarian cancer (PROC). We report the results of the expanded portion of a phase II study of EP in patients with PROC who received prior pegylated liposomal doxorubicin (PLD) or who were unable to receive it. Methods This multicenter, open-label, phase II study evaluated EP q21d for PROC. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.0. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Patient populations evaluated included a modified intent-to-treat (mITT) group consisting of all patients who received at least one dose and with measurable disease and a primary efficacy (pEFF) group (subset of the mITT population who received prior PLD). Results One hundred thirty-nine patients were enrolled. Of the 132 patients in the mITT group, 20 achieved an ORR (15.2%; 95% CI 9.5–22.4); median PFS and OS were 4.4 months and 10.2 months, respectively. In the pEFF group (n=104), 15 patients (14.4%; 95% CI 8.3–22.7) achieved an ORR; median PFS and OS were 4.4 months and 10.9 months, respectively. The most common grade 3/4 toxicities were diarrhea (20%), abdominal pain (17%), vomiting (14%), dehydration (13%), and nausea (13%). Severe diarrhea was reduced to 15% with strict adherence to screening and management guidelines. Conclusions This study confirms the activity and safety of single-agent EP in patients with PROC, including patients who received prior PLD. Further evaluation earlier in the disease course and in combination is warranted.

Objective To assess the endometrial response rates to treatment with the levonorgestrel intrauterine device in post-menopausal women with atypical hyperplasia/endometrial intraepithelial neoplasia and grade 1 endometrioid (AH/EC) endometrial carcinoma who are not surgical candidates. Methods Chart review was undertaken of patients with AH/EC who underwent levonorgestrel intrauterine device insertion by a gynecologic oncologist within two academic health systems between 2002 and 2013. When available, tissue blocks were evaluated with immunohistochemical staining for progesterone receptor expression. Results A total of 41 patients received treatment for AH/EC with the levonorgestrel intrauterine device. Follow up sufficient to assess response occurred in 36 women (88%). Complete response was documented in 18 of 36 women (50%), no response in 8 patients (22%), partial response in 3 women (8%) and progression of disease in 7 patients (19%). Four of 18 patients with complete response (22%) later experienced relapse of hyperplasia or cancer. Four patients (10%) died during the study period: none had evidence of metastatic disease and 1 of the 4 woman died of perioperative complications following hysterectomy for stage I disease. Patients responding to treatment had significantly lower progesterone receptor expression on post-treatment biopsies. Conclusions Intrauterine levonorgestrel is a viable treatment option for post-menopausal women with AH/EC who are poor candidates for standard surgical management. The response rate in this series is similar to published reports in premenopausal patients and includes cases of disease recurrence following conversion to benign endometrium.

Gestational trophoblastic neoplasia (GTN) is one of the most chemo-responsive and highly curative gynecologic malignancies. In selected patients with persistent or drug-resistant disease, surgical resection of metastatic foci can be critical. Here, we report two cases of durable remission following pulmonary wedge resection. These cases are unique due to their unusual initial presentations. 1.1. Case 1 Healthy 26 year-old G3P2012 (SAB at age 12, term SVD x2 with post-partum tubal ligation in 2013) presented with chest tightness and dyspnea in December 2016 (40 months from antecedent pregnancy). Chest X-ray (CXR) revealed a 3 cm ovoid mass at the periphery of the left upper lobe (LUL); chest computed tomography (CT) scan confirmed a 3.4 × 3.2 cm mass in the LUL, see Fig. 1. She was scheduled for outpatient Pulmonology follow-up; but re-presented to the ED weeks later with vaginal bleeding and nausea, last menstrual period (LMP) 3 months prior. CT abdomen/pelvis revealed only a cystic structure in the left adnexa. Her bHCG was 516 and no intra-uterine pregnancy was identified. She was given a dose of intramuscular methotrexate (IM MTX) by her gynecologist for presumed ectopic pregnancy (day#1, D1). Despite an additional dose on D9, her bHCG continued to rise and she was referred to Gynecology Oncology (GYO). Open in a separate window Fig. 1 Left upper lobe mass measuring 4.8 cm × 4.3 cm demonstrating enhancement at the periphery with a necrotic center.

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3+3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1–2. Once

PURPOSE: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in gynecologic oncology surgical patients. Many centers use neuraxial analgesia (NA), which affects the timing of prophylactic anticoagulation. In 2012, we determined that the rate of VTE in patients undergoing laparotomy with NA was higher than in those who received alternative pain control. In addition, compliance with preoperative anticoagulation guidelines was only 40%. We undertook a quality initiative (QI) project to increase compliance to 80% in NA cases and maintain 90% in non-NA cases. METHODS: A multidisciplinary working group designed and deployed a QI intervention bundle. Compliance was defined as the receipt of a prophylactic dose of anticoagulant within 1 hour after NA or before skin incision regardless of anesthesia type. Data were abstracted from the medical record after the study period. Cases from the year before QI were used for comparison. Primary outcome was compliance and secondary outcome was the rate of VTE. RESULTS: One hundred women were treated under the QI project and 182 historical cases (HCs) were used for comparison. Overall compliance improved (96% QI v 73% HC; P < .001). This difference was marked in cases with NA (95% QI v 40% HC; P < .001) and remained stable in non-NA cases (97% QI v 91% HC; P = .29). The overall rate of VTE, independent of anesthesia type, remained unchanged (2.1% HC v 0% QI; P = .3). CONCLUSION: Relatively simple and inexpensive initiatives to improve routine processes within the surgical pathway are feasible and attract staff participation. Such efforts are likely to translate into greater levels of patient safety.

3104 Background: Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). EZH2 is frequently overexpressed in cancers and correlates with poor prognosis. CPI-0209 is an oral, small molecule, second-generation, selective inhibitor of EZH2 designed to achieve comprehensive target coverage through extended on-target residence time. The compound demonstrates more potent anti-tumor activity in preclinical cancer models, compared to first-generation EZH2 inhibitors. CPI-0209 is currently being evaluated in a Phase 1/2, open-label, FIH study (NCT04104776). Methods: Patients (pts) with advanced tumors were enrolled in a 3+3 design. Primary objective is to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CPI-0209. Secondary objectives are to evaluate the safety, PK, and PD in pts who received CPI-0209 QD in 28 days cycles (C). Results: As of December 16, 2020, 33 pts were treated: pancreatic cancer (n = 6), mesothelioma, breast, colorectal, and ovarian cancer (n = 5 each), leiomyosarcoma, melanoma, cholangiocarcinoma, prostate, bladder, endometrial clear cell and gastric cancer (n = 1 each). Pts received CPI-0209 at 50 mg (n = 4), 100 mg, 137.5 mg, and 187.5 mg (n = 6 each), 225 mg (n = 7), and 275 mg (n = 4) daily dose. Median treatment duration was 43 days (range 1-239); 4 pts are ongoing. Median age was 64 yrs (range 24-79); 15 (45%) pts were male. Patients were heavily pretreated, with 67% of pts had ≥ 3 prior lines of therapy. No dose limiting toxicities have been observed. The most frequent treatment-emergent adverse events (TEAEs) (≥10%) were fatigue (27%), diarrhea (24%), nausea (21%), abdominal pain, alopecia, anemia, thrombocytopenia, and dysgeusia (15% each), and vomiting, headache, decreased appetite, and alkaline phosphatase increased (12% each); usually grade 1 or 2 in severity. Thrombocytopenia was dose-dependent and not associated with bleeding or clinical sequalae. Three pts (9%) discontinued CPI-0209 due to TEAEs. Comprehensive target engagement (assessed by global reduction in H3K27me3 levels in monocytes) was observed within the first cycle at all dose levels. CPI-0209 also increased the expression of PRC2-controlled gene sets in blood in a dose-dependent manner. Updated safety, PK, PD, and preliminary efficacy results from Phase 1 will be presented. Conclusions: CPI-0209 achieved robust PD effects and a PK-PD relationship has been established. CPI-0209 monotherapy was generally well tolerated, and treatment related AEs were manageable and reversible. The MTD has not been reached. Clinical trial information: NCT04104776.

5581 Background: Traditional platinum-based systemic chemotherapy continue to be the SOC for aEC in the first line. Phase 2 clinical trials of chemotherapy (GOG 129 series) and some targeted therapies (229 series) for second line advanced endometrial cancer (aEC) have proved disappointing. Recently the treatment landscape for aEC patients has significantly changed with newer targeted therapies focusing on the microsatellite instability (MSI) status of endometrial tumors. The objective of the ECHO study was to describe real-world treatment patterns and outcomes in non-MSI-high or DNA mismatch repair proficient (pMMR) aEC patients in clinical practice in the United States (US) prior to 2019. Methods: The ECHO study is a multicenter, retrospective chart review study in women diagnosed with aEC in the US. Data were obtained from medical records of adult women (≥18 years) diagnosed with advanced or inoperable aEC (stages III or IV) with known MSI status, who had received at least one prior systemic therapy and progressed between July 1, 2016 – June 30, 2019. De-identified patient data extracted by treating oncologists included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate real-world progression-free survival (rwPFS) and overall survival (OS). Results: A total of 124 non-MSI-high or pMMR aEC patients who had progression following first line therapy were included in this interim analysis. Average age was 63 years, 62.9% White/Caucasian, 16.9% Hispanic/Latino, and 86% had ECOG ≤1. Metastases were observed in 70% of patients at diagnosis, with the most common metastatic sites being lung (47.6%), liver (32.3%), and distant lymph nodes (29%). As 2nd line therapy, 69% of patients received mono or combination chemotherapy (primarily with doxorubicin), 13% hormonal therapy, and 18% targeted therapy ± chemotherapy. Median duration of 2nd line therapy was 4 months. The majority (86.3%) discontinued 2nd line therapy, with disease progression the most common reason (66.4%). A quarter (26.6%) of patients initiated an additional line of therapy. Median rwPFS from initiation of 2nd line therapy was 5 months (95% confidence interval [CI]: 4-9). Median OS from initiation of 2nd line therapy was 12 months (95%CI: 9-18). Estimated OS rates from initiation of 2nd line therapy at 6, 12, and 24 months were 66%, 47%, and 30%, respectively. Conclusions: In this retrospective, chart review study, patients with non-MSI-high/pMMR aEC in the US who failed at least one systemic therapy had poor prognosis on subsequent therapies. There continues to be a significant unmet need in this group of women. Novel therapies are needed that delay progression and/or improve overall survival and further research is indicated to explore this.

5527 Background: Treatment options for patients with recurrent cervical and endometrial cancer remain limited. Even with optimum care, median survival has stalled at 12-17 months. The PARP inhibitor rucaparib has demonstrated activity in both BRCA wild-type and mutant cancers. Furthermore, preclinical studies suggest a synergistic effect of PARP inhibitors and antiangiogenic agents. We hypothesized that the combination of rucaparib and the VEGF inhibitor bevacizumab would yield a clinically-significant anti-cancer effect in patients with persistent or recurrent cervical or endometrial carcinoma. Methods: NCT03476798 is a phase II trial of adults with histologically-documented carcinoma of the cervix or endometrium. Patients with evaluable lesions who had undergone at least one prior line of systemic therapy, had adequate performance status and organ function, with a life expectancy of at least three months were eligible. Biopsies were obtained prior to treatment initiation for assessment of baseline tumor biomarkers, including ARID1A mutation status. Each cycle comprised 21 days. Rucaparib was administered orally at 600 mg, twice daily. Bevacizumab was administered by IV at 15 mg/kg on day 1 of each cycle. The primary objective was to estimate the proportion of patients with persistent or recurrent cervical or endometrial cancer who survive progression-free for at least six months (PFS6). Kaplan-Meier analysis was used to estimate progression-free survival. Results: There were 28 evaluable patients; six had cervical and 22 had endometrial cancer. Median age was 60.5 years (range, 30-74). Self-reported patient races were White (82.1%), Black (10.7%), and Native American (7.1%). Self-identified Hispanic or Latina patients comprised 3.6% of the cohort. Twenty-two of 28 patients had progressive disease by six months [survival distribution function estimate = 0.214 (lower CI, 0.087; upper CI, 0.378)]. Of the six patients who achieved PFS6, one had cervical and five had endometrial cancer. Six patients had a mutation in the ARID1A gene and those patients achieved PFS6 at a rate of 66.7%. Conclusions: The study hypothesis was evaluated in a two-stage design, and the interim analysis occurred once 28 evaluable patients were enrolled. In order to move on to the second stage, at least seven patients needed to remain progression-free at six months, but only six did. Thus, the study was ended after the interim analysis. The combination of rucaparib and bevacizumab did not provide the expected clinical benefit in this cohort of patients, but may warrant further exploration in patients with ARID1A mutations. Clinical trial information: NCT03476798.

Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01, a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. We report response and survival outcomes in EEC patients (pts) treated with DKN-01 monotherapy by tumor genetics (Wnt signaling alterations and PI3K/AKT mutations). Methods: Pts with recurrent EEC were treated with DKN-01 as monotherapy (mono) or in combination with paclitaxel in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on EEC mono group only. Clopper-Pearson confidence intervals and logistic regression were used to study the association of Wnt signaling alterations with clinical benefit (CR, PR or SD) following DKN-01 monotherapy; Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). Results: As of 30 December 2019, 29 EEC pts enrolled; 21 pts (72%) had Wnt signaling alterations [ARID1A most common (11 pts, 38%)] and 25 (86%) had PI3K/AKT mutations [PIK3CA in 13 pts (45%)]. Median number of prior therapies was 4 (range 1, 9); 20 pts (69%) had endometrioid histology and 19 pts (66%) had G2/G3 tumor grade at diagnosis. 26 pts were evaluable, 20 pts Wnt altered and 6 pts non-Wnt altered; 24 pts with and 2 pts without PI3K/AKT mutations. In the Wnt altered group, there was 1 cCR, 1 cPR, 8 SD (6 durable SD >120 days) and 10 PD compared with 0 responders, 1 SD and 5 PD in the non-Wnt altered group. In the 24 pts with PI3K/AKT mutations there was 1 cCR, 1 cPR, 8 SD (6 durable SD >120 days) and 14 PD compared with 1 SD and 1 PD in the 2 pts without PI3K/AKT mutations. The 2 responding pts had PI3KCA mutations in common. Probability of 6 month PFS/OS was 30% (95% CI:12.3, 50.1) and 70% (95% CI: 45.1, 85.3) for Wnt altered pts vs 18% (95% CI: 0.8, 53.8) and 50% (95% CI: 11.1, 80.4) for non-Wnt altered, respectively. Conclusions: DKN-01 has single agent activity in heavily pretreated EEC pts. EEC pts frequently had Wnt signaling alterations and PIK3/AKT mutations; greater clinical benefit was demonstrated in pts whose tumors had Wnt signaling alterations. This study is ongoing and updated results will be presented. Citation Format: Rebecca Arend, Cesar Castro, Erica Hamilton, Kristopher LyBarger, Linda Duska, Michael Kagey, William Bradley, Jasgit Sachdev, Cynthia A. Sirard, David M. O'Malley. Patients with recurrent epithelial endometrial cancers (EEC) and Wnt signaling alterations demonstrated greater clinical benefit when treated with DKN-01 monotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO036.

Introduction: NRG Study GY011 is a surgical window trial of medroxy-progesterone acetate (MPA) +/- entinostat (E), a histone deacetylase inhibitor hypothesized to upregulate PR levels through epigenetic modifications. The principal goal of this trial was to determine the impact of treatment on the level as well as the activity of progesterone receptors (PR) in women with endometrial cancer. However, a reliable marker for PR activity was needed, and the most promising choice was Ki-67. To be approved for inclusion in the study as an integrated biomarker, Ki-67 had to first undergo rigorous evaluation by the participating pathologists with oversight by the NIH Biomarker Review Committee. Methods: Fifty patients were enrolled on GY011, and specimen collection was planned by biopsy prior to receiving study drugs and by tissue sample at the time of the hysterectomy. There were 42 pre-drug administration specimens with tumor for analysis and 1 without and 43 hysterectomy specimens with tumor. Ki-67 immunohistochemistry performed on pre and post drug specimens was evaluated by three experienced reviewers (MS, KC and AR) using a qualitative approach, blinded to treatment arm. Pre and post-drug samples for each individual patient were compared and scored as increased, decreased, or unchanged. The Fleiss kappa statistic was chosen as the measure of concordance as it allows for more than two reviewers and more than two categories. Percent agreement and standard weighted kappa statistics were calculated for individual pairs of reviewers. Results: There was very good concordance between reviewers using the qualitative comparison of post to pre-drug Ki-67 staining with Fleiss’ Kappa of 0.91 and weighted Kappa’s ranging between 0.85 and 0.95. Reviewers 1 and 2 had the highest level of concordance. Reviewer agreement ranged from 0.92 to 0.98. The reviewer-specific (marginal) score distributions were similar. Each reviewer scored about 80% (79.5%-82.5%) of pairs as decreasing, with the remainder split similarly between no change (7.5%-10%) and increasing (10%-12.8%). Conclusion: Based upon the high concordance between reviewers, the NIH Biomarker Review Committee approved Ki-67 as an integrated biomarker for GY011, setting the stage for its use as an approved biomarker of therapeutic effectiveness in future endometrial cancer trials. Citation Format: Megan I. Samuelson, Virginia Filiaci, Kelley Carrick, Anand Rajan KD, William H. Rodgers, Kristina W. Thiel, Linda R. Duska, Kimberly K. Leslie. Approval for the proliferative marker Ki-67 as an integrated biomarker for endometrial cancer in NRG study GY011 [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO020.

Endometrial cancer is the most common gynecologic cancer, and with a median age of 62 at diagnosis, it affects a significant number of older women. With increasing age and obesity rates in the world’s population, there is an anticipated concomitant increase in older women with endometrial cancer. Older women are more likely to die of endometrial cancer compared with younger patients. Reasons for this include more aggressive tumor biology, less favorable clinicopathologic features, and more advanced disease. Other factors, however, such as reluctance to offer surgical treatment to the older patient and increased complications of treatment are likely to be important. Management of endometrial cancer requires multidisciplinary care (surgery, radiation therapy, and systemic therapy). For each treatment, the feasibility (related to technical aspect of the procedure/treatment), side effects and safety (related to older-patient factors), and the overall benefit as it pertains to older women with endometrial cancer should be assessed carefully with a multidisciplinary approach. Despite the importance of these issues, the data are limited to answer these issues with clarity. In this article, we will review each treatment modality for older women with endometrial cancer. We will introduce the components of comprehensive geriatric assessment and their practical implication for older women with cancer in general and older women with endometrial cancer specifically.