PURPOSE: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression. The pivotal, phase 3 ENGOT-ov50/GOG-3029/INNOVATE-3 study evaluated efficacy and safety of TTFields therapy with paclitaxel (PTX) vs PTX in patients with platinum-resistant ovarian cancer (PROC). PATIENTS AND METHODS: Adult patients with PROC with ≤ 5 total prior lines of therapy (LOT), including ≤ 2 prior LOT for platinum-resistant disease, and ECOG PS of 0-1 were randomized 1:1 to receive TTFields (200 kHz; ≥ 18 h/day) + PTX (80 mg/m2 weekly) or PTX. Primary endpoint was overall survival (OS). Exploratory post-hoc analyses assessed OS in pegylated liposomal doxorubicin (PLD)-naive patients. RESULTS: Between March 2019 and November 2021, 558 patients (ECOG PS 0, 60.2 %; median [range] age, 62 [22-91] years) were assigned TTFields+PTX (n = 280) or PTX (n = 278). 24.4 % had 4 + prior LOT. Median OS was 12.2 months with TTFields+PTX vs 11.9 months with PTX (HR, 1.01; 95 % CI, 0.83-1.24; p = 0.89). Grade ≥ 3 adverse events (AEs) were similar between treatment groups. Grade 1/2 device-related skin AEs occurred in 83.6 % of patients receiving TTFields therapy. In exploratory post-hoc analysis in PLD-naive patients, median OS was 16 months with TTFields+PTX (n = 113) vs 11.7 months with PTX (n = 88; nominal HR, 0.67; 95 % CI, 0.49-0.94; p = 0.03). CONCLUSIONS: No new safety signals were identified. TTFields+PTX did not significantly improve OS compared with PTX in the intent-to-treat population. An exploratory post-hoc analysis suggests a potentially favorable benefit-risk profile for TTFields therapy in PLD-naive patients.
- MeSH
- chemorezistence * MeSH
- dospělí MeSH
- elektrostimulační terapie metody škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory vaječníků * farmakoterapie terapie mortalita patologie MeSH
- paclitaxel * terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
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.
- MeSH
- dvojitá slepá metoda MeSH
- hydraziny * aplikace a dávkování terapeutické užití MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- lokální recidiva nádoru * farmakoterapie patologie MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory endometria * farmakoterapie patologie MeSH
- triazoly * aplikace a dávkování MeSH
- udržovací chemoterapie metody MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- protokol klinické studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. METHODS: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. RESULTS: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. CONCLUSIONS: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.).
- MeSH
- analýza přežití MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * terapeutické užití MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru * farmakoterapie MeSH
- nádory děložního čípku * farmakoterapie mortalita patologie MeSH
- oligopeptidy * terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
PURPOSE: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS: Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION: The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.
- MeSH
- dvojitá slepá metoda MeSH
- hydraziny * škodlivé účinky MeSH
- lidé MeSH
- nádory endometria * farmakoterapie MeSH
- prospektivní studie MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- triazoly škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.
- MeSH
- anemie * farmakoterapie MeSH
- bevacizumab škodlivé účinky MeSH
- karboplatina škodlivé účinky MeSH
- lidé MeSH
- lokální recidiva nádoru etiologie MeSH
- nádory děložního čípku * farmakoterapie MeSH
- nádory plic * farmakoterapie MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- multicentrická studie MeSH
INTRODUCTION: Recurrent or primary advanced metastatic cervical cancer (R/M CC) has a poor prognosis with a 5-year-survival rate of 16.5%, demanding novel and improved therapies for the treatment of these patients. The first-line standard of care for R/M CC now benefits from the addition of the immune checkpoint inhibitor, pembrolizumab, to platinum-based chemotherapy with paclitaxel and bevacizumab. Additionally, new options for second-line treatment have become available in recent years. AREAS COVERED: Here, we review current investigational drugs and discuss their relative targets, efficacies, and potential within the R/M CC treatment landscape. This review will focus on recently published data and key ongoing clinical trials in patients with R/M CC, covering multiple modes of action, including immunotherapies, antibody-drug conjugates, and tyrosine kinase inhibitors. We searched clinicaltrials.gov for ongoing trials and pubmed.ncbi.nih.gov for recently published trial data, as well as recent years' proceedings from the annual conferences of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO), and the International Gynecologic Cancer Society (IGCS). EXPERT OPINION: Therapeutics currently attracting attention include novel immune checkpoint inhibitors, therapeutic vaccinations, antibody-drug conjugates, such as tisotumab vedotin, tyrosine kinase inhibitors targeting HER2, and multitarget synergistic combinations.
- MeSH
- diagnostické techniky porodnicko-gynekologické MeSH
- epiteliální ovariální karcinom diagnostické zobrazování patologie prevence a kontrola MeSH
- lidé MeSH
- nádory vaječníků * diagnostické zobrazování patologie prevence a kontrola MeSH
- plošný screening MeSH
- senzitivita a specificita MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
