Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Loss of copy numbers of retrotransposons (HERVK) on chromosome 7p11.2 impacts EGFR (Epidermal Growth Factor Receptor)-induced phenotypes for platinum sensitivity and long-term survival in ovarian cancer-A study from the OVCAD consortium.

We analyzed variations in the epidermal growth factor receptor (EGFR) gene and 5'-upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA-SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity (n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA-SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109-0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR-mutated cancers. Notably, the inherited length of the CA-SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow-up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.

Comparison of the ADNEX and ROMA risk prediction models for the diagnosis of ovarian cancer: a multicentre external validation in patients who underwent surgery.

BACKGROUND: Several diagnostic prediction models to help clinicians discriminate between benign and malignant adnexal masses are available. This study is a head-to-head comparison of the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model with that of the Risk of Ovarian Malignancy Algorithm (ROMA). METHODS: This is a retrospective study based on prospectively included consecutive women with an adnexal tumour scheduled for surgery at five oncology centres and one non-oncology centre in four countries between 2015 and 2019. The reference standard was histology. Model performance for ADNEX and ROMA was evaluated regarding discrimination, calibration, and clinical utility. RESULTS: The primary analysis included 894 patients, of whom 434 (49%) had a malignant tumour. The area under the receiver operating characteristic curve (AUC) was 0.92 (95% CI 0.88-0.95) for ADNEX with CA125, 0.90 (0.84-0.94) for ADNEX without CA125, and 0.85 (0.80-0.89) for ROMA. ROMA, and to a lesser extent ADNEX, underestimated the risk of malignancy. Clinical utility was highest for ADNEX. ROMA had no clinical utility at decision thresholds <27%. CONCLUSIONS: ADNEX had better ability to discriminate between benign and malignant adnexal tumours and higher clinical utility than ROMA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01698632 and NCT02847832.

Antitumor activity and safety of the PD-1 inhibitor retifanlimab in patients with recurrent microsatellite instability-high or deficient mismatch repair endometrial cancer: Final safety and efficacy results from cohort H of the POD1UM-101 phase I study.

OBJECTIVE: Retifanlimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1 being investigated in several solid tumor types. We report final results from patients with recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer treated with retifanlimab in a POD1UM-101 expansion cohort. METHODS: Eligible patients (≥18 years; histologically proven/unresectable/recurrent, MSI-H/dMMR endometrial cancer; checkpoint inhibitor naive) received retifanlimab 500 mg intravenously every 4 weeks for ≤2 years. Primary endpoint was safety/tolerability. RESULTS: At data cutoff (May 17, 2023), 76 patients had received at least one retifanlimab dose. Median (range) age was 67 (49-88) years; 88.2% of patients had recurrent metastatic disease and 80.3% had visceral metastases. Seventy-five patients (98.7%) had received at least one prior systemic therapy. Median retifanlimab exposure was 10.0 (0.03-25.9) months; 23 patients completed treatment. 38 patients (50.0%) had grade ≥3 treatment-emergent adverse events (TEAEs), most commonly anemia (n = 10 [13.2%]). 63 patients (82.9%) had treatment-related AEs (TRAEs; grade ≥3, n = 14 [18.4%]); most common was fatigue (n = 14 [18.4%]). Two patients had TEAEs that led to death; no TRAEs were fatal. 39 patients had objective responses (51.3%; 95% CI, 39.6-63.0%); 19 patients (25.0%) had complete response and 20 (26.3%) had partial response. Median progression-free survival was 12.2 months; 30 patients (76.9%) had duration of response (DOR) ≥12 months. Median DOR was not reached after median follow-up time of 26.0 months. CONCLUSIONS: Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer.

Safety and tolerability of mirvetuximab soravtansine monotherapy for folate receptor alpha-expressing recurrent ovarian cancer: An integrated safety summary.

OBJECTIVE: Mirvetuximab soravtansine-gynx (MIRV) is a novel antibody-drug conjugate targeting folate receptor alpha (FRα), which is overexpressed in epithelial ovarian cancer (EOC), with limited expression on normal tissues. This integrated safety summary sought to characterize the safety profile of MIRV monotherapy in participants with FRα-expressing recurrent EOC. METHODS: Safety data were retrospectively analyzed from 4 clinical studies (phase 1 trial [NCT01609556], phase 3 FORWARD I [NCT02631876], phase 2 SORAYA [NCT04296890], phase 3 MIRASOL [NCT04209855]) that evaluated participants with FRα-expressing recurrent EOC who received ≥1 dose of MIRV 6 mg/kg adjusted ideal body weight every 3 weeks. RESULTS: In this analysis of 682 participants, 94 % had platinum-resistant ovarian cancer (PROC). Blurred vision (43 %), nausea (41 %), diarrhea (39 %), and fatigue (35 %) were the most common treatment-emergent adverse events (TEAEs) and were primarily grade 1-2 in severity. Grade ≥ 3 TEAEs occurred in 48 % of participants, with the most common being keratopathy and blurred vision (5 % each). Most TEAEs were managed with supportive care and dose modifications, and only 12 % of participants experienced a TEAE leading to discontinuation (1 % due to ocular events). No corneal ulcerations or perforations have been reported. Median time to onset of blurred vision and keratopathy was 5.9 and 6.7 weeks, respectively. Most blurred vision events and keratopathy events resolved completely (71 % and 66 %, respectively) or partially (15 % and 14 %, respectively). CONCLUSIONS: As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

Sentinel lymph node pathological ultrastaging: Final outcome of the Sentix prospective international study in patients with early-stage cervical cancer.

OBJECTIVE: To report the outcome of SLN staging in the SENTIX international prospective trial of SLN biopsy in patients with cervical cancer with an intensive ultrastaging protocol and central quality control and to evaluate how the intensity of pathological assessment correlates with metastatic detection rate in SLNs. METHODS: Eligible were patients with stages T1a1/LVSI+ to T1b2 (<4 cm, ≤2 cm for fertility sparing), common tumor types, no suspicious lymph nodes on imaging, and bilateral SLN detection. SLNs were examined intraoperatively and processed by an intensive protocol for ultrastaging (paraffin blocks sectioned completely in 150-µm intervals/levels). SLNs from each site were submitted for central quality control. RESULTS: In the SENTIX SLN study, 647 out of 733 enrolled patients underwent SLN ultrastaging, identifying 12.5% (81/647) with node positive, N1 cases. Intraoperative detection revealed metastases in 56.8% (46/81) of these cases, categorized into macrometastases (83.7%), micrometastases (26.3%), and isolated tumor cells (9.1%). Ultrastaging identified additional metastatic involvement in 43.2% (35/81) of patients, with detailed sectioning revealing metastases (MAC/MIC) at first level in 20 cases (24.7%), at levels 2-4 in 9 cases (11.1%), and at level ≥5 in 6 cases (7.4%). CONCLUSION: SLN ultrastaging detects additional 43% of N1 (MAC/MIC) in patients with negative LNs by imaging and intraoperative pathological assessment. The detection rate of positive SLN correlates with the intensity (number of levels) of ultrastaging. Examination of four levels from paraffin blocks, which detects >90% of patients with N1, is a reasonable compromise for an international standard for ultrastaging. STUDY REGISTRATION: NCT02494063 (ClinicalTrials.gov).

Long-term follow-up of efficacy and safety of selinexor maintenance treatment in patients with TP53wt advanced or recurrent endometrial cancer: A subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study.

OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

Maintenance with mirvetuximab soravtansine plus bevacizumab vs bevacizumab in FRα-high platinum-sensitive ovarian cancer.

At first recurrence, platinum-sensitive ovarian cancer (PSOC) is frequently treated with platinum-based chemotherapy doublets plus bevacizumab, then single-agent bevacizumab. Most patients' disease progresses within a year after chemotherapy, emphasizing the need for novel strategies. Mirvetuximab soravtansine-gynx (MIRV), an antibody-drug conjugate, comprises a folate receptor alpha (FRα)-binding antibody and tubulin-targeting payload (maytansinoid DM4). In FRα-high PSOC, MIRV plus bevacizumab previously showed promising efficacy (objective response rate, 69% [95% CI: 41-89]; median progression-free survival, 13.3 months [95% CI: 8.3-18.3]; median duration of response, 12.9 months [95% CI: 6.5-15.7]) and safety. The Phase III randomized GLORIOSA trial will evaluate MIRV plus bevacizumab vs. bevacizumab alone as maintenance therapy in patients with FRα-high PSOC who did not have disease progression following second-line platinum-based doublet chemotherapy plus bevacizumab.Clinical Trial Registration: ClinicalTrials.gov ID: NCT05445778; GOG.org ID: GOG-3078; ENGOT.ESGO.org ID: ENGOT-ov76.

Most patients with ovarian cancer are initially treated with platinum-based chemotherapy. If the cancer reappears/recurs after more than 6 months following this therapy, it is called platinum-sensitive ovarian cancer (PSOC). Patients with PSOC usually receive additional platinum-based chemotherapy along with bevacizumab, a drug that reduces tumor growth by decreasing its blood supply. If patients improve or are stable on this therapy, they are usually kept on bevacizumab alone for 'maintenance therapy'. Unfortunately, this maintenance therapy does not work long-term in all patients, so better long-term treatments are needed. The GLORIOSA (NCT05445778) clinical trial will compare maintenance therapy with bevacizumab alone to maintenance therapy with bevacizumab plus a drug called mirvetuximab soravtansine-gynx (MIRV) to determine which therapy leads to better results in patients with PSOC. MIRV is made up of an antibody that binds to a specific protein (folate receptor alpha [FRα]) on cancer cells to directly deliver a cancer-killing drug. MIRV received US FDA approval to be used as a therapy for patients with ovarian cancer who are resistant to platinum-based chemotherapy and express high levels of FRα. The GLORIOSA trial will study maintenance therapy with MIRV plus bevacizumab in patients with PSOC who have not had cancer progression after second-line platinum-based chemotherapy plus bevacizumab, and whose cancer expresses high amounts of FRα. The main purpose of this trial is to determine if MIRV plus bevacizumab leads to better patient survival and decreases cancer growth and spread when compared with bevacizumab alone.

A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial.

BACKGROUND: Low-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often treated with conventional chemotherapy, although response rates are disappointing. PRIMARY OBJECTIVE: To determine the overall response rate of the combination therapy of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancers. STUDY HYPOTHESIS: The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%. TRIAL DESIGN: This is a phase II, international, multicenter, open-label, single-arm study to evaluate the efficacy and safety of abemaciclib and letrozole in patients with advanced, recurrent, and/or metastatic estrogen receptor-positive, rare ovarian cancer. The study will follow a tandem two-stage design. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients must have histologically confirmed low-grade serous/endometrioid ovarian cancer or adult-type granulosa cell tumor with estrogen receptor positivity on immunohistochemistry. Patients need to have recurrent and measurable disease according to Radiologic Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A maximum of two prior lines of endocrine therapy are allowed, and patients cannot have previously received a cyclin-dependent kinase inhibitor. Patients with platinum-refractory disease are not allowed in any stage of the study. PRIMARY ENDPOINT: Investigator-assessed confirmed overall response rate, defined as the proportion of patients with a complete or partial response according to RECIST v1.1. SAMPLE SIZE: 40 to 100 patients will be included, depending on the results of the interim analysis. Patients will be included in Belgium, France and the Netherlands. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed by the end of 2025 and reporting of the final study results will be done by the end of 2027. TRIAL REGISTRATION NUMBER: NCT05872204.

Mirvetuximab soravtansine-gynx: first antibody/antigen-drug conjugate (ADC) in advanced or recurrent ovarian cancer.

Mirvetuximab soravtansine-gynx (MIRV) is a conjugate of a folate receptor alpha (FRα)-directed antibody and the maytansinoid microtubule inhibitor, DM4. Accumulating pre-clinical and clinical data supported the safety and anti-tumor activity of MIRV in tumors expressing FRα. In 2017, a phase I expansion study reported the first experience of MIRV in FRα-positive platinum-resistant ovarian cancer with promising results. However, the phase III FORWARD I study failed to demonstrate a significant benefit of MIRV in FRα-positive tumors. On the basis of the data reported from this latter study, MIRV was then explored in the FRα-high population only and using a different folate receptor assay. The phase II SORAYA trial supported the adoption of MIRV in this setting. Hence, the US Food and Drug Administration granted accelerated approval of MIRV for patients with FRα-positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. Moreover, the results of the MIRASOL trial showed a significant reduction in the risk of tumor progression or death among patients treated with MIRV versus chemotherapy. VENTANA FOLR1 (FOLR-2.1) was approved as a companion diagnostic test to identify FRα patients. MIRV appears to be a significant asset in managing advanced or recurrent ovarian cancer. Further trials are needed to confirm these promising results, even in the neoadjuvant, adjuvant, and maintenance settings.

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.

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer.

OBJECTIVES: Maintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe, a Delphi study was conducted among European experts to understand the heterogeneity of clinical practice and identify key factors driving maintenance treatment decisions for advanced ovarian cancer. METHODS: A pragmatic literature review was conducted to identify key questions regarding maintenance treatment strategies in patients with advanced ovarian cancer. Utilizing a Delphi methodology, consensus was assessed among a panel of 16 experts using a questionnaire based on results of the pragmatic literature review. RESULTS: Panelists agreed that BRCA mutation and homologous recombination status should be assessed in parallel at diagnosis, and that first-line platinum chemotherapy may be initiated concurrently. There was a consensus that alternative homologous recombination deficiency tests are acceptable provided they are clinically validated. Panelists agreed that Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 elimination rate constant K (KELIM) scores can help assess tumor chemosensitivity and guide treatment-related decisions. Panelists defined high-risk disease as International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or stage III with residual disease after initial/interval cytoreduction. Risk of disease progression was a key determinant of choice between PARP inhibitor, bevacizumab, or both in combination, as maintenance therapy in advanced ovarian cancer. CONCLUSIONS: Key drivers for selecting advanced ovarian cancer maintenance treatments include tumor mutational status as a key biomarker and clinician perception of the risk for early disease progression.

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.

BACKGROUND: Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and individualized treatment that could impact patient outcomes. In an exploratory analysis of the phase III ENGOT-EN5/GOG-3055/SIENDO study of selinexor maintenance monotherapy 80 mg in advanced/recurrent endometrial cancer, a pre-specified subgroup of patients with TP53 wild type (wt) endometrial cancer showed preliminary activity at long-term follow-up with a generally manageable safety profile (median progression-free survival 27.4 months vs 5.2 months placebo, HR=0.41). PRIMARY OBJECTIVE: To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. STUDY HYPOTHESIS: Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with TP53wt advanced/recurrent endometrial cancer after systemic therapy versus placebo. TRIAL DESIGN: 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 TP53wt endometrial cancer. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have histologically confirmed endometrial cancer, TP53wt confirmed by next-generation sequencing, completed at least 12 weeks of platinum-based therapy with or without immunotherapy, with confirmed partial response or complete response, and primary Stage IV disease or at first relapse. PRIMARY ENDPOINT: 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. SAMPLE SIZE: A total of 220 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: NCT05611931.

Association of the Single Nucleotide Polymorphisms rs11556218, rs4778889, rs4072111, and rs1131445 of the Interleukin-16 Gene with Ovarian Cancer.

Single nucleotide polymorphisms (SNPs) of the IL-16 gene have been reported to influence the risk of several cancers, but their role in ovarian cancer (OC) has not been studied. Using the restriction fragment length polymorphism (PCR-RFLP) method, we examined four IL-16 SNPs: rs11556218 (T > G), rs4778889 (T > C), rs4072111 (C > T), and rs1131445 (T > C) in blood samples from 413 women of Central European descent, including 200 OC patients and 213 healthy controls. Among the patients, 62% were postmenopausal, 84.5% were diagnosed in late stages (FIGO IIb-IV), and 73.5% had high-grade serous OC (HGSOC). Minor allele frequencies in controls were 9.2% for rs11556218 (G allele), 13.7% for rs4778889 (C allele), 10.4% for rs4072111 (T allele), and 32.3% for rs1131445 (C allele). We found significant associations of rs11556218 (G vs. T allele: OR 2.76, 95% CI 1.84-4.14, p < 0.0001) with elevated OC risk in the whole cohort (p < 0.001) and in both premenopausal (p < 0.001) and postmenopausal (p = 0.001) subgroups. These associations remained significant across heterozygote (p < 0.001), dominant (p < 0.001), and overdominant (p < 0.001) models. IL-16 rs4778889 was associated with OC risk predominantly in premenopausal women (p < 0.0001 in almost all models). In the whole cohort, the C allele was associated with OC risk (OR 1.54, CI 95% 1.06-2.23, p = 0.024), and the association of rs4778889 was significant in dominant (p = 0.019), overdominant (p = 0.033), and heterozygote (p = 0.027) models. Furthermore, rs4778889 was linked with HGSOC (p = 0.036) and endometriosis-related OC subtypes (p = 0.002). No significant associations were found for rs4072111 or rs1131445 (p = 0.81 or 0.47, respectively). In conclusion, rs11556218 and rs4778889 SNPs are associated with OC risk, especially in premenopausal women.

Lifestyle and personal factors associated with having macroscopic residual disease after ovarian cancer primary cytoreductive surgery.

OBJECTIVE: The presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery. METHODS: This analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS. RESULTS: Menopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53). CONCLUSIONS: The association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.

Predicting resectable disease in relapsed epithelial ovarian cancer by using whole-body diffusion-weighted MRI.

OBJECTIVE: To determine the diagnostic value of whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to predict resectable disease at the time of secondary cytoreductive surgery for relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months. METHODS: A retrospective cohort study between January 2012 and December 2021 in a tertiary referral hospital. Inclusion criteria were: (a) first recurrence of epithelial ovarian cancer; (b) platinum-free interval of ≥6 months; (c) intent to perform secondary cytoreductive surgery with complete macroscopic resection; and (d) WB-DWI/MRI was performed.Diagnostic tests of WB-DWI/MRI for predicting complete resection during secondary cytoreductive surgery are calculated as well as the progression-free and overall survival of the patients with a WB-DWI/MRI scan that showed resectable disease or not. RESULTS: In total, 238 patients could be identified, of whom 123 (51.7%) underwent secondary cytoreductive surgery. WB-DWI/MRI predicted resectable disease with a sensitivity of 93.6% (95% confidence interval [CI] 87.3% to 96.9%), specificity of 93.0% (95% CI 87.3% to 96.3%), and an accuracy of 93.3% (95% CI 89.3% to 96.1%). The positive predictive value was 91.9% (95% CI 85.3% to 95.7%).Prediction of resectable disease by WB-DWI/MRI correlated with improved progression-free survival (median 19 months vs 9 months; hazard ratio [HR] for progression 0.36; 95% CI 0.26 to 0.50) and overall survival (median 75 months vs 28 months; HR for death 0.33; 95% CI 0.23 to 0.47). CONCLUSION: WB-DWI/MRI accurately predicts resectable disease in patients with a platinum-free interval of ≥6 months at the time of secondary cytoreductive surgery and could be of complementary value to the currently used models.

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer.

OBJECTIVE: Comparison of olaparib (OLA) monotherapy versus chemotherapy in patients with platinum-sensitive (PSOC) or platinum-resistant ovarian cancer (PROC). METHODS: Patients with measurable disease and ≥ 1 prior line of chemotherapy (CT) were randomized 2:1 to OLA (300 mg tablets, BID) or physician's choice CT.: for PSOC: Carboplatin-Pegylated-Liposomal-Doxorubicin (PLD) or Carboplatin-Gemcitabine; for PROC: PLD, Topotecan, Paclitaxel or Gemcitabine. RESULTS: 160 patients (60 with PSOC and 100 with PROC) were randomized 2:1 to OLA (n = 107) or CT (n = 53). Baseline characteristics were similar between both arms. Overall objective response rate (ORR) for OLA and CT were similar (24.3% (26/107) and 28.3% (15/53), respectively). Clinical benefit rate (≥ 12 weeks) was similar with 54.2% (58/107) and 56.6% (30/53), respectively. In PSOC, ORR was 35.0% (14/40) and 65.0% (13/20) for OLA and CT (p = 0.053); in PROC, ORR was 17.9% (12/67) and 6.1% (2/33) for OLA and CT (p = 0.134). ORR in heavily pretreated PROC (>4 prior lines) was 22.9% (8/35) with OLA versus 0% (0/14) for CT. ORR of 35.7% (5/14) and 13.2% (7/53) was observed in BRCA-mutated and -wildtype PROC cases, respectively. Median PFS in PROC was not significantly different with 2.9 months (95% CI 2.8-5.1 in the OLA group versus 3.8 months (95% CI 3.0-6.4) in the CT group (hazard ratio [HR] 1.11 [95% CI 0.72-1.78]; log-rank p = 0.600). CONCLUSION: OLA monotherapy showed overall an equal response rate in relapsed ovarian cancer compared with CT. In PROC, ORR and TFST tended to be higher with OLA than with CT. In heavily pretreated patients (four lines or more) with PROC disease, OLA treatment seemed to be more effective than CT.

Prospective non-interventional BELOVA/BGOG-ov16 study on safety of frontline bevacizumab in elderly patients with FIGO stage IV ovarian cancer: a study of the Belgian and Luxembourg Gynaecological Oncology Group.

OBJECTIVE: Because elderly patients with ovarian cancer are underrepresented in randomized studies, this study aimed to expand our knowledge on the safety and effectiveness of frontline treatment with bevacizumab in combination with standard carboplatin and paclitaxel chemotherapy in patients aged 70 years and older with a diagnosis of Federation of Gynecology and Obstetrics (FIGO) stage IV ovarian cancer in routine clinical practice in Belgium. METHODS: Patients aged 70 years and older with FIGO stage IV ovarian cancer were included in a multicenter, non-interventional prospective studyto evaluate the safety and effectiveness of treatment with bevacizumab in combination with frontline carboplatin and paclitaxel chemotherapy. Comprehensive geriatric assessments were performed at baseline and during treatment. RESULTS: The most frequently reported adverse events for bevacizumab were hypertension (55%), epistaxis (32%) and proteinuria (21%). The Kaplan-Meier estimate of progression-free survival was 14.5 months. The results of the comprehensive geriatric assessments during treatment indicated a slight improvement in the geriatric eight health status screening tool score for general health status and the mini-nutritional assessment score for nutritional status. The median change from baseline score was close to zero for the instruments measuring independency, activity of daily living and instrumental activities of daily living, and for the mobility-tiredness test measuring self-perceived fatigue. CONCLUSIONS: No new safety signals were registered in this study in patients aged 70 years and older treated with bevacizumab and frontline carboplatin and paclitaxel for FIGO stage IV ovarian cancer. Elderly patients should not be excluded from treatment for advanced ovarian cancer based on age alone. EU PAS REGISTER: ENCEPP/SDPP/13849. CLINICALTRIALSGOV IDENTIFIER: NCT02393898.

TRP channel expression correlates with the epithelial-mesenchymal transition and high-risk endometrial carcinoma.

Transient receptor potential (TRP) channels excel in cellular sensing as they allow rapid ion influx across the plasma membrane in response to a variety of extracellular cues. Recently, a distinct TRP mRNA expression signature was observed in stromal cells (ESC) and epithelial cells (EEC) of the endometrium, a tissue in which cell phenotypic plasticity is essential for normal functioning. However, it is unknown whether TRP channel mRNA expression is subject to the phenotypic switching that occurs during epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), and whether TRP channel mRNA expression is associated with aggressive phenotypes in endometrial cancer (EC). Here, we induced EMT and MET in vitro using in primary EEC and ESC, respectively, and analyzed expression and functionality of TRP channels using RT-qPCR and intracellular Ca2+ imaging. The outcome of these experiments showed a strong association between TRPV2 and TRPC1 mRNA expression and the mesenchymal phenotype, whereas TRPM4 mRNA expression correlated with the epithelial phenotype. In line herewith, increased TRPV2 and TRPC1 mRNA expression levels were observed in both primary and metastatic EC biopsies and in primary EC cells with a high EMT status, indicating an association with an aggressive tumor phenotype. Remarkably, TRPV2 mRNA expression in primary EC biopsies was associated with tumor invasiveness and cancer stage. In contrast, increased TRPM4 mRNA expression was observed in EC biopsies with a low EMT status and less aggressive tumor phenotypes. Taken together, this dataset proved for the first time that TRP channel mRNA expression is strongly linked to cellular phenotypes of the endometrium, and that phenotypic transitions caused by either experimental manipulation or malignancy could alter this expression in a predictable manner. These results implicate that TRP channels are viable biomarkers to identify high-risk EC, and potential targets for EC treatment.

Radical hysterectomy without adjuvant radiotherapy in patients with cervix carcinoma FIGO 2009 IB1, with or without positive Sedlis criteria.

INTRODUCTION: Lymphovascular space invasion (LVSI), deep (>1/3) stromal invasion (DSI) and large tumor size (>4 cm) have been identified as predictors for intermediate risk for recurrence according to Sedlis (at least two of the prior risk factors) in FIGO stage I cervical cancer. Adjuvant radiotherapy (RT) has been advocated in these patients(1,2), but remains controversial. METHOD: All consecutive patients (1997-2017) with cervical cancer FIGO (2009) stage IB1 (≤4 cm) were included. Primary aim was to analyze the recurrence rate. Secondary aim was to identify the risk factors for disease recurrence and survival. RESULTS: One-hundred-and-eighty-two patients were included in this retrospective study. Median follow-up was 13 years (range 8-17). Postoperatively, 21 patients received adjuvant therapy due to presence of positive lymph nodes, positive section margins or if a simple hysterectomy was performed (RT: n = 7, concomitant chemo radiotherapy (CCRT): n = 14). None of the patients with a combination of intermediate risk factors according to Sedlis (excluding patients >4 cm) underwent adjuvant RT/CCRT. Disease recurrence was observed in 19 patients (10%). Eleven patients died of disease. LVSI influenced progression-free survival (PFS) (HR 3.950, p = 0.0163) and disease-specific survival (DSS) (HR 4.637, p = 0.0497) significantly. However, the combination of LVSI, tumor size and DSI according to Sedlis did not influence overall survival (OS), DSS or PFS. CONCLUSION: Recurrence rate was low (10%), despite the fact that patients with intermediate risk factors according to Sedlis did not receive postoperative RT/CCRT. LVSI was the sole risk factor influencing PFS and DSS. Combinations of risk factors according to Sedlis did not predict worse outcome.