Safety of dostarlimab in combination with chemotherapy in patients with primary advanced or recurrent endometrial cancer in a phase III, randomized, placebo-controlled trial (ENGOT-EN6-NSGO/GOG-3031/RUBY).

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin-paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting. Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial. Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC. Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03. Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm.The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm. Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit-risk profile and is a new standard of care for patients with primary advanced or recurrent EC. Trial registration: NCT03981796.

Safety of dostarlimab plus carboplatin-paclitaxel compared with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer For many years, patients with primary advanced or recurrent endometrial cancer were treated with chemotherapy, specifically with a combination of carboplatin and paclitaxel. Recently, new treatments called immune checkpoint inhibitors have been used to treat endometrial cancer. Dostarlimab, an immune checkpoint inhibitor, is being tested to treat many types of cancer, including endometrial cancer. In the RUBY trial, a combination of dostarlimab plus chemotherapy was compared with chemotherapy alone as treatment for primary advanced or recurrent endometrial cancer. Results showed that patients treated with dostarlimab plus chemotherapy had a lower risk of their cancer becoming worse and a lower risk of dying. Results in this article describe the safety of dostarlimab plus chemotherapy compared with chemotherapy alone. All patients in the RUBY trial experienced at least one adverse event (an undesired effect that happens while receiving treatment or shortly after stopping treatment); most were determined to be caused by the cancer treatments. No differences in the frequency of the overall cancer treatment-related adverse events were seen in patients who received dostarlimab plus chemotherapy compared with those patients who received chemotherapy alone. Some patients experienced an immune-related adverse event. These are a specific type of undesired effect that can occur when patients are treated with immune checkpoint inhibitors. Immune-related adverse events occurred more frequently in patients who received dostarlimab plus chemotherapy than in those who received chemotherapy alone. Physicians were generally able to treat the immune-related adverse events, and only a low percentage of patients discontinued treatment because they experienced an immune-related adverse event. The types of adverse events seen were similar to a combination of those seen in patients who received dostarlimab alone or patients who received chemotherapy alone as treatment for endometrial cancer. Dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.

Patient-reported outcomes in the subpopulation of patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy compared with chemotherapy alone in the ENGOT-EN6-NSGO/GOG3031/RUBY trial.

OBJECTIVE: In the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin-paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin-paclitaxel, with manageable toxicity, in patients with primary advanced or recurrent endometrial cancer. Here we report on patient-reported outcomes in the mismatch repair-deficient/microsatellite instability-high population, a secondary endpoint in the trial. METHODS: Patients were randomized 1:1 to dostarlimab+carboplatin-paclitaxel or placebo+carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo monotherapy every 6 weeks for ≤3 years or until disease progression. Patient-reported outcomes, assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Endometrial Cancer Module, were prespecified secondary endpoints. A mixed model for repeated measures analysis, a prespecified exploratory analysis, was conducted to generate least-squares means to compare between-treatment differences while adjusting for correlations across multiple time points within a patient and controlling for the baseline value. Results are provided with 2-sided, nominal p values. RESULTS: Of 494 patients enrolled, 118 were mismatch repair-deficient/microsatellite instability-high. In this population, mean change from baseline to end of treatment showed visual improvements in global quality of life (QoL), emotional and social function, pain, and back/pelvis pain for dostarlimab+carboplatin-paclitaxel. Meaningful differences (least-squares mean [standard error]) favoring the dostarlimab arm were reported for change from baseline to end of treatment for QoL (14.7 [5.45]; p=0.01), role function (12.7 [5.92]); p=0.03), emotional function (14.3 [4.92]; p<0.01), social function (13.5 [5.43]; p=0.01), and fatigue (-13.3 [5.84]; p=0.03). CONCLUSIONS: Patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin-paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin-paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin-paclitaxel as a standard of care in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT03981796.

Activity of pembrolizumab and lenvatinib in mismatch repair deficient (dMMR) endometrial cancer patients who have failed pembrolizumab monotherapy: A case series.

To evaluate the efficacy of the combination of pembrolizumab and lenvatinib in MMR deficient (dMMR) endometrial cancer (EC) patients who previously failed to respond to single-agent pembrolizumab. A retrospective review of MMR deficient endometrial cancer patients was performed. Patients who failed to respond to pembrolizumab as a single-agent and subsequently received a combination of pembrolizumab and lenvatinib were analyzed. RECIST 1.1 criteria was used to establish clinical response (complete response, partial response, stable disease, and progression) based on CT and/or PET, comparing imaging before and after the addition of lenvatinib. Radiologic review was conducted by an independent radiologist. Eight patients with dMMR EC meeting treatment criteria were identified. The patients' ages ranged from 54 to 80 and all tumors identified were of endometrioid histology. Initial pathologic stage ranged from FIGO stage IB to IVB and recurrence confirmed via imaging or tissue biopsy. Patients received a median of 14 cycles of therapy with pembrolizumab and lenvatinib (range 1-39). All patients had decrease in measurable disease with an objective response of 75 % (PR 62.5 %, CR 12.5 %). Both patients who received the initial recommended dose of 20 mg daily required a dose reduction. Based on this retrospective study, patients with dMMR EC without significant benefit from pembrolizumab monotherapy have a significant clinical response after the addition of lenvatinib. Combination therapy should be considered for dMMR EC patients who fail pembrolizumab monotherapy.

Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer.

SELDI-TOF MS analysis of ovarian cyst fluids revealed that peaks m/z 8696 and 8825 discriminate malignant, borderline, and benign tumors. These peaks correspond to isoforms of apoA2. ELISA demonstrates that apoA1, A2, B, C2, C3, and E cyst fluid concentrations are uncorrelated and higher in malignant ovarian tumors, but only apoA2, apoE, and age are independent classifiers of malignant ovarian tumors, yielding 55.1% sensitivity, 95% specificity, and 88.1% accuracy to discern malignant from benign and borderline tumors. These data suggest that lipoprotein metabolism is dysregulated in ovarian cancer and that apoA2 and apoE warrant further investigation as ovarian tumor biomarkers.

Ten-year relative survival for epithelial ovarian cancer.

OBJECTIVE: Most patients with epithelial ovarian cancer who are alive at 5 years have active disease. Thus, 10-year survival rather than 5-year survival may be a more appropriate endpoint. Relative survival adjusts for the general survival of the United States population for that race, sex, age, and date at which the diagnosis was coded. Our objective was to estimate relative survival in epithelial ovarian cancer over the course of 10 years. METHODS: Using the Surveillance, Epidemiology and End Results 1995-2007 database, epithelial ovarian cancer cases were identified. Using the actuarial life table method, relative survival over the course of 10 years was calculated, stratified by stage, classification of residence, surgery as the first course of treatment, race, and age. RESULTS: There were 40,692 patients who met inclusion criteria. The overall relative survival was 65%, 44%, and 36% at 2, 5, and 10 years, respectively. The slope of decline in relative survival was reduced for years 5-10 as compared with years 1-5 after diagnosis. Relative survival at 5 years was 89%, 70%, 36%, and 17%, and at 10 years relative survival was 84%, 59%, 23%, and 8% for stages I, II III, and IV, respectively. At all stages, patients with nonsurgical primary treatment and those with advanced age had reduced relative survival. CONCLUSIONS: The 10-year relative survival for stage III is higher than expected. This information provides the physician and the patient with more accurate prognostic information.

Primary radiation therapy for medically inoperable patients with clinical stage I and II endometrial carcinoma.

OBJECTIVE: To determine the outcomes associated with primary radiation therapy for medically inoperable, clinical stage I and II, endometrial adenocarcinoma (EAC). METHODS: A multi-institution, retrospective chart review from January 1997 to January 2009 was performed. Overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) and time to progression (TTP) were assessed using the Kaplan-Meier method. Disease-specific survival was analyzed using a competing risks approach. RESULTS: Seventy-four patients were evaluable. The median age and BMI were 65 years (range 36-92 years) and 46 kg/m(2) (range 23-111 kg/m(2)), respectively. 85.1% had severe systemic disease, most frequently cardiopulmonary risk and morbid obesity. With a mean follow-up of 31 months, 13 patients (17.6%) experienced a recurrence. The median PFS and OS were 43.5 months and 47.2 months, respectively. Overall, 35 women died, including 4 women who died of unknown cause. Of the remaining 31 women, 7 patients (9.5%) died of disease, while 24 died of other causes (32.4%). The hazard ratio comparing the risk of death due to other causes to the risk of death due to disease was 3.4 (95% CI 1.4-9.4, p=0.003). Among patients who are alive three years after diagnosis, 14% recurred and the conditional recurrence estimate did not exceed 16%. CONCLUSIONS: Primary radiation therapy for clinical stage I and II EAC is a feasible option for medically inoperable patients and provides disease control, with fewer than 16% of surviving patients experiencing recurrence.

Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening.

OBJECTIVE: To estimate the effect of ultrasonographic screening on stage at detection and long-term disease-specific survival of women with epithelial ovarian cancer. METHODS: Eligibility included all asymptomatic women aged 50 years and older and women aged 25 years and older with a documented family history of ovarian cancer. From 1987 to 2011, 37,293 women received annual ultrasonographic screening. Women with abnormal screens underwent tumor morphology indexing, serum biomarker analysis, and surgery. RESULTS: Forty-seven invasive epithelial ovarian cancers and 15 epithelial ovarian tumors of low malignant potential were detected. No women with low malignant potential tumors experienced recurrent disease. Stage distribution for invasive epithelial cancers was: stage I, 22 (47%); stage II, 11 (23%); stage III, 14 (30%), and stage IV, 0 (0%). Follow-up varied from 2 months to 20.1 years (mean, 5.8 years). The 5-year survival rate for invasive epithelial ovarian cancers detected by screening was: stage I, 95%±4.8%; stage II, 77.1%±14.5%; and stage III, 76.2%±12.1%. The 5-year survival rate for all women with invasive epithelial ovarian cancer detected by screening as well as interval cancers was 74.8%±6.6% compared with 53.7%±2.3% for unscreened women with ovarian cancer from the same institution treated by the same surgical and chemotherapeutic protocols (P<.001). CONCLUSION: Annual ultrasonographic screening of asymptomatic women achieved increased detection of early-stage ovarian cancer cases and an increase in 5-year disease-specific survival rate for women with ovarian cancer. LEVEL OF EVIDENCE: II.

Cervical cancer survival for patients referred to a tertiary care center in Kentucky.

OBJECTIVES: To identify prognostic factors influencing cervical cancer survival for patients referred to a tertiary care center in Kentucky. METHODS: A cohort study was performed to assess predictive survival factors of cervical cancer patients referred to the University of Kentucky from January 2001 to May 2010. Eligibility criteria included those at least 18 years-old, cervical cancer history, and no prior malignancy. Descriptive statistics were compiled and univariable and multivariable Cox proportional hazard analysis were performed. RESULTS: 381 patients met entry criteria. 95% were Caucasian (N=347) and 66% (N=243) lived in Appalachian Kentucky. The following covariates showed no evidence of a statistical association with survival: race, body mass index, residence, insurance status, months between last normal cervical cytology and diagnosis, histology, tumor grade, and location of primary radiation treatment. After controlling for identified significant variables, stage of disease was a significant predictor of overall survival, with estimated relative hazards comparing stages II, III, and IV to stage I of 3.09 (95% CI: 1.30, 7.33), 18.11 (95% CI: 7.44, 44.06), and 53.03(95% CI: 18.16, 154.87), respectively. The presence of more than two comorbid risk factors and unemployment was also correlated with overall survival [HR 4.25 (95% CI: 1.00, 18.13); HR 2.64 (95% CI 1.29, 5.42), respectively]. CONCLUSIONS: Residence and location of treatment center are not an important factor in cervical cancer survival when a tertiary cancer center can oversee and coordinate care; however, comorbid risk factors influence survival and further exploration of disease comorbidity related to cervical cancer survival is warranted.

Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors.

OBJECTIVE: To compare the effectiveness of physician assessment with a new multivariate index assay in identifying high-risk ovarian tumors. METHODS: The multivariate index assay was evaluated in women scheduled for surgery for an ovarian tumor in a prospective, multi-institutional trial involving 27 primary- care and specialty sites throughout the United States. Preoperative serum was collected, and results for the multivariate index assay, physician assessment, and CA 125 were correlated with surgical pathology. Physician assessment was documented by each physician before surgery. CA 125 cutoffs were chosen in accordance with the referral guidelines of the American College of Obstetricians and Gynecologists. RESULTS: The study enrolled 590 women, with 524 evaluable for the multivariate index assay and CA 125, and 516 for physician assessment. Fifty-three percent were enrolled by nongynecologic oncologists. There were 161 malignancies and 363 benign ovarian tumors. Physician assessment plus the multivariate index assay correctly identified malignancies missed by physician assessment in 70% of nongynecologic oncologists, and 95% of gynecologic oncologists. The multivariate index assay also detected 76% of malignancies missed by CA 125. Physician assessment plus the multivariate index assay identified 86% of malignancies missed by CA 125, including all advanced cancers. The performance of the multivariate index assay was consistent in early- and late-stage cancers. CONCLUSION: The multivariate index assay demonstrated higher sensitivity and lower specificity compared with physician assessment and CA 125 in detecting ovarian malignancies.

Performance of the American College of Obstetricians and Gynecologists' ovarian tumor referral guidelines with a multivariate index assay.

OBJECTIVE: The American College of Obstetricians and Gynecologists (the College) published referral guidelines for women with a pelvic mass that incorporate CA 125. A new multivariate index assay assesses the malignant risk of ovarian tumors before surgery. Our objective was to estimate the performance of the College guidelines with this new multivariate index assay. METHODS: This prospective, multi-institutional trial included 27 primary care and specialty sites throughout the United States. The College guidelines were evaluated in women scheduled for surgery for an ovarian mass. Clinical criteria and blood for biomarkers were collected before surgery. A standard CA 125-II assay was used and the value applied to the multivariate index assay algorithm and the CA 125 analysis. Study results were correlated with surgical pathology. RESULTS: Of the 590 women enrolled with ovarian mass on pelvic imaging, 516 were evaluable. There were 161 malignancies (45 premenopausal and 116 postmenopausal). The College referral criteria had a modest sensitivity in detecting malignancy. Replacing CA 125 with the multivariate index assay increased the sensitivity (77-94%) and negative predictive value (87-93%) while decreasing specificity (68-35%) and positive predictive value (52-40%). Similar trends were noted for premenopausal women and early-stage disease. CONCLUSION: Replacing CA 125 with the multivariate index assay improves the sensitivity and negative predictive value of the College referral guidelines while decreasing specificity and positive predictive value. The high sensitivity is maintained in premenopausal women and early-stage disease.

Risk of malignancy in sonographically confirmed septated cystic ovarian tumors.

OBJECTIVE: To determine the risk of malignancy in septated cystic ovarian tumors. MATERIALS: 1319 (4.4%) of 29,829 women were identified by transvaginal sonography (TVS) as having a complex cystic ovarian tumor with septations without solid areas or papillary projections and were placed on long-term ultrasound surveillance for ovarian malignancy. RESULTS: These 1319 patients had a total of 2870 septated cystic ovarian tumors. 2288 tumors (79.7%) had a septal width <2 mm and 582 (20.3%) had a septal width >or=2 mm. 2286 tumors (79.6%) were <5 cm in diameter and 584 (20.4%) were>or=5 cm in diameter. 1114 septated cystic tumors (38.8%) resolved spontaneously (mean duration to resolution-12 months) and 1756 (61.2%) tumors persisted. 128 patients underwent surgical tumor removal within 3 months of ultrasound. Most common histopathology was: serous cystadenoma (75), mucinous cystadenoma (13), and endometrioma (10). One patient had an ovarian tumor of borderline malignancy (Stage IB). There were no cases of ovarian cancer. Patients were followed from 4 to 252 months (mean-77 months). One patient developed papillary morphology in the contralateral ovary 3.2 years after detection of a septated ovarian cyst and had epithelial ovarian cancer in that ovary and in the omentum (Stage IIIC disease). The remaining patients are all free of ovarian neoplasia after a total of 7642 follow-up years. CONCLUSIONS: Septated cystic ovarian tumors without solid areas or papillary projections have a low risk of malignancy and can be followed sonographically without surgery.

Vaginal cleansing before cesarean delivery to reduce postoperative infectious morbidity: a randomized, controlled trial.

OBJECTIVE: The objective of the study was to determine whether vaginal preparation with povidone iodine before cesarean delivery decreased the risk of postoperative maternal morbidities. STUDY DESIGN: The design of the study was a randomized, controlled trial in women undergoing cesarean delivery with subjects assigned to have a preoperative vaginal cleansing with povidone iodine or to a standard care group (no vaginal wash). The primary outcome was a composite of postoperative fever, endometritis, sepsis, readmission, wound infection, or complication. RESULTS: There were 155 vaginal cleansing subjects and 145 control subjects. Overall, 9.0% developed the composite outcome, with fewer women in the cleansing group (6.5%) compared with the control group (11.7%), although the difference was not statistically significant (relative risk, 0.55; 95% confidence interval, 0.26-1.11; P = .11). Length of surgery, being in labor, and having a dilated cervix were all associated with the composite morbidity outcome. CONCLUSION: Vaginal cleansing with povidone iodine before cesarean delivery may decrease postoperative morbidities, although the reduction is not statistically significant.