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Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite‐instable, metastatic disease, anti– programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.

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.

ObjectiveHigh glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status.MethodsWhole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis.ResultsCombined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2. In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed.ConclusionsIncreased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.

Host tissue microenvironment plays key roles in cancer progression and colonization of secondary organs. One example is ovarian cancer, which colonizes the peritoneal cavity and especially the omentum. Our research indicates that the interaction of ovarian cancer cells with the omental microenvironment can activate a stress-kinase pathway involving the mitogen-activated protein kinase kinase 4 (MKK4). A combination of clinical correlative and functional data suggests that MKK4 activation suppresses growth of ovarian cancer cells lodged in omentum. These findings prompted us to turn our focus to the cellular composition of the omental microenvironment and its role in regulating cancer growth. In this review, in addition to providing an overview of MKK4 function, we highlight a use for metastasis suppressors as a molecular tool to study cancer cell interaction with its microenvironment. We review features of the omentum that makes it a favorable microenvironment for metastatic colonization. In conclusion, a broader, evolutionary biology perspective is presented which we believe needs to be considered when studying the evolution of cancer cells within a defined microenvironment. Taken together, this approach can direct new multi-dimensional lines of research aimed at a mechanistic understanding of host tissue microenvironment, which could be used to realize novel targets for future research.

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

Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.

ObjectivesFolate receptor-alpha (FRα) expression is associated with poor prognosis in endometrial cancer (EC). Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 dose expansion study in FRα+ advanced/recurrent EC (NCT01609556). In addition to direct target-mediated cytotoxicity, MIRV activates monocytes and promotes phagocytosis of tumor cells through Fc-FcγR interactions. We hypothesized that addition of MIRV may improve the low response to immunotherapy in MSS EC.MethodsThis is a Phase 2, single cohort study of MIRV with pembrolizumab in recurrent/persistent EC (NCT03835819). Patients must have advanced or recurrent MSS serous EC with FRα expression (≥50% of cells with ≥2+ by IHC performed at Ventana, Inc) and have received 1–3 prior lines of therapy. Prior receipt of ICI is allowed. Patients receive MIRV 6 mg/kg AIBW and pembrolizumab 200 mg every 21 days. The co-primary endpoint is progression-free survival at 6 months and objective response rate by RECIST 1.1. Translational objectives include assessment of tumor-infiltrating immune cells, expression of immune checkpoint markers, and whole exome sequencing. Statistical considerations are for a Simon two-stage optimal design with 16 patients in Stage 1 and 19 patients in Stage 2, to a total of 35. Prespecified activity for the first stage of accrual was met; second stage accrual began November 2020.ResultsTrial in progress: no available results at time of submission.ConclusionsTrial in progress: no available results at time of submission.

Introduction/BackgroundDostarlimab is a programmed death 1 (PD-1) inhibitor approved as monotherapy in patients with mismatch repair deficient (dMMR) recurrent/advanced endometrial cancer (EC) that has progressed on or after platinum-based chemotherapy or solid tumours that have progressed on or after prior treatment, with no satisfactory alternative treatment options. We report a post hoc analysis of antitumour activity by PDL1 expression and tumour mutational burden (TMB) in patients with dMMR and MMR proficient (MMRp) solid tumours in the GARNET trial.Abstract 2022-RA-945-ESGO Table 1MethodologyGARNET (NCT02715284) is a phase 1, multicentre, open-label, single-arm study of dostarlimab in patients with advanced/recurrent solid tumours. Three expansion cohorts enrolled patients based on MMR status: dMMR (A1) and MMRp (A2) advanced/recurrent EC, and dMMR non-EC solid tumours (F). Patients received dostarlimab 500 mg IV Q3W for 4 cycles, then 1000 mg IV Q6W until progression or discontinuation. TMB and PDL1 were exploratory biomarkers. TMB status was determined by FoundationOne test; TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PDL1 expression was determined by combined positive score (CPS) by Ventana assay; PDL1-high (PDL1-H) was defined as CPS ≥1. The study was not powered to assess antitumour activity within subgroups.ResultsTMB-H and PDL1-H were common in dMMR solid tumours; PDL1-H was observed in 39.4% of MMRp EC tumours (table 1). Objective response rate (ORR) was higher in patients with TMB-H/PDL1-H tumours (55.6% for all cohorts, combined; Table). Safety for each cohort was previously reported.1 ConclusionPDL1-H and TMB-H were frequently observed in the dMMR EC and non-EC cohorts, regardless of tumour type; PDL1-H was also prevalent in MMRp EC tumours. Although not a powered analysis, ORR by BICR per RECIST v1.1 was higher in patients with TMB-H and PDL1-H solid tumours. Across cohorts, dMMR status was predictive of response.ReferenceAndre T, et al. Ann Oncol 2021;32(suppl 5):S829-S866. 991P.

ObjectivesDostarlimab is an approved programmed death 1 (PD-1) inhibitor. PD-1 therapy can lead to immune-related adverse events (irAEs). Here we report on the management of irAEs across multiple tumor types evaluated in GARNET.MethodsGARNET is a multicenter, open-label, single-arm phase 1 study with dose expansion in multiple tumor types: dMMR solid tumors, mismatch repair proficient EC, non-small cell lung cancer, and platinum-resistant ovarian cancer. Patients received 500 mg of dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal.ResultsAt this third interim analysis of GARNET, the safety population included 605 patients. irAEs were experienced by 32.2%, with 10.1% of patients experiencing grade ≥3 irAEs (table 1). Few, 5.5%, discontinued treatment because of an irAE. No irAEs led to death. Of patients experiencing irAEs, 64.6% were treated with immune modulatory medications (IMMs; referring to steroids, immune suppressant, and/or thyroid therapy); 58.7% of these patients experienced resolution. Average time to resolution was 69 days. For the 35.4% of patients not treated with IMMs, 56.5% experienced a resolution. Average time to resolution was 67 days. The most common irAEs were hypothyroidism (7.6%; 45 of 46 [97.8%] patients treated with thyroid therapy) and arthralgia (5.6%; 8 of 34 [23.5%] patients treated with steroids).Abstract 6/#455 Table 1ConclusionsAcross all tumor types evaluated in GARNET, 32.2% of patients experienced irAEs, 68.7% of whom experienced grade 2 events. 58.7% of patients experienced resolution of irAEs upon treatment with an IMM. Overall discontinuation due to irAEs was low.

ObjectivesMismatch repair (MMR) deficiency is caused by loss of expression of MMR proteins, MLH1, PMS2, MSH2, and/or MSH6, that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to mediate DNA repair. Loss of function caused by mutation or epigenetic methylation leads to defective MMR and genomic instability. MMR deficient (dMMR) tumors can respond to anti-programmed death 1 (PD-1) therapy. We report on a post-hoc analysis of ORR with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab.MethodsGARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. MMR protein status (presence or loss) was determined by local IHC. MMR gene mutation was determined by Foundation One. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation.ResultsCohort A1 included 143 patients; MMR gene mutation data was available for 101 (table 1). Cohort A1 ORR was 45.5%. 66% of patients had loss of MLH1/PMS2; ORR was 48.9%. 11.2% of patients had loss of MSH2/MSH6; ORR was 56.2%. ORR was 41.7% for MLH1 loss with MMR gene mutation and 39.4% for MLH1 loss without MMR gene mutation.Abstract O007/#456 Table 1ConclusionsPatients with dMMR advanced/recurrent EC benefitted from dostarlimab, with no noticeable difference by dimer-pair loss or MMR gene methylation/mutation status. These data suggest route to MMR deficiency does not influence response to dostarlimab.