INTRODUCTION:We evaluated the efficacy of the addition of the anti-diabetic drug metformin to standard-of-care paclitaxel and carboplatin (PC) in patients with advanced and recurrent endometrial cancer (EC). METHODS:In this phase II/III trial, EC patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) disease were randomly assigned to PC/metformin (850 mg BID) versus PC/placebo. Metformin or placebo was continued as maintenance therapy after completion of PC until disease progression. The primary endpoint of phase II was progression-free survival (PFS). The primary endpoint of phase III was overall survival (OS). Secondary endpoints were objective response, duration of response, and toxicity. RESULTS:From 3/17/2014 to 12/22/2017, 448 patients were randomized to phase II/III studies, and the data were frozen for interim analysis. The phase II study deemed metformin worthy of further investigation in the phase III study. The interim phase III analysis stopped accrual for futility on 2/1/2018. The addition of metformin to PC had a slightly higher hazard of death compared to the PC regimen (HR = 1.088; 90% CI 0.803 to 1.475), which was sufficient to close the study early. The PFS had (HR = 0.814; 90% CI 0.635 to 1.043). At a median follow-up of 10 months and 121 deaths, median OS was not determined and 28 months, on PC/placebo and PC/metformin, respectively. CONCLUSION:The hazard ratios for PFS and OS endpoints was not sufficiently decreased with the addition of metformin to PC to justify continuing the trial.

Introduction. Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO -1 inhibitor epacadostat in patients with recurrent OCCC. Methods. This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression -free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). Results. Between September 28, 2018 and April 10, 2019,14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had >= 2 prior regimens. ORR was 21% (95% 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9 -NR). Most common grade >= adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed maturely in February 2021 due to insufficient drug supply. Conclusions. Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with (c) 2024 Elsevier Inc. All rights reserved.

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PURPOSE Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. MATERIALS AND METHODS Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. RESULTS The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. CONCLUSION Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.

This randomized phase III trial aimed to determine whether treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for four cycles (chemoradiotherapy [C-RT]) increased recurrence-free survival (RFS) and overall survival (OS) when compared with carboplatin and paclitaxel for six cycles (chemotherapy [CT]) in locally advanced endometrial cancer (UC). Previously reported results showed that C-RT did not improve RFS compared with CT. Here we report the final OS analysis. Patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage III-IVA UC or stage I/II serous or clear cell UC and positive cytology were enrolled. The primary objective was RFS. Secondary objectives were OS, toxicity, and quality of life. Cumulative probabilities of OS were estimated using the Kaplan-Meier method. Subgroup analyses of treatment effect for FIGO stage, age, race, gross residual disease, histology, lymph-vascular space invasion, and body mass index were performed. In total, 813 patients were randomly assigned (407 C-RT and 406 CT). The median follow-up was 112 months. Median OS was not achieved in either arm. The stratified hazard ratio for death comparing C-RT versus CT was 1.05 (95% CI, 0.82 to 1.34, log-rank two-sided P value = .72). None of the factors analyzed predicted OS benefit from C-RT. Although C-RT reduced the rate of local recurrence compared with CT, it did not increase OS or RFS in stage III/IVA UC.

e17546 Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance & muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred >120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]

<p>Supplemental data for the investigation of growth inhibition induced by SMAP treatment in EMCA</p>

5533 Background: NRG-RTOG 1203 reported that intensity-modulated radiation therapy (IMRT) reduced patient-reported GI and GU toxicities in cervical/endometrial cancer patients receiving adjuvant RT, as compared to standard whole field pelvic RT (WPRT). We conducted a secondary analysis of patient-reported sexual function (PR-SF) to compare this endpoint among treatment groups and identify factors associated with sexual dysfunction. Methods: Patients on NRG-RTOG 1203 were randomly assigned to WPRT vs. IMRT and completed the PRO-CTCAE for GI toxicity and the cervical cancer FACT-Cx at baseline, week 5 of RT, and at 4-6 weeks, 1-year, and 3-years post-RT. Patient responses to FACT-Cx sexual function questions were analyzed. The between arm frequency and severity of responses were tested using chi-square. PR-SF was compared with PRO-CTCAE GI toxicity using chi-square. A repeated measures logistic regression model was used to determine the impact of clinical/treatment factors on sexual function by dichotomizing the responses. Results: Of the 279 patients included for primary analysis, 236 (85%) completed PR-SF questions; 125 (53%) in the WPRT arm and 111 (47%) IMRT. There were no significant differences in PR-SF between treatment groups (p>0.05). PR-SF improved for both groups post-RT, except responses to “my vagina feels too narrow or short” worsened (Table). Women without abdominal pain interference at 4-6 weeks post-RT were less likely to fear sex (74.2% vs. 25.8%, P=0.03) and more likely to like their body appearance at 1 year (95.7% vs. 4.3%, P<0.01) compared to women with interference. Women liked the appearance of their body less during RT vs. at baseline (OR 1.95, 95% CI 1.04-3.64, P=0.04). Women were less interested in sex during RT in both arms (WPRT: OR 3.61, 95% CI 1.40-9.34; IMRT: OR 3.96, 95% CI 1.02-15.34) and at 4-6 weeks post-RT for IMRT (OR 3.16, 95% CI 1.14-8.72) vs. at baseline. Conclusions: PR-SF was similar between treatment groups. PR-SF during and post-RT was not significantly reduced compared to baseline with the exception of patients with abdominal pain interference, who had significantly worse PR-SF at 4-6 weeks and 1-year post-RT. Clinical trial information: NCT01672892 . [Table: see text]

OBJECTIVES:Clear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. METHODS:The term "mixed" was applied to tumors with multiple identifiable components, and "indeterminate" was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. RESULTS:One hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. CONCLUSION:In clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.

Supplementary Figure Legends and Methods

Sequencing outcomes and PPP2R1A hotspot mutation frequency for the Case Comprehensive Cancer Center Gynecologic Tumor Biobank

IntroductionIn this multicentre randomized, phase II/III trial, we sought to examine if the 1) combination of anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab (ATEZO) with pegylated-liposomal- doxorubicin (PLD) [Arm 1] and/or 2) addition of ATEZO to PLD and bevacizumab (BEV) [Arm 2] result in an improvement in survival for patients with platinum resistant ovarian cancer (PROC) compared to the standard PLD/BEV [Arm 3].MethodsPatients were randomly assigned 1:1:1 to PLD/ATEZO, PLD/BEV/ATEZO or PLD/BEV (IV PLD 40 mg/m2 q4weeks; BEV 10 mg/kg q2weeks; ATEZO 800 mg q2weeks). Key eligibility: 1–2 prior lines of therapy (no PLD), ECOG 0–2, and RECIST measurable/evaluable PROC. No stratification by PD-L1 status. The phase II primary endpoint was PFS. The phase III coprimary endpoints were PFS/OS.ResultsFrom 05/2017–10/2021 444 patients with PROC were enrolled. The median age was 63 yrs (35–86). All had received prior chemotherapy; 434 (97.7%) prior surgery and 9 (2%) prior biological therapy. At the phase III interim analysis Arm 1 (PLD/ATEZO) was discontinued for futility. The phase III OS/PFS analysis included accruals to Arms 2 (PLD/BEV/ATEZO) and 3 (PLD/BEV) from all phases. With median follow-up of 47 months, median PFS was 7.4 months and 5.6 months (HR 0.79 with 99.99% 1-sided CI 0.0–1.21), and median OS was 14.9 months and 12.3 months (HR 0.80; 98.78% 1-sided CI 0.00–1.06; 1-sided p=0.038) for Arms 2 and 3, respectively. Adverse events were as expected.Conclusion/ImplicationsThe addition of ATEZO to PLD/BEV did not result in a statistically significant longer OS than PLD/BEV in PROC. Subset analysis are planned to evaluate survival outcomes with high PD-L1 expression (NRG-GY009/NCT02839707).

PP2A Aα-, C-, and B55α-subunit protein abundance in PPP2R1A wildtype and P179-mutant patient EMCA tumor samples

Objective. This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. Methods. This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone >_1 radiographic evaluation (approximately 9 weeks from the first treatment). Results. The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. Conclusions. The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.

OBJECTIVE:To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS:Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS:Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS:Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

<p>Supplemental data for the classical and enhanced sampling molecular dynamics simulations</p>