Robert L. Coleman

Gemogenovatucel-T Advantage in Clonal Tumor Mutation Burden–High Ovarian Cancer

PURPOSE Frontline ovarian cancer treatment protocols involving bevacizumab, poly (ADP-ribose) polymerase inhibitors, and PD-1/PD-L1 inhibitors have failed to improve overall survival (OS) in patients with homologous recombination–proficient (HRP) tumors. To determine mechanistic mutation signatures associated with OS advantage, we constructed a whole-exome sequencing bioinformatic pipeline assay to analyze all 91 patients enrolled in the double-blind randomized placebo-controlled phase II VITAL trial. METHODS We hypothesized that patients with stage IIIb-IV ovarian cancer who have HRP profile and high clonal tumor mutation burden (cTMB-H) will achieve greater response when undergoing maintenance therapy with gemogenovatucel-T. Our primary objective was assessment of OS using the Kaplan-Meier method among randomly assigned patients receiving either gemogenovatucel-T or placebo. RESULTS The median OS in cTMB-H/HRP patients treated with gemogenovatucel-T was 68 months versus 19 months in those treated with placebo (hazard ratio [HR], 0.23; 95% CI, 0.06 to 0.83; 1-sided P = .008). The cTMB-H patients in the non-HRP group did not demonstrate OS advantage (HR, 0.99; 95% CI, 0.39 to 2.47; 1-sided P = .488). No grade 3 treatment-related toxicity was observed in the gemogenovatucel-T group with a follow-up of 8.4 years. CONCLUSION These results demonstrate OS advantage for maintenance treatment of adult females with newly diagnosed, advanced stage IIIb-IV ovarian cancer with HRP status and cTMB-H profile who are in complete response after debulking surgery and frontline platinum-based doublet chemotherapy.

Phase II Trial of Ribociclib Plus Letrozole in Women With Recurrent Low-Grade Serous Carcinoma of the Ovary, Fallopian Tube, or Peritoneum: A GOG Partners Trial (GOG 3026)

PURPOSE Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)–p16–Rb pathway, features shared with hormone receptor–positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

Molecular Profiling and Tumor Biomarker Analysis of GOG281/LOGS: A Positive Late-Phase Trial of Trametinib for Recurrent/Persistent Low-Grade Serous Ovarian Carcinoma

Abstract Purpose: Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm. Experimental Design: Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort. Results: High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021). Conclusions: This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Repurposing Food and Drug Administration-approved cancer therapies: exploring endocrine and targeted pathways in low-grade serous ovarian cancer treatment

Low-grade serous ovarian cancer is a rare epithelial ovarian cancer with limited responsiveness to conventional chemotherapy, particularly, in advanced or recurrent settings. Low-grade serous ovarian cancer is characterized by an indolent growth pattern and a high prevalence of mitogen-activated protein kinase pathway alterations (KRAS, BRAF, NRAS) and hormone receptor positivity, highlighting the potential for targeted therapies. MEK inhibitors (eg, trametinib, binimetinib) specifically target the mitogen-activated protein kinase pathway, whereas endocrine therapies and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors exploit hormone-driven pathways. This review explores the repurposing of the therapeutic potential of both MEK inhibitors and breast cancer therapies, as endorsed by the National Comprehensive Cancer Network, to improve outcomes in low-grade serous ovarian cancer. This review synthesizes evidence supporting the repurposing of MEK inhibitors and breast cancer therapies (endocrine therapies, CDK4/6 inhibitors, and mammalian target of rapamycin inhibitors) as treatment approaches for low-grade serous ovarian cancer. Trametinib significantly improved progression-free survival in the GOG 281 trial, establishing MEK inhibition as a key therapeutic option. In addition, molecular similarities in estrogen receptor/progesterone receptor, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin, and CDK4/6 pathways between low-grade serous ovarian cancer and breast cancer provide a strong rationale for therapeutic crossover. Endocrine therapies demonstrated efficacy in low-grade serous ovarian cancer, particularly when combined with targeted agents to address resistance mechanisms. CDK4/6 inhibitors showed promise by blocking cell cycle progression and enhancing the response to endocrine therapies. In addition, mammalian target of rapamycin inhibitors have yielded clinical benefits in selected patients, emphasizing the importance of biomarker-driven treatment. Repurposing MEK inhibitors and endocrine-based approaches is shaping the treatment landscape for low-grade serous ovarian cancer, particularly in recurrent or advanced cases with limited treatment options. However, the variability in pathway alterations necessitates precise molecular profiling and optimized combination strategies. Future studies leveraging patient-derived models and advanced profiling techniques are critical for refining these approaches. These efforts may help expand National Comprehensive Cancer Network-endorsed options, and provide new hope for patients with hormone-sensitive low-grade serous ovarian cancer.

Mirvetuximab soravtansine in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer: final overall survival and post hoc sequence of therapy subgroup results from the SORAYA trial

Objective The single-arm, phase II SORAYA trial ( NCT04296890 ) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. Methods Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. Results At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. Conclusion These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.

Exploring global barriers to optimal ovarian cancer care: thematic analysis

To explore the barriers to ovarian cancer care, as reported in the open ended responses of a global expert opinion survey, highlighting areas for improvement in global ovarian cancer care. Potential solutions to overcome these barriers are proposed. Data from the expert opinion survey, designed to assess the organization of ovarian cancer care worldwide, were analyzed. The survey was distributed across a global network of physicians. We examined free text, open ended responses concerning the barriers to ovarian cancer care. A qualitative thematic analysis was conducted to identify, analyze, and report meaningful patterns within the data. A total of 1059 physicians from 115 countries completed the survey, with 438 physicians from 93 countries commenting on the barriers to ovarian cancer care. Thematic analysis gave five major themes, regardless of income category or location: societal factors, inadequate resources in hospital, economic barriers, organization of the specialty, and need for early detection. Suggested solutions include accessible resource stratified guidelines, multidisciplinary teamwork, public education, and development of gynecological oncology training pathways internationally. This analysis provides an international perspective on the main barriers to optimal ovarian cancer care. The themes derived from our analysis highlight key target areas to focus efforts to reduce inequalities in global care. Future regional analysis involving local representatives will enable country specific recommendations to improve the quality of care and ultimately to work towards closing the care gap.

ENGOT-EN20/GOG-3083/XPORT-EC-042 – A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design

Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 ( To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with This is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent Eligible patients must have histologically confirmed endometrial cancer, The primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population. A total of 220 patients will be enrolled. Accrual is expected to be completed in 2024 with presentation of results in 2025. NCT05611931.

Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor

PURPOSE Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

Homologous recombination deficiency in endometrial cancer: shedding light on recent clinical findings

Endometrial cancer is the most common gynecologic malignancy in the United States, with rising incidence and high recurrence rates. Immune checkpoint inhibitors (ICIs) benefit patients with mismatch repair-deficient (dMMR) tumors, but options remain limited for those with mismatch repair-proficient (pMMR) disease. Homologous recombination deficiency (HRD), a genomic instability phenotype, has emerged as a therapeutic target. Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) are being investigated in endometrial cancer, with studies exploring whether HRD predicts response, particularly in combination with ICIs or chemotherapy. This review examines HRD in endometrial cancer, focusing on its molecular basis, clinical implications, and emerging therapeutic strategies. HRD occurs in a sub-set of endometrial cancers, particularly non-endometrioid sub-types, and is linked to genomic instability and platinum sensitivity. The Cancer Genome Atlas (TCGA) molecular classification has improved understanding of HRD prevalence across sub-types. HRD testing remains challenging due to a lack of standardization, with current methods including genomic-scar assays, next-generation sequencing, and functional assays. Clinical trials, such as DUO-E and RUBY-2, suggest that PARPi combined with ICIs or chemotherapy may improve outcomes in pMMR tumors, whereas PARPi monotherapy offers limited benefits. Resistance to PARPi is common, driven by the restoration of homologous recombination repair, replication fork stabilization, and drug efflux. HRD is a promising biomarker and therapeutic target in endometrial cancer. Evidence supports the integration of PARPi for select populations, although further research is needed to refine testing, optimize patient selection, and overcome resistance. Future trials should prioritize predictive biomarkers and novel combinations to maximize the benefits of PARPi in HRD endometrial cancer.

An evaluation of selinexor as a maintenance therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma

Tumor protein 53 gene ( This review examines the mechanism of action of selinexor related to p53, contextualizes the effectiveness of selinexor among EC subtypes within the context of the evolving diagnostic, predictive, and therapeutic landscape for treatment, and presents the relevant clinical studies for selinexor dose for its use in gynecological malignancies. Literature review was conducted on the PubMed database. The promising efficacy signal suggests selinexor has potential as a maintenance therapy for

The new 2023 endometrial cancer FIGO staging system: balancing innovation with complexity

In August 2023, the International Federation of Gynecology and Obstetrics introduced an updated staging system for endometrial cancer that integrates histopathologic and molecular characteristics (optional) of the tumor alongside with anatomic extent of the disease. This innovative approach aims to improve the prognostication of the system and the identification of treatment-relevant patient populations by more accurately stratifying patients based on tumor biology, representing a significant advancement toward personalized medicine. However, its implementation poses challenges, including the heterogeneous availability of molecular testing worldwide, and the need for further standardization and prospective validation of some of the newly introduced histopathological parameters. To address these innovations and related controversies, a meeting of physicians, including gynecologic oncologists and pathologists, was held. This article summarizes the reflections that emerged from this meeting, focusing on key elements such as the integration of histopathologic features (eg, "high-grade, aggressive histologic types," "substantial lymphovascular space invasion"), molecular classification, and the implications for global reproducibility and applicability. It also addresses the basic approach toward staging: should it offer integrated, patient-relevant information to enable accurate prognostication and inform treatment decisions or should a staging system simply provide a common language to communicate disease extent? The meeting provided an opportunity for a group of physicians to share considerations on this evolving topic. Our article highlights focal points of change in the new staging system and identifies key areas for future research, advocating for collaborative efforts to generate more robust evidence on some variables introduced in the staging system through prospective studies. By addressing these challenges, we aim to improve the applicability and effectiveness of the new International Federation of Gynecology and Obstetrics staging system in real-world scenarios and identify elements that may require further refinement, ultimately advancing precision medicine in endometrial cancer care.

Biomarker-driven therapy in endometrial cancer

This article reviews treatments and targets of interest in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes-mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H); copy number high (CNH)/p53abn; copy number low (CNL)/no specific molecular profile (NSMP); and POLEmut-which are validated and highly prognostic. Treatment consideration by subtype is now recommended. In March and April 2022, respectively, the US Food and Drug Administration (FDA) fully approved and the European Medicines Agency adopted a positive opinion recommending the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab for advanced/recurrent dMMR/MSI-H endometrial cancer which has progressed on or following a platinum-containing therapy. A second anti-PD-1, dostarlimab, received accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency in this group. The combination of pembrolizumab/lenvatinib for mismatch repair proficient/microsatellite stable endometrial cancer, including p53abn/CNH and NSMP/CNL, received accelerated FDA approval in conjunction with Australia's Therapeutic Goods Administration and Health Canada in September 2019. The FDA and European Medicines Agency made full recommendations in July 2021 and October 2021. Trastuzumab is National Comprehensive Cancer Network (NCCN) compendium listed for human epidermal growth factor receptor-2-positive serous endometrial cancer, which is primarily within the p53abn/CNH subtype. In addition to hormonal therapy, maintenance therapy with selinexor (exportin-1 inhibitor) showed potential benefit in

Integrating antibody drug conjugates in the management of gynecologic cancers

The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor. Over the years, this novel class of drugs expanded to agents with a more sophisticated design and structure, targeting tissue factor (TF) in cervical cancer or human epidermal growth factor receptor 2 (HER2) in endometrial cancer. Despite the impressive number of patients included in clinical trials investigating different ADCs across gynecological cancers, it was only recently that the Food and Drug Administration (FDA) granted accelerated approvals to the first ADCs in gynecologic cancer. In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Currently, the field of ADCs is rapidly expanding and more than 20 ADC formulations are in clinical trials for the treatment of ovarian, cervical and endometrial tumors. This review summarizes key evidence supporting their use and therapeutic indications, including results from late-stage development trials investigating MIRV in ovarian cancer and TV in cervical cancer. We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination therapies, including chemotherapy, anti-angiogenic and immunotherapeutic agents.

Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study

Abstract Purpose: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC. Patients and Methods: A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. Results: Sixty-two patients were enrolled. Median age was 62 years (40–77) with 401 cycles completed, median of 6 cycles (1–31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2–47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0–8.1] and OS was 19.6 months (95% CI, 14.2–26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001). Conclusions: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor–positive tumors may have better response; validation studies are needed. See related commentary by Madariaga et al., p. 523

Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial

To evaluate the safety and preliminary efficacy of demcizumab (DLL4 targeted IgG2 humanized monoclonal antibody; potent inhibitor of the Notch pathway) in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (EOC); and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). We conducted a 3 + 3 dose-escalation trial in patients with recurrent, platinum-resistant EOC with RECIST v. 1.1 measurable disease and ≤4 prior chemotherapy regimens. Two dosing cohorts (2.5 mg/kg and 5 mg/kg) were targeted; however, an intermediate dose level (3.5 mg/kg) was to be evaluated if the 5 mg/kg dose was not tolerable. Demcizumab was administered on days 1 and 15 and paclitaxel, weekly on days 1, 8, and 15 for each of three 28-day cycles: the 3-cycle doublet could be repeated once if safe. Thereafter, paclitaxel was administered until unacceptable toxicity or disease progression. Nineteen patients were enrolled. No dose-limiting toxicities (DLT) were observed; however, the intermediate dose level (3.5 mg/kg) was enrolled and expanded based on emerging safety data from other trials in the demcizumab program. The MTD was not reached. The most common treatment emergent adverse events (TEAE) were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Pulmonary hypertension, grade 2 (n = 2) and grade 1 (n = 1), was observed. Overall response rate (ORR) was 21% (95% CI: 6-45%); clinical benefit rate (CBR) was 42% (95% CI: 20-66%). Demcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer.

LACC Trial: Final Analysis on Overall Survival Comparing Open Versus Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The aim of this study was to compare overall survival between open and minimally invasive radical hysterectomy with participants followed for 4.5 years. The primary objective was to evaluate whether minimally invasive surgery was noninferior in disease-free survival (DFS) to abdominal radical hysterectomy. Secondary outcomes included overall survival. Sample size was based on DFS of 90% at 4.5 years and 7.2% noninferiority margin for minimally invasive surgery. A total of 631 patients were enrolled: 319 assigned to minimally invasive and 312 to open surgery. Of these, 289 (90.6%) patients underwent minimally invasive surgery and 274 (87.8%) patients open surgery. At 4.5 years, DFS was 85.0% in the minimally invasive group and 96% in the open group (difference of –11.1; 95% CI, –15.8 to –6.3; P = .95 for noninferiority). Minimally invasive surgery was associated with lower rate of DFS compared with open surgery (hazard ratio [HR], 3.91 [95% CI, 2.02 to 7.58]; P < .001). Rate of overall survival at 4.5 years was 90.6% versus 96.2% for the minimally invasive and open surgery groups, respectively (HR for death of any cause = 2.71 [95% CI, 1.32 to 5.59]; P = .007). Given higher recurrence rate and worse overall survival with minimally invasive surgery, an open approach should be standard of care.

Systemic therapy de-escalation in advanced ovarian cancer: a new era on the horizon?

Poly(ADP-ribose) polymerase inhibitors (PARPi) have sculpted the current landscape of advanced ovarian cancer treatment. With the advent of targeted maintenance therapies, improved survival rates have led to a timely interest in exploring de-intensified strategies with the goal of improving quality of life without compromising oncologic outcomes. The emerging concept of systemic treatment de-escalation would represent a new frontier in personalizing therapy in ovarian cancer. PARPi are so effective that properly selected patients treated with these agents might require less chemotherapy to achieve the same oncologic outcomes. The fundamental key is to limit de-escalation to a narrow subpopulation with favorable prognostic factors, such as patients with

Can fluorescence-guided surgery improve optimal surgical treatment for ovarian cancer? A systematic scoping review of clinical studies

The predicament of achieving optimal surgical intervention faced by surgeons in treating ovarian cancer has driven research into improving intra-operative detection of cancer using fluorescent materials. To provide a literature overview on the clinical use of intra-operative fluorescence-guided surgery for ovarian cancer, either for cytoreductive surgery or sentinel lymph node (SLN) biopsy. The systematic review included studies from June 2002 until October 2021 from PubMed, Web of Science, and Scopus as well as those from a search of related literature. Studies were included if they investigated the use of fluorescence-guided surgery in patients with a diagnosis of ovarian cancer. Authors charted variables related to study characteristics, patient demographics, baseline clinical characteristics, fluorescence-guided surgery material, and treatment details, and surgical, oncological, and survival outcome variables. After screening 2817 potential studies, 24 studies were included. Studies investigating the role of fluorescence-guided surgery to visualize tumor deposits or SLN biopsy included the data of 410 and 118 patients, respectively. Six studies used indocyanine green tracer with a mean SLN detection rate of 92.3% with a pelvic and para-aortic detection rate of 94.8% and 96.7%, respectively. The sensitivity, specificity, and positive predictive value for micrometastases detection of OTL38 and 5-aminolevulinc acid at time of cytoreduction were 92.2% vs 79.8%, 67.3% vs 94.8%, and 55.8% vs 95.8%, respectively. Fluorescence -guided surgery is a technique that may improve the detection rate of micrometastases and SLN identification in ovarian cancer. Further research is needed to establish whether this will lead to improved patient outcomes.

Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study

Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer. NCT02751918.

PARP inhibitor era: current status and future directions

The role of secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer: what do the trials tell us?

NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors

Abstract XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE in vitro and in vivo. Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.

Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer

Abstract Purpose: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. Patients and Methods: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days. Results: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics. Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.

Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models

Abstract CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.

Maintenance treatment with rucaparib for recurrent ovarian carcinoma in ARIEL3, a randomized phase 3 trial: The effects of best response to last platinum‐based regimen and disease at baseline on efficacy and safety

AbstractBackgroundThe efficacy and safety of rucaparib maintenance treatment in ARIEL3 were evaluated in subgroups based on best response to most recent platinum‐based chemotherapy and baseline disease.MethodsPatients were randomized 2:1 to receive either oral rucaparib at a dosage of 600 mg twice daily or placebo. Investigator‐assessed PFS was assessed in prespecified, nested cohorts: BRCA‐mutated, homologous recombination deficient (HRD; BRCA mutated or wild‐type BRCA/high loss of heterozygosity), and the intent‐to‐treat (ITT) population.ResultsMedian PFS for patients in the ITT population with a complete response to most recent platinum‐based chemotherapy was 11.1 months in the rucaparib arm (126 patients) versus 5.6 months in the placebo arm (64 patients) (HR, 0.33 [95% CI, 0.23–0.48]), and in patients with a partial response (249 vs. 125), it was 9.0 versus 5.3 months (HR, 0.38 [0.30–0.49]). In subgroups of the ITT population based on baseline disease, median PFS was 8.2 versus 5.3 months (HR, 0.40 [0.28–0.57]) in patients with measurable disease (141 rucaparib vs. 66 placebo), 10.4 versus 4.5 months (HR, 0.31 [0.20–0.48]) in those with nonmeasurable but evaluable disease (104 vs. 56), and 14.1 versus 7.3 months (HR, 0.35 [0.24–0.51]) in those with no residual disease (130 vs. 67). Across subgroups, significantly longer median PFS was observed with rucaparib versus placebo in the BRCA‐mutated and HRD cohorts. Objective responses were reported in patients with measurable disease and in patients with nonmeasurable but evaluable baseline disease. Safety was consistent across subgroups.ConclusionRucaparib maintenance treatment provided clinically meaningful efficacy benefits across subgroups based on response to last platinum‐based chemotherapy or baseline disease.

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer

AbstractBackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk.Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

PURPOSE In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable < 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study

PURPOSE In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib. PATIENTS AND METHODS Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status ( BRCA mutation, HR deficiency [HRD], or HR proficiency [HRP]). RESULTS The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and BRCA mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or BRCA wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a BRCA mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect. CONCLUSION In addition to HRD/ BRCA status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer

Abstract Purpose: Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody–drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623). Patients and Methods: Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity. Results: Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%−37%]. Median duration of response (DOR) was 4.2 months (range: 1.0+−9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%−43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%−35%), median DOR of 6.0 months (range: 1.0+−9.7), and 6-month PFS rate of 40% (95% CI: 24%−55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed. Conclusions: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.

Veliparib concomitant with first-line chemotherapy and as maintenance therapy in ovarian cancer: Final overall survival and disease-related symptoms results

In the VELIA trial, the addition of veliparib to standard first-line platinum-based chemotherapy and continued as maintenance resulted in significantly longer median progression-free survival (PFS) compared with carboplatin plus paclitaxel induction therapy alone (23.5 vs 17.3 months; p < 0.001) in patients with ovarian cancer. We now report final overall survival (OS) and updated safety and disease-related symptoms (DRS) from patient-reported outcomes of the trial. This randomized, placebo-controlled, double-blind, multicenter, phase 3 study enrolled adult women with an initial diagnosis of stage III/IV high-grade serous ovarian cancer undergoing primary or interval cytoreductive surgery. Patients were randomized 1:1:1 to chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout), chemotherapy plus veliparib followed by placebo maintenance (veliparib-combination-only), or chemotherapy plus placebo followed by placebo maintenance (placebo-throughout). PFS was the primary endpoint; OS and DRS were secondary endpoints. In the intention-to-treat population (N = 1140), median OS was 59.2 months (95 % confidence interval: 52.1, 68.2) for the veliparib-throughout group, 58.0 (50.6, 64.1) months for veliparib-combination-only, and 57.8 (52.3, 63.8) months for placebo-throughout. OS outcomes were not significantly different between arms overall or in the BRCA-deficient and homologous recombination-deficient cohorts. No new safety signals were identified during the longer follow-up period and DRS analyses indicated there was no significant additional symptom-related burden overall when veliparib was added to chemotherapy or used for maintenance. No OS or DRS benefit of addition of veliparib to platinum-based chemotherapy and continued as maintenance therapy was detected in this study, despite an observed benefit over chemotherapy alone in PFS.

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer

Abstract Purpose: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Patients and Methods: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan–Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. Results: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31–0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43–1.59). Conclusions: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

Oncologist perceptions of “cure” and long-term management in advanced ovarian cancer in the United States: results from a cross-sectional survey

Treatment advancements have improved survival outcomes for patients with advanced ovarian cancer. In advanced ovarian cancer, some physicians believe discussing "cure" as a potential treatment goal may be premature. In contrast, others note that the durable responses observed among some patients may suggest that long-term remission or "cure" are legitimate outcomes to strive for. Despite this, the term 'cure' has no accepted definition in this setting, and whether physicians are willing to use this language is unknown. A cross-sectional, internet-based survey was conducted to evaluate United States oncologists' attitudes and beliefs related to "cure" in the context of treating patients with newly diagnosed advanced ovarian cancer. The survey included questions on attitudes and beliefs toward patient prognosis with newly diagnosed advanced ovarian cancer, oncologists' perceptions of clinical outcomes, oncologist characteristics, and clinical practice details. Among 150 oncologists, when addressing the topic of disease prognosis or treatment goals in patients newly diagnosed with stage III-IV ovarian cancer, the terms endorsed by more than half of oncologists were "achieve long-term remission" and "achieve long-term response." Terms including "cure" or "curable" were endorsed by less than 35% of oncologists. Among several patient characteristics evaluated, no evidence of disease for 5 to 10 years was most indicative of cure. In the context of primary disease, the proportion of oncologists who would tell a patient with advanced ovarian cancer they were cured, even if they believe it to be true, decreased with the stage (II = 73.8%; III = 60.8%; IV = 50.5%). The current study found that while oncologists may believe a cure is possible across early stages of ovarian cancer, many remain hesitant to discuss the potential of "cure" with patients, particularly those with stage IV disease.

Combination Therapy with Copanlisib and Niraparib in Patients with Recurrent Endometrial and Ovarian Cancer (COPANIRA): Efficacy, Toxicity, and Translational Insights

Abstract Purpose: Patients with recurrent endometrial or ovarian cancer have poor survival outcomes. We evaluated the clinical efficacy and toxicity of copanlisib [a phosphatidylinositol 3-kinase (PI3K) inhibitor] and niraparib [a poly (ADP-ribose) polymerase inhibitor (PARPi)] in this patient population with translational insights. Patients and Methods: This was a phase Ib trial. Copanlisib was administered intravenously on days 1, 8, and 15 of a 28-day cycle, and niraparib was given orally once daily. Four dose levels were explored over a dose-limiting toxicity (DLT) window of 28 days. The primary objective was to determine the recommended phase II dose (RP2D) of this combination. Secondary objectives included safety, objective response rate (ORR), and pharmacokinetics. Tumor biopsies were analyzed using reverse phase protein array (RPPA) to identify molecular correlates of response. Results: Thirty patients were enrolled. An RP2D was not established due to DLTs, most commonly a grade 3 maculopapular rash attributed to copanlisib. The ORR was 12.5% (95% confidence interval, 2.8%–33.6%). RPPA was performed on tumors from eight patients. PI3K pathway activity did not correlate with PI3K mutational status. Nineteen proteins were differentially expressed between patients with stable disease and those with progressive disease; many were substrates of Akt (protein kinase B), implicating downstream PI3K signaling in response. Conclusions: The combination of copanlisib and niraparib demonstrated limited tolerability, and the ORR was modest. However, functional proteomic analyses identified candidate biomarkers—particularly Akt pathway substrates—which may inform future strategies to optimize PI3K and PARPi combinations.

Selinexor in Maintenance Therapy After Systemic Therapy for Participants With p53 Wild-Type, Advanced or Recurrent Endometrial Carcinoma

The purpose of this study is to evaluate the efficacy and safety of selinexor as a maintenance treatment in patients with p53 wt endometrial carcinoma (EC), who have achieved a partial response (PR) or complete response (CR) (per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v 1.1\]) after completing at least 12 weeks of platinum-based therapy. A total of 276 participants will be enrolled in the study and randomized in a 1:1 ratio to maintenance therapy with either selinexor or placebo.

A Study of Mirvetuximab Soravtansine in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

This study is designed to evaluate the efficacy and safety of mirvetuximab soravtansine (MIRV) in participants with platinum-resistant high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, whose tumors express a high-level of Folate Receptor-Alpha (FRα). Participants will be, in the opinion of the Investigator, appropriate for single-agent therapy for their next line of therapy. All participants will receive single-agent MIRV at 6 mg/kg adjusted ideal body weight administered on Day 1 of every 3-week cycle.

Phase Ib Study of Anetumab Ravtansine in Combination With Pegylated Liposomal Doxorubicin in Patients With Recurrent Mesothelin-expressing Platinum-resistant Cancer

Anetumab ravtansine is developed for the treatment of patients with recurrent platinum-resistant ovarian cancer. The purpose of the proposed trial is to identify the maximum tolerated dose of anetumab ravtansine that could be safely combined with pegylated liposomal doxorubicin in this indication.

Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors

The purpose of the trial is to establish the tolerability of HuMax-TF-ADC in a mixed population of patients with specified solid tumors.

A Study Comparing the Combination of Trabectedin (YONDELIS) and DOXIL/CAELYX With DOXIL/CAELYX for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

The purpose of this study is to assess the efficacy and safety of trabectedin+DOXIL as a third-line chemotherapy regimen (treatment) in patients with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy.

A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer

The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer) is a Phase 3 study during which patients with recurrent or persistent low-grade serous (LGS) carcinomas of the ovary, fallopian tube or primary peritoneum will receive either investigational study drug MEK162 or a chemotherapy chosen by the physician (liposomal doxorubicin, paclitaxel or topotecan). Patients will be followed to compare the effectiveness of the study drug to that of the selected chemotherapies. Patients may be eligible to crossover from physician's choice chemotherapy to MEK162 if they meet certain inclusion criteria including centrally confirmed disease progression. Approximately 360 patients from North America, Europe and Australia will be enrolled in this study.

Laparoscopic Approach to Cervical Cancer

The goal of this clinical research study is to compare the long-term outcomes of different surgical methods for the treatment of cervical cancer. The long-term outcome of a total abdominal radical hysterectomy (TARH) will be compared against laparoscopy. In this study, the laparoscopy will be done with or without robotic technology.

Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

This randomized phase III trial studies carboplatin, paclitaxel, and bevacizumab to see how well they work compared to carboplatin, paclitaxel, and placebo in treating patients with stage III or stage IV ovarian epithelial, primary peritoneal, or fallopian tube cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether carboplatin, paclitaxel, and bevacizumab are more effective than carboplatin, paclitaxel, and placebo in treating ovarian epithelial, primary peritoneal, or fallopian tube cancer.

An Efficacy and Safety Study for Yondelis (Trabectedin) in Patients With Advanced Relapsed Ovarian Cancer

The purpose of the study is to compare the progression-free survival (PFS) of the combination of trabectedin + DOXIL with DOXIL monotherapy in patients with ovarian cancer.