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Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0–2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0–50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI –6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3–4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. National Health and Medical Research Council and National Cancer Institute.

BackgroundDostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.MethodsGARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.ResultsScreening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5–22.1) for cohort A1 and 11.5 months (IQR 11.0–25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1–2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.ConclusionDostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.Trial registration numberNCT02715284.

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC. The primary endpoint was the fraction of expanded tumor-associated T-cell receptor (TCR) clones in blood at day 21 as a surrogate measure of anti-tumor immune response. Secondary objectives were safety and feasibility, 2-year disease-free survival (DFS), and predictive value of PD-L1 expression. Forty patients were randomized, 36 received treatment, and 25 were evaluable for the primary endpoint. After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B ( p  = 0.0025) that remained higher at day 21, meeting the pre-specified endpoint on two-sample T-test ( p  = 0.052), but not on sensitivity analysis by Wilcoxon test ( p  = 0.13). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B ( p  = 0.28). There were no new safety signals. In conclusion, neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies. Combination of immune checkpoint inhibitors with chemoradiation is now standard of care for patients with locally advanced cervical cancer (LACC). Here, the authors report the results of a phase I trial of neoadjuvant vs concurrent atezolizumab (anti-PD-L1) with chemoradiation for LACC.

Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms. Finally, we provided early evidence from an ongoing phase I study demonstrating the clinical activity of monotherapy azenosertib in patients with Cyclin E1/CDK2-activated ovarian and uterine serous carcinomas.

Among women with advanced ovarian cancer with a BRCA mutation who had a response after platinum-based therapy, the median progression-free survival was approximately 3 years longer with the use of olaparib maintenance therapy for 2 years than with placebo.

In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone.

To study obstetric and gynecologic (OBGYN) resident comfort with performing a salpingectomy at cesarean delivery after a simulation workshop utilizing a low-cost, easy-to-construct model. OBGYN residents were taught how to counsel a patient on a salpingectomy and perform the steps of the procedure utilizing our simulation model. We performed a pre- and post- survey. Thirty-two OBGYN residents completed the pre-questionnaire (response rate 100%) and 30 completed the post-questionnaire (response rate 94%). After the simulation, OBGYN residents felt more comfortable completing a bilateral salpingectomy at cesarean delivery (pre: 50.0% vs. post: 84.4%, p=0.001) and counseling a patient on the procedure (pre: 59.4% vs. post: 90.6%, p=0.006). After the simulation, 96.7% of residents felt the simulation workshop was useful to clinical practice. We developed an easy-to-construct bilateral salpingectomy at cesarean delivery model to practice preoperative counseling and surgical techniques. The direct impact on surgical competency and outcomes requires further study.

ObjectiveThere is an increase in patient-reported outcome assessments to gain information on new drug candidates from the patient’s perspective. A data gap remains in patient-reported outcome measurements for anti-programmed death 1 (anti-PD-1) therapies in endometrial cancer. We present patient-reported outcome measures collected from patients with mismatch repair-deficient/microsatellite instability-high advanced or recurrent endometrial cancer treated with dostarlimab, an anti-PD-1 monoclonal antibody, in an expansion cohort of the GARNET trial.MethodsGARNET (NCT02715284) is a phase I single-arm study of dostarlimab monotherapy in multiple tumor types. Patients with advanced or recurrent mismatch repair-deficient/microsatellite instability-high endometrial cancer were treated with 500 mg of intravenous dostarlimab once every 3 weeks for four cycles, then 1000 mg of intravenous dostarlimab every 6 weeks. Patient-reported outcome assessments were an exploratory endpoint, measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).ResultsAt data cut-off, 88 patients with mismatch repair-deficient endometrial cancer were included in the analysis. Patient-reported outcome assessment completion was >95.5% throughout cycle 7 of the trial, with no individual domain completion <90.9%. Quality of life, emotional functioning, and social functioning showed improvement compared with baseline. All symptom scores showed either improvement or stability from baseline through cycle 7. Categorical change in response across all symptom scales and single-item response scores showed stability or improvement for most patients. For patients who saw a worsening of their categorical change in response, ≤7.4% experienced a 2-category worsening and ≤2.5% experienced a 3-category worsening.ConclusionsMost patients remained stable or had improved quality of life while receiving dostarlimab for the treatment of recurrent or advanced mismatch repair-deficient endometrial cancer.Trial registration number NCT02715284.