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.

BACKGROUND:Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. METHODS:ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

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.).

Introduction/Background Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to tissue factor. In the US, TV monotherapy received accelerated approval for the treatment of adult patients with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. Here, innovaTV 301 (NCT04697628) study results are presented. Methodology Eligible patients had r/mCC with disease progression on/after treatment with standard of care chemotherapy doublet ± bevacizumab ± anti-PD-(L)1 therapy, measurable disease per RECIST v1.1, and ECOG PS 0–1. Patients were randomized 1:1 to TV monotherapy or investigator's choice of topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed. The primary endpoint was OS. Key secondary endpoints included PFS and confirmed ORR by investigator. Results 502 patients were randomized (TV: 253; chemotherapy: 249); median survival follow-up was 10.8 months (95% CI, 10.3–11.6). Arms were balanced for demographics and disease characteristics, with 63.9% and 27.5% of patients receiving prior bevacizumab and prior anti-PD-(L)1 therapy, respectively. The TV arm had a 30% reduction in risk of death versus chemotherapy (HR 0.70; 95% CI 0.54–0.89; P=0.0038), with significantly longer median OS (11.5 months [95% CI 9.8–14.9] versus 9.5 months [95% CI 7.9–10.7]). PFS was superior in the TV versus chemotherapy arm (HR: 0.67 [95% CI, 0.54–0.82]; P<0.0001). The OS and PFS benefits in the prespecified subgroups were generally consistent with the ITT population. Confirmed ORR was 17.8% and 5.2% in the TV and chemotherapy arms, respectively (odds ratio: 4.0; 95% CI, 2.1–7.6; P<0.0001). Most patients experienced ≥1 treatment-related adverse event (TV: 87.6% [grade ≥3: 29.2%] versus chemotherapy: 85.4% [grade ≥3: 45.2%]). AEs were consistent with the known TV safety profile. Conclusion In the phase 3 innovaTV 301 study, TV showed a statistically significant and clinically meaningful improvement in OS, PFS, and ORR versus chemotherapy, with a manageable and tolerable safety profile in patients with 2L/3L r/mCC. Disclosures Previously presented in part at ESMO 2023, 'LBA9: innovaTV 301/ENGOT-cx12/GOG-3057: A Global, Randomized, Open-Label, Phase 3 Study of Tisotumab Vedotin vs Investigator's Choice of Chemotherapy in 2L or 3L Recurrent or Metastatic Cervical Cancer ', Ignace Vergote et al. - Reused with permission.

Tisotumab vedotin (TV) is an investigational antibody-drug conjugate composed of a tissue factor-directed human monoclonal antibody covalently linked to cytotoxic MMAE. In the US, TV monotherapy received accelerated approval for the treatment of adult pts with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. Here, innovaTV 301 (NCT04697628) study results of TV vs investigator’s choice of chemotherapy in pts with r/mCC following 1L therapy are presented.

Introduction/Background Single agent chemotherapies are commonly used in platinum-resistant ovarian cancer, but outcomes are generally poor. Cortisol, which acts by binding to the glucocorticoid receptor (GR), can suppress apoptotic pathways used by cytotoxic agents. The GR is abundantly expressed in ovarian tumours and high GR expression is associated with poor outcomes. Data indicate that the selective GR modulator relacorilant can reverse cortisol's anti-apoptotic effects, thereby enhancing chemotherapy efficacy. In a phase 2 study in patients with recurrent, platinum-refractory or platinum-resistant ovarian cancer, intermittently dosed relacorilant + nab-paclitaxel showed clinically meaningful improvement in progression-free survival (PFS), duration of response (DoR), and a trend toward improved overall survival (OS) without increased side effect burden compared to nab-paclitaxel monotherapy. This phase 3 study aims to confirm the findings of the phase 2 study in a larger patient population. Methodology ROSELLA (GOG-3073, ENGOT-Ov72/MITO, NCT05257408) is a randomised, phase 3, 2-arm, open-label study of relacorilant + nab-paclitaxel vs nab-paclitaxel monotherapy. Women with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer who have received 1–3 lines of prior systemic anticancer therapy, including prior bevacizumab, and at least 1 line of platinum-based therapy are being enrolled. Patients with primary platinum-refractory disease are excluded from the trial. Approximately 360 patients are being randomised 1:1 to relacorilant (150 mg the day before, of, and after nab paclitaxel infusion) + nab-paclitaxel (80 mg/m2) or nab paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel is administered on days 1, 8, and 15 of each 28-day cycle. Stratification factors are prior lines of therapy (1 vs >1) and region of world (North America vs. Europe vs. rest of world). Results The primary endpoint is PFS assessed by blinded independent central review. Key secondary endpoints include OS, PFS by investigator assessment, objective response rate, best overall response, DoR, safety, pharmacokinetics, pharmacodynamics, patient-reported outcomes, and quality of life. Conclusion N/A Disclosures DL reports receipt of grants/research supports from Clovis Oncology, GSK, MSD, PharmaMa, AstraZeneca, genmab, Immunogen, Incyte, Roche, Seagen, and Novartis; receipt of honoraria or consultation fees from Clovis Oncology, GSK, MSD, PharmaMa, AstraZeneca, genmab, Immunogen, Seagen, Novartis, Oncoinvest, Corcept, and Sutro; participation in a company sponsored speaker's bureau for Seagen, Immunogen, Genmab,AstraZzeneca, Clovis Oncology, GSK, MSD and PharmaMar; and travel expenses from AstraZeneca, Clovis Oncology, GSK. AB reports receipt of honoraria or consultation fees from Astra-Zeneca. LG reports receipt of honoraria or consultation fees from, and participation in a company sponsored speaker's bureau for Astra-Zeneca, GSK, MSD, and Esai. LM reports receipt of funding for investigator-initiated trial from BeiGene. BJM reports honoraria for serving as a consultant to Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna Health Care, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieres, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, Verastem, and Zentalis; and reports honoraria for speaker/consultant roles for AstraZeneca, Clovis, Esai, Merck, Roche/Genentech, and Tesaro/GSK. SN reports receipt of grants/research from AstraZeneca and GSK; receipt of honoraria or consultation fees from AstraZeneca, GSK, Clovis, and MSD; participation in a company sponsored speaker's bureau for AstraZeneca and GSK; and spouse/partner shared with AstraZeneca and GSK. AN-R reports receipt of honoraria or consultation fees from AZ, Roche, Daiichi, Eisai, MSD, Pfizer and Libbs; and participation in a company sponsored speaker's bureau for AZ, Roche, Daiichi, Eisai, MSD, Pfizer, Libbs, and Gilead. AO reports receipt of honoraria or consultation fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, and F. Hoffmann-La Roche; and travel and accommodation from Astra Zeneca, PharmMar, and Roche. DO'M reports institution received funds for research from Abbvie, Advaxis, Agenus Inc, Alkermes, Aravive, Inc, Arcus Biosciences, AstraZeneca, BeiGene USA Inc., Boston Biomedical, Bristol Meyers Scribb, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serano, Inc., Exelixis, Genentech, Inc., Genmab, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche Inc.,ImmunoGen, Inc., Incyte Corporation, IOVANCE Biotherapeutics, Karyopharm, Leap Therapeutics, Inc., Ludwig Institute for Ca, Merck & Co, Merck Sharpe & Dohme Corp, Mersana Therapeutics, Inc, NCI, Novartis, NovoCure, NRG Oncology, OncoC4, Inc., OncoQuest Inc., Pfizer Inc., Precision Therapeutics, Inc., Prelude Therapeutics, Regeneron Pharmaceuticals, Inc., RTOG, Rubius Therapeutics, Seattle Genetics (SeaGen), Sutro Biopharma, SWOG, TESARO, and Verastem, Inc.; and reports receipt of personal fees for consultation and/or advisory boards from Abbvie, AdaptImmune, Agenus, Inc., Arquer Biosciences, Inc., AstraZeneca, Atossa Therapeutics, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis Oncology, Corcept Therapeutics, Duality Bio, Eisai, Elevar, Exelixix, Genentech Inc., Genulux, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche Inc., ImmunoGen, Inc., Imvax, InterVenn, INXMED, IOVANCE Biotherapeutics, Janssen, Jazz Pharmaceuticals, Laekna, Leap Therapeutics, Luzsana Biotechnology, Merck & Co, Merck Sharpe & Dohme Corp., Mesana Therapeutics, Inc., Myriad, Novartis, NovoCure, OncoC4, Inc., Onconova, Regeneron Pharmaceuticals, Inc., RepImmune, R Pharm, Roche Diagnostics, Seattle Genetics (SeaGen), Sorrento, Sutro Biopharma, Tarveda Therapeutics, Toray, Trillium, Umoja, Verstem, Inc., VBL Therapeutics, Vincerx Pharma, Xencor, and Zentalis. LD reports Corcept stock/stock options. ABO reports receipt of grants/research support from Corcept and AstraZeneca; and receipt of honoraria or consultation fees from AZ, GSK, Merck, and Genentech. EB, AC-G, AD, MEG, J-WK, JK, MEMcC, MO, ICT and X have no potential conflicts of interest to report.

Introduction Single-agent chemotherapies are commonly used in platinum-resistant ovarian cancer (OC), but outcomes are generally poor. Cortisol, which binds to the glucocorticoid receptor (GR), can suppress apoptotic pathways used by chemotherapy. The selective GR modulator relacorilant may reverse cortisol's anti-apoptotic effects to enhance chemotherapy efficacy. In a phase 2 study in patients with recurrent, platinum-refractory/resistant OC (NCT03776812), intermittently dosed relacorilant + nab-paclitaxel showed clinically meaningful improvement in progression-free survival (PFS), duration of response (DoR), and overall survival (OS) without increased side effect burden vs. nab-paclitaxel monotherapy. The ROSELLA study aims to confirm these findings in a larger patient population. Methods ROSELLA (NCT05257408) is a randomized, phase 3, 2-arm, open-label study of relacorilant + nab-paclitaxel vs. nab-paclitaxel monotherapy. Approximately 360 women with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer who have received 1–3 prior systemic anticancer therapies, including prior bevacizumab, and ≥1 platinum-based therapy are being enrolled. Patients with primary platinum-refractory disease are excluded. Patients are being randomized 1:1 to relacorilant (150 mg the day before, of, and after nab-paclitaxel) + nab-paclitaxel (80 mg/m2) or nab-paclitaxel monotherapy (100 mg/m2); stratified by prior lines of therapy (1 vs >1) and region of world (North America vs. Europe vs. rest of world). Nab-paclitaxel is administered on days 1, 8, and 15 of each 28-day cycle. The primary endpoint is PFS by blinded independent central review. Key secondary and exploratory endpoints include OS, PFS by investigator assessment, objective response rate, best overall response, DoR, safety, pharmacokinetics, pharmacodynamics, patient-reported outcomes, and quality of life. Current Trial Status Currently enrolling

PURPOSE Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte-associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1-positive and programmed death ligand-1-negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte-associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing. (C) 2021 by American Society of Clinical Oncology