Search

Background: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan., Methods: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR)., Results: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively., Discussion: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To evaluate tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) as second- or third-line therapy for PD-L1-positive persistent/recurrent cervical cancer., Methods: In the open-label, non-comparative, randomized phase II SKYSCRAPER-04 trial (NCT04300647), patients with PD-L1-positive (SP263 tumor area positivity ≥5%) recurrent/persistent cervical cancer after 1-2 chemotherapy lines (≥1 platinum-based) were randomized 3:1 to atezolizumab 1200 mg with/without tiragolumab 600 mg every 3 weeks until disease progression or unacceptable toxicity. Stratification factors were performance status, prior (chemo)radiotherapy, and disease status. The primary endpoint was independent review committee-assessed confirmed objective response rate per RECIST v1.1 in patients receiving tiragolumab plus atezolizumab. An objective response rate ≥21% (one-sample z-test p≤0.0245) was required for statistical significance versus a historical reference., Results: Protocol-defined independent review committee-assessed objective response rates were 19.0% (95% CI 12.6 to 27.0) in 126 patients receiving tiragolumab plus atezolizumab (p=0.0787 vs historical reference) and 15.6% (95% CI 6.5 to 29.5) in 45 atezolizumab-treated patients. Response rates were higher in PD-L1 high (tumor area positivity ≥10%) than PD-L1 low (tumor area positivity 5%-9%) subgroups with both regimens. At 8.5 months' median follow-up, independent review committee-assessed progression-free survival was 2.8 months (95% CI 1.7 to 4.1) with tiragolumab plus atezolizumab and 1.9 months (95% CI 1.5 to 3.0) with atezolizumab. In post hoc analyses (10.4 months' median follow-up), median overall survival was 11.1 months (95% CI 9.6 to 14.5) with the combination and 10.6 months (95% CI 6.9 to 13.8) with atezolizumab (crossover permitted). In the combination group, 3% of patients had adverse events requiring treatment discontinuation and 8% had grade ≥3 adverse events of special interest; corresponding values in the single-agent arm were 4% and 11%. There were no treatment-related deaths or new safety findings., Conclusion: The objective response rate with the tiragolumab-plus-atezolizumab combination was numerically higher than the historical reference but did not reach statistical significance., Competing Interests: Competing interests: Medical writing support and article processing charges were funded by F. Hoffmann-La Roche Ltd. RSal reports personal consulting fees from Merck, Eisai, Regeneron, GSK, ImmunoGen, Karyopharm, Genentech, Clovis, AstraZeneca, and Mersana. Y-MK reports clinical study grants (to institution) from MSD, AstraZeneca, ImmunoGen, Zentalis, and BeiGene, and unpaid leadership roles for KGOG and EAGOT. SG reports consulting fees from GSK, Eisai, and Seagen; speaker honoraria from GSK; research contracts (with institution) from GSK, Merck, Takeda, BMS, Sutro, Jounce, AstraZeneca, and Eisai; and an unpaid leadership role with the GOG Foundation. DL reports personal fees for consulting from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, MSD, PharmaMar, Seagen, and Novartis; speaker honoraria from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; research grants to institution from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, PharmaMar, Seagen, and Roche; participation on data safety monitoring or advisory boards for AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; and support for meeting attendance/travel from GSK, AstraZeneca, Clovis Oncology, and MSD. LG reports grants (to institution) from IMV, Pfizer, Sutro Biopharma, MSD, Corcept Therapeutics, ImmunoGen, Shattuck Labs, Roche, Tesaro, K-Group Beta, Inc., GOG Foundation, GSK, AstraZeneca, Oncquest Laboratories, Novocure GmbH, Alkermes Inc., Esperas, and Mersana; consulting fees from GSK and Merck; meeting support/travel from GSK, Merck, Genentech, and Zentalis Pharma; and advisory board participation for GSK, Merck, Eisai, Novocure, Kora Healthcare, Corcept Therapeutics, ImmunoGen, and Canaribio Inc. AGR reports speaker honoraria from Roche, Pfizer, and Janssen; support for attending meetings/travel from Novartis, Roche, and Pfizer; and participation in data safety monitoring or advisory boards for Roche and Novartis. RSab reports consulting/advisory roles for Eisai, and GSK; speaker honoraria from Clovis, GSK, MSD, Seagen, Eisai, and Novartis; research funding to institution from AstraZeneca; and travel/accommodation support from MSD, GSK, and Novartis. NC reports honoraria from AstraZeneca, Novartis, Clovis Ocology, GSK, MSD/Merck, and Eisai; consulting/advisory roles for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, Roche, Novocure, and Eisai; research funding (to institution) from GSK, Roche, and AstraZeneca; leadership for ACTO onlus - Chair, Scientific Committee, and travel/accommodation/expenses from AstraZeneca. YH, VK, LM, YF, NK, MC, and YGL are employees of Roche/Genentech and hold shares in Roche. BJM reports consulting fees from Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem, and Zentalis; and speaker honoraria from AstraZeneca, Eisai, Myriad, Roche/Genentech, and Tesaro/GSK. All remaining authors report no conflict of interest., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: GB: Consulting/advisory role with Novartis. RLC: Consulting/advisory role: Merck, Genentech/Roche, Paravance, AstraZeneca, Novartis, Genmab, GSK, Gilead, Daiichi-Sankyo, Easai, OncXerna, Immunogen, Mersana, Novocure, Verastem, AbbVie; research funding: AstraZeneca, Clovis, Merck, Roche/Genentech, Abbott/AbbVie, Karyopharm. IV: Consulting fees from Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Regeneron, Seagen, Sotio, Verastem Oncology, Zentalis. IRC: Consulting fees from Agenus, Amgen, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F Hoffmann-La Roche, Genmab, GSK, Immunogen, Mersana, MSD, Novocure, Novartis, Netrispharma, OncXerna, Sanofi, Transgene, Seagen, Adaptimmune, Verastem Oncology. AO: Consulting/Advisory role: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, ImmunoGen, Genmab, Mersana, GSK, Deciphera, AGENUS, Corcept Therapeutics, Eisai, EMD Serono, Medison, Merck Sharp & Dohme, Novocure, prIME Oncology, Shattuck Labs, Sutro Biopharma, ITeos Therapeutics, Amgen; research funding: AbbVie, Abililty Pharmaceuticals, Advaxis, Aeterna Zentaris, Aprea Therapeutics, Clovis Oncology, Eisai, Roche, Regeneron, Agenus, AstraZeneca, BeiGene, Belgian Gynaecological Oncology Group (BGOG), Bristol Myers Squibb International Corporation (BMS), Corcept Therapeutics, ImmunoGen, Iovance Biotherapeutics, Lilly, Medimmune, Merck, Merck Sharp & Dohme, Mundipharma Research, Novartis FarmacÃutica, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, Verastem (all payments institutional); travel, accommodations, expenses: AstraZeneca, Clovis Oncology, PharmaMar, Roche. DOM: Consult and/or Advisory Boards: AbbVie, AdaptImmune, Agenus, Arquer Diagnostics, AstraZeneca, Atossa Therapeutics, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis Oncology, Celcuity, Clovis Oncology, Corcept Therapeutics, Duality Bio, Eisai, Elevar, Exelixis, Genentech, Genelux, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche, ImmunoGen, Imvax, InterVenn, INXMED, IOVANCE Biotherapeutics, Janssen, Jazz Pharmaceuticals, Laekna, Leap Therapeutics, Luzsana Biotechology, Merck & Co, Merck Sharp & Dohme Corp, Mersana Therapeutics, Myriad, Novartis, NovoCure, OncoC4, Onconova, Regeneron Pharmaceuticals, RepImmune, R Pharm, Roche Diagnostics, Seattle Genetics (SeaGen), Sorrento, Sutro Biopharma, Tarveda Therapeutics, Toray, Trillium, Umoja, Verastem, VBL Therapeutics, Vincerx Pharma, Xencor, Zentalis. Institution received funds for research: AbbVie, Advaxis, Agenus, AlkermesAravive, Aravive, Arcus Biosciences, AstraZeneca, BeiGene USA, Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Exelixis, Genentech, Genmab, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche, ImmunoGen, Incyte Corporation, IOVANCE Biotherapeutics, Karyopharm, Leap Therapeutics, Ludwig Institute, Merck & Co, Merck Sharp & Dohme Corp, Mersana Therapeutics, NCI, Novartis, NovoCure, NRG Oncology, OncoC4, OncoQuest, Pfizer, Precision Therapeutics, Prelude Therapeutics, Regeneron Pharmaceuticals, RTOG, Rubius Therapeutics, Seattle Genetics (SeaGen), Sutro Biopharma, SWOG, TESARO, Verastem. FR: Honoraria from GSK, Pharmamar, Clovis, MSD and Roche. UAM: Consulting or advisory fees: NextCure, Allarity, Ovarian Cancer Research Alliance, Pfizer, Profound Bio, Eisai, CureLab, Immunogen, Trillium, Agenus, Novartis, Boerhinger Ingelheim; participation in a Data Safety Monitoring Board: Alkermes, Symphogen; speakers’ bureau: Med Learning Group. TVG: Consulting/advising with AstraZeneca, Eisai, GSK, ImmunoGen, MSD/Merck, OncXerna Therapeutics, Seagen and Tubulis; travel, accommodations, and/or expenses from AstraZeneca, ImmunoGen, MSD/Merck, and PharmaMar; research funding from Amgen, Roche and AstraZeneca. All payments institutional. GS: research funding from MSD/Merck and honoraria from Clovis Oncology; consultant for Tesaro and Johnson & Johnson. BJM: consulting with Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novocure, Novartis, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL; speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: The KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown., Objective: To assess efficacy outcomes in patient subgroups of KEYNOTE-826., Design, Setting, and Participants: Exploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021., Interventions: Pembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg., Main Outcomes and Measures: Overall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1-positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population., Results: A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations., Conclusions and Relevance: The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT03635567.

Purpose: To evaluate the efficacy and safety of tucatinib and trastuzumab in patients with previously treated human epidermal growth factor receptor 2-positive (HER2+) metastatic biliary tract cancer (mBTC)., Methods: SGNTUC-019 (ClinicalTrials.gov identifier: NCT04579380) is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors. In the biliary tract cancer cohort, patients had previously treated HER2 overexpressing or amplified (HER2+) tumors (identified with local testing) with no prior HER2-directed therapy. The primary end point was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks)., Results: Thirty patients were enrolled. As of data cutoff (January 30, 2023), the median duration of follow-up was 10.8 months. The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively. At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8). The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs., Conclusion: Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC.

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. We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m 2 intravenously once every 3 weeks or paclitaxel 80 mg/m 2 intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.

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., Competing Interests: David M. O'MalleyConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute, Agenus, Marker Therapeutics, Eisai, Genelux, Iovance Biotherapeutics, Ambry Genetics, Tarveda Therapeutics, Leap Therapeutics, Myriad Genetics, GlaxoSmithKline, Regeneron, Sorrento Therapeutics, Rubius Therapeutics, Elevar Therapeutics¸ Novartis, Seattle Genetics, BBI Healthcare, Arquer Diagnostics¸ Toray Medical, Takeda, InxMed, Celsion, Roche Diagnostics MSAResearch Funding: Amgen (Inst), AstraZeneca (Inst), Genentech/Roche (Inst), Regeneron (Inst), Immunogen (Inst), Janssen Research & Development (Inst), Clovis Oncology (Inst), EMD Serono (Inst), Ergomed (Inst), Ajinomoto (Inst), Immunogen (Inst), Cerulean Pharma (Inst), PharmaMar (Inst), Array BioPharma (Inst), Bristol Myers Squibb (Inst), Agenus (Inst), Tesaro (Inst), TRACON Pharma (Inst), Genmab (Inst), Seattle Genetics (Inst), Iovance Biotherapeutics (Inst), Merck (Inst), AbbVie/Stemcentrx (Inst), AbbVie (Inst), Mersana (Inst), Eisai (Inst), BBI Healthcare (Inst), Sumitomo Dainippon Pharma Oncology (Inst), Bradley J. MonkLeadership: US OncologyHonoraria: AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoID, Clovis Oncology, Deciphera Pharmaceuticals, Eisai¸ Geistlich Pharma, Genmab/Seattle Genetics, ImmunoGen, Immunomedics, Incyte, Iovance Biotherapeutics, Laekna Health Care, Mersana, Merck, Myriad Pharmaceuticals, NuCana, OncoMed, OncoQuest, OncoSec, Perthera, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Senti Biosciences, Takeda, Tarveda Therapeutics, Tesaro/GSK, Vavotar Life Sciences, Vascular Biogenics, Vigeo Therapeutics, GOG Foundation, Starton Therapeutics, Elevar Therapeutics, Novocure, Iovance Biotherapeutics, Gradalis, Karyopharm TherapeuticsConsulting or Advisory Role: AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoID, Clovis Oncology, Deciphera Pharmaceuticals, Eisai¸ Geistlich Pharma, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Immunomedics, Iovance Biotherapeutics, Laekna Health Care, Mersana, Merck, Myriad Pharmaceuticals, NuCana, OncoMed, OncoQuest, OncoSec, Perthera, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Senti Biosciences, Takeda, Tarveda Therapeutics, Tesaro/GSK, Vavotar Life Sciences, Vascular Biogenics, Vigeo Therapeutics, Gradalis, Karyopharm Therapeutics, Sorrento Therapeutics, Novocure, ChemocareSpeakers' Bureau: Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, Tesaro/GSK, MerckResearch Funding: Amgen (Inst), Genentech (Inst), Lilly (Inst), Janssen (Inst), Array BioPharma (Inst), Tesaro (Inst), Morphotek (Inst), Pfizer (Inst), Advaxis (Inst), AstraZeneca (Inst), ImmunoGen (Inst), Regeneron (Inst), NuCana (Inst) Marilyn HuangConsulting or Advisory Role: Tesaro, Seattle Genetics, Aptitude Health, Agenus, Cooper Surgical, touchExpert opinionsResearch Funding: Merck (Inst) Tarek M. MeniawyHonoraria: AstraZeneca/MedImmuneConsulting or Advisory Role: AstraZeneca/MedImmune, Novartis, GlaxoSmithKline, BMSResearch Funding: Bristol Myers Squibb (Inst), BeiGene (Inst), Incyte (Inst), AstraZeneca/MedImmune (Inst), Regeneron (Inst), Bayer (Inst), Merck Serono (Inst), Roche/Genentech (Inst)Travel, Accommodations, Expenses: BMS Waldo Ortuzar FeliuEmployment: AgenusStock and Other Ownership Interests: AgenusTravel, Accommodations, Expenses: Agenus Marek AncukiewiczEmployment: Agenus, LFB Biotechnologies, Boston Scientific (I)Stock and Other Ownership Interests: Agenus, Boston Scientific (I) Iwona LugowskaHonoraria: Roche, Agen7s, MSD, AmgenResearch Funding: Roche (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Roche/GenentechNo other potential conflicts of interest were reported.

Background: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population., Methods: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed., Results: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy., Conclusions: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab., Methods: In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis., Results: In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively)., Conclusions: Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.)., (Copyright © 2021 Massachusetts Medical Society.)

Objective: This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer., Methods: Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee., Results: At data cutoff, 161 women (median age, 53 years [range 25-81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%-21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%-57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events., Conclusion: Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer., Competing Interests: Declaration of Competing Interest DMO reports personal fees and institutional grants from AstraZeneca, GSK/Tesaro, ImmunoGen, Janssen/Johnson & Johnson, Abbvie, Regeneron, Amgen, Clovis Oncology, Novocure, Genentech/Roche, Iovance, Eisai, Agenus, Merck, SeaGen, Novartis, Mersana; personal fees from Ambry, GOG Foundation, Myriad Genetics, Tarveda, Rubis, and Elevar; additional institutional funding from VentiRx Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research Stemcentrx, Inc., CERULEAN Pharma, Bristol-Myers Squibb, Serono, TRACON Pharmaceuticals, INC Research, Inc., inVentiv Health Clinical, PRA Intl and GenMab. AO reports personal fees from AstraZeneca, PharmaMar, Roche, Clinical Care Options, Clovis Oncology, Deciphera Pharmaceuticals, ImmunoGen, GenMab, Mersana, prIME Oncology, GlaxoSmithKline, and Tesaro; funding from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck Sharp & Dohme, Novartis, Pfizer, Piqur Therapeutics, Roche, Synthon, and Zenith Pharmaceuticals. BJM reports personal fees from Agenus, Akeso Bio, AstraZeneca, Genmab/Seattle Genetics, Iovance, Merck, Puma, Roche/Genentech, GOG Foundation, and GSK/Tesaro. FS reports personal fees and travel support from AstraZeneca, GSK/Tesaro, Merck Sharp & Dohme, Sandoz (Novartis), and Clovis Oncology, and Roche. CR reports personal fees from Merck, BMS, Roche, AstraZeneca, and Pfizer. LG reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, and Roche; travel support from AstraZeneca and PharmaMar. AL reports personal fees from AstraZeneca, Tesaro, Clovis Oncology, Merck Sharp & Dohme, BIOCAD, AbilityPharma, Seattle Genetics, and Zentalis; institutional fees, grant and travel support from GlaxoSmithKline and Merck Serono. KNM reports personal fees from Aravive, AstraZeneca, Bristol Myers Squibb, Eisai, Elevar, GSK/Tesaro, Genentech/Roche, ImmunoGen, Merck, Mersana, Myriad, OncXerna, Sorrento, and VBL Therapeutics; funding from PTC Therapeutics, Lilly, and Merck. ACHB reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Novartis, Pfizer, Roche, and Seagen. JA reports personal fees from AstraZeneca, GlaxoSmithKline, Roche, Merck Sharp & Dohme, PharmaMar; funding from Janssen and Merck Sharp & Dohme; travel support from Janssen, GlaxoSmithKline, and Novartis. CPO reports personal fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genmab, GlaxoSmithKline, Tesaro, Mersana, PharmaMar; funding from Lilly, Roche, and Sanofi. CRdA reports personal fees from Merck Sharp & Dohme. LMR reports personal fees from AstraZeneca, Clovis Oncology, Eisai, EMD Serono, Genentech/Roche, GlaxoSmithKline, GOG Foundation, Mersana Therapeutics, Merck, Myriad Genetics, OnTarget, Rubius, BluPrint Oncology, Products in Knowledge; grant funding from Akeso Bio, Genentech, and Merck; travel support from GlaxoSmithKline. WOF reports employment by, and stock ownership in, Agenus Inc. MA reports employment by Agenus Inc. IRC reports personal fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genmab, GlaxoSmithKline, Tesaro, Mersana, PharmaMar, and Roche; research funding from Bristol Myers Squibb, GlaxoSmithKline, and Merck Sharp & Dohme. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer., Methods: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III-IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m 2 every 3 weeks or 80 mg/m 2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed., Findings: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1-14·9); 11·1 months (7·0-15·3) for the avelumab maintenance group, 11·0 months (7·4-14·5) for the avelumab combination group, and 10·2 months (6·7-14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5-not estimable [NE]) with avelumab maintenance, 18·1 months (14·8-NE) with avelumab combination treatment, and NE (18·2 months-NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05-1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83-1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3-4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression)., Interpretation: Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer., Funding: Pfizer and Merck KGaA, Darmstadt, Germany., Competing Interests: Declaration of interests BJM reports receiving honoraria from and serving as a consultant or advisor for Agenus, Akeso, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, Genmab and Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Karyopharm Therapeutics, Iovance Biotherapeutics, Merck & Co, US Oncology Network (owned by McKesson), Mersana Therapeutics, Novocure, Myriad Genetics, Pfizer, Puma Biotechnology, Genentech (subsidiary of Roche), Sorrento Therapeutics, Tesaro (owned by GlaxoSmithKline), and VBL Therapeutics. NC reports receiving honoraria from and serving as a consultant or advisor for Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Pfizer, Roche, and Tesaro; receiving honoraria from Novartis; serving as a consultant or advisor for Advaxis, BioCad, ImmunoGen, OncXerna, Merck Sharp & Dohme, and Takeda; and participating on a data safety monitoring board or advisory board for Advaxis, Amgen, AstraZeneca, BioCad, Clovis Oncology, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme, OncXerna, Pfizer, Roche, Takeda, and Tesaro. KF reports receiving research funding and reimbursement for travel, accommodation, and expenses from Pfizer. MJB reports participating on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology, GlaxoSmithKline, OncoQuest, and VBL Therapeutics. LR reports receiving honoraria from AstraZeneca, GlaxoSmithKline, and Merck & Co; serving as a consultant or advisor for Agenus, Akeso Bio, AstraZeneca, Clovis Oncology, EMD Serono, GlaxoSmithKline, Genentech, Intuitive Surgical, Myriad, Novartis, and Rubius; and having received institutional research grants from Akeso Biopharma, AstraZeneca, Genentech, GOG Foundation, GlaxoSmithKline, Incyte, Karyopharm, Merck & Co, Mersana Therapeutics, On Target Laboratories, and Seagen. GS reports receiving honoraria from Clovis Oncology; serving as a consultant or advisor for Johnson & Johnson and Tesaro; and having received research funding from Merck Sharp & Dohme. JS has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. KY reports receiving honoraria from AstraZeneca, Chugai Pharma, Eisai, Novartis, Pfizer, and Takeda; and serving as a consultant or advisor for AstraZeneca, Chugai Pharma, Eisai, Novartis, Ono Pharmaceutical, and Takeda. RAS reports employment at Pfizer at the time the study was done and owns stock in Pfizer. XZ reports employment at and owns stock in Pfizer. JPS reports employment at and owns stock in Pfizer. CL reports employment at Pfizer and owns stock in Eli Lilly and Pfizer. JAL reports receiving honoraria from AstraZeneca, GlaxoSmithKline, and Pfizer; and is the vice president of the European Society of Gynaecological Oncology and an editor of the gynaecological clinical practice guidelines for the European Society for Medical Oncology. AMO, EVP, YVS, MCL, and SMB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer., Methods: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m 2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints., Findings: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction)., Interpretation: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer., Funding: Pfizer and Merck KGaA, Darmstadt, Germany., Competing Interests: Declaration of interests EP-L reports personal fees from AstraZeneca, Clovis Oncology, Incyte, Pfizer, Roche, and Tesaro; non-financial support from AstraZeneca, Roche, and Tesaro; and is the chair of ARCAGY-Research. KF reports grants and personal fees from Pfizer during the conduct of the study; and grants and personal fees from AstraZeneca, Chugai Pharma, Eisai, Genmab, Merck & Co, Taiho Pharmaceutical, and Zeria Pharmaceutical; grants from GSK, Immunogen, Lilly, OncoTherapy, and Regeneron; and personal fees from Daiichi Sankyo, Janssen, Kyowa Hakko Kirin, Mochida, Nippon Kayaku, and Novartis outside the submitted work. JAL reports serving as a consultant or advisor for Artios Pharma, AstraZeneca, Clovis Oncology, Eisai, GSK, Merck & Co, and Pfizer; has received research funding from AstraZeneca and Merck & Co; has received honoraria from AstraZeneca, Clovis Oncology, Eisai, and GSK; and has participated in an independent monitoring committee for Regeneron. RK reports personal fees from Clovis Oncology, Eisai, GSK, Incyte, and Roche; has received non-financial support from GSK; and grants from Merck & Co. I-LR-C reports personal fees from AstraZeneca, Clovis Oncology, GSK, Merck KGaA, Mersana Therapeutics, and Roche; received grants from Bristol Myers Squibb and GSK; and has received reimbursement for travel and accommodation expenses from AstraZeneca and GSK. KY reports serving as a consultant or advisor for AstraZeneca, Chugai Pharma, Eisai, Novartis, and Takeda; and received honoraria from AstraZeneca, Eisai, Pfizer, Takeda, and Taiho Pharmaceutical. SB reports personal fees from AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck KGaA, Mersana Therapeutics, Pfizer, Roche, and Tesaro; and has received grants from AstraZeneca, GSK, Merck & Co, and Tesaro. AL reports grants from Pfizer during the conduct of the study; serving as a consultant or advisor for AstraZeneca, BIOCAD, Clovis Oncology, GSK/Tesaro, Merck KGaA, Merck & Co, and Zentalis Pharmaceuticals; and has received reimbursement for travel and accommodation expenses from AstraZeneca, Clovis Oncology, and GSK/Tesaro. AVT has received honoraria and grants from AstraZeneca. KHJ reports personal fees from AstraZeneca, Celgene, Novartis, Roche, and Takeda Pharmaceuticals. FZ reports employment at and holds stock in Pfizer. RAS reports employment at Pfizer at the time when the study was conducted. CW reports employment at and holds stock in Pfizer. SSD reports employment at Pfizer. BJM reports serving as a consultant or advisor for and has received honoraria from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Merck & Co, Mersana Therapeutics, Myriad Pharma, Novocure, Pfizer, Puma Biotechnology, Roche/Genentech, Tesaro/GSK, and VBL Therapeutics; is a member of a speakers' bureau for AstraZeneca, Clovis Oncology, Eisai, Merck & Co, Roche/Genentech, and Tesaro/GSK; and reports employment at McKesson/US Oncology. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population., Methods: This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396., Findings: 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes., Interpretation: Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer., Funding: Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups., Competing Interests: Declaration of interests RLC has received funding for consulting from AstraZeneca, Merck, Tesaro, Medivation, Clovis, GamaMabs, Genmab, Roche, Janssen, Agenus, Regeneron, and OncoQuest, and grant support from AstraZeneca, Merck, Clovis, Genmab, Roche, and Janssen. DL reports advisory board membership for Roche, Tesaro/GlaxoSmithKline, Clovis, Merck, PharmaMar, ImmunoGen, Genmab, Amgen, and AstraZeneca; grant support from Tesaro/GlaxoSmithKline, Merck, Roche, PharmaMar, and Clovis; consultancy for Clovis; travel support from Roche, PharmaMar, AstraZeneca, Tesaro/GlaxoSmithKline, AstraZeneca, and Amgen; and acting as principal investigator for registrational clinical trials for Roche, PharmaMar, Tesaro, Clovis, ImmunoGen, Genmab, AstraZeneca, and Merck. CG has received clinical trial institutional support from Genmab; is an advisory board member for Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Novartis, and Lilly; has received consultancy fees from GlaxoSmithKline and Roche; has received institutional grant support from Roche, PharmaMar, Merck Sharp & Dohme, and AstraZeneca; and has received travel support from Pfizer, PharmaMar, Ipsen, and Roche. AG-M has received consultancy fees or honoraria from AstraZeneca, Clovis, Genmab, ImmunoGen, Merck Sharp & Dohme, Amgen, Oncoinvent, Merck/Pfizer, Roche, Sotio, and Tesaro/GlaxoSmithKline, and institutional grant support from Roche and Tesaro/GlaxoSmithKline. LW has received honoraria from Genmab and Tesaro; travel support from Genmab, Tesaro, and medac; institutional grant support from Genmab and Roche; and fees for development of educational presentations from Roche, Pfizer, and medac. SP has received honoraria from Genmab, Roche, AstraZeneca, Merck Sharp & Dohme, GlaxoSmithKline, PharmaMar, Incyte, Pfizer, Merck, and Clovis, and research funding from Roche, AstraZeneca, Merck Sharp & Dohme, and Pfizer. FF has received institutional funding from Genmab for travel. AR has received consultancy fees from AstraZeneca, GlaxoSmithKline, Roche, PharmaMar, Clovis, and Amgen; institutional grant support from Roche, PharmaMar, and Eisai; honoraria from AstraZeneca, GlaxoSmithKline, Roche, PharmaMar, and Clovis; and travel support from Roche, AstraZeneca, and PharmaMar. SDV, MC, JRH, and MS are employees of and own stock in Genmab. LVN and MSLT are employees of and own stock in Seagen. RR is a former employee of and owns stock in Genmab. LM has received consultancy fees from Roche, Novartis, Pfizer, AstraZeneca, and GlaxoSmithKline, and institutional grant support from Tesaro. MM has received consultancy fees or honoraria from Genmab. BJM has received consultancy fees or honoraria from AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoID, Clovis, Deciphera, Eisai, Geistlich, Genmab, GOG Foundation, ImmunoGen, Immunomedics, Incyte, Iovance, Laekna Health Care, Merck, Mersana, Myriad, NuCana, OncoMed, OncoQuest, OncoSec, Perthera, Pfizer, Puma, Regeneron, Roche/Genentech, Seagen, Senti Biosciences, Starton Therapeutics, Takeda, Tesaro/GlaxoSmithKline, Vavotar Life Sciences, VBL, and Vigeo. IV has received institutional funding for the following: consultancy or honoraria from Amgen, AstraZeneca, Clovis Oncology, Carrick Therapeutics, Debiopharm, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, ImmunoGen, Medical University of Vienna (Vienna, Austria), Millennium Pharmaceuticals, Merck Sharp & Dohme Belgium, Octimet Oncology, Oncoinvent, PharmaMar-Doctaforum Servicios SL, Roche, Sotio, Tesaro, Deciphera, and Verastem Oncology; institutional grant support from Amgen and Roche; institutional research support from Oncoinvent and Genmab; and institutional travel support from Amgen, AstraZeneca, Merck, Sharp & Dohme, Roche, and Tesaro. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the cost-effectiveness of bevacizumab in recurrent/persistent and metastatic cervical cancer using recently reported updated survival and toxicology data., Methods: A Markov decision tree based on the Gynecologic Oncology Group 240 randomized trial was created. The 2013 MediCare Services Drug Payment Table and Physician Fee Schedule provided costs. In the 5-year model subjects transitioned through the following states: response, progression, minor complications, severe complications, and death. Patients experiencing a health utility per month according to treatment effectiveness were calculated. Because cervical cancer survival is measured in months rather than years, results were reported in both quality adjusted cervical cancer life months and years (QALmonth, QALY), adjusted from a baseline of having advanced cervical cancer during a month., Results: The estimated total cost of therapy with bevacizumab is approximately 13.2 times that for chemotherapy alone, adding $73,791 per 3.5months (0.29year) of life gained, resulting in an incremental cost-effectiveness ratio (ICER) of $21.083 per month of added life. The ICER increased to $5775 per month of added life and $24,597/QALmonth ($295,164/QALY) due to the smaller difference in QALmonths. With 75% bevacizumab cost reduction, the ICER is $6737/QALmonth ($80,844/QALY), which translates to $23,580 for the 3.5month (0.29year) gain in OS., Conclusions: Increased costs are primarily related to the cost of drug and not the management of bevacizumab-induced complications. Cost reductions in bevacizumab result in dramatic declines in the ICER, suggesting that cost reconciliation in advanced cervical cancer may be possible through the availability of biosimilars, and/or less expensive, equally efficacious anti-angiogenesis agents., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Women with metastatic, recurrent, or persistent cervical carcinoma historically have had extremely limited treatment options. Systemic chemotherapy in these settings is predominantly palliative and has been associated with platinum resistance, nondurable responses, rapid progression of disease with deterioration in quality of life, and early death. At the cooperative group level, efforts to breach this clinical impasse have focused on incorporation of antiangiogenesis therapy, medical optimization, and identification of less toxic regimens. Gynecologic Oncology Group protocols 204 and 240, along with the Japanese Clinical Oncology Group protocol 0505, make up the pivotal phase 3 clinical trials that have provided 3 distinct treatment options. These options incorporate the antiangiogenesis humanized monoclonal antibody bevacizumab in combination with either a platinum-based or nonplatinum-based chemotherapy doublet. This review will highlight the development of bevacizumab in advanced cervical cancer and address the relevance of the survival gain obtained using antiangiogenesis therapy in this high-risk population.

The objective of this study was to evaluate a cost-effectiveness strategy of bevacizumab in a subset of high-risk advanced ovarian cancer patients with survival benefit. Methods. A subset analysis of the International Collaboration on Ovarian Neoplasms 7 trial showed that additions of bevacizumab (B) and maintenance bevacizumab (mB) to paclitaxel (P) and carboplatin (C) improved the overall survival (OS) of high-risk advanced cancer patients. Actual and estimated costs of treatment were determined from Medicare payment. Incremental cost-effectiveness ratio per life-year saved was established. Results. The estimated cost of PC is $535 per cycle; PCB + mB (7.5 mg/kg) is $3,760 per cycle for the first 6 cycles and then $3,225 per cycle for 12 mB cycles. Of 465 high-risk stage IIIC (>1 cm residual) or stage IV patients, the previously reported OS after PC was 28.8 months versus 36.6 months in those who underwent PCB + mB. With an estimated 8-month improvement in OS, the incremental cost-effectiveness ratio of B was $167,771 per life-year saved. Conclusion. In this clinically relevant subset of women with high-risk advanced ovarian cancer with overall survival benefit after bevacizumab, our economic model suggests that the incremental cost of bevacizumab was approximately $170,000.

Background: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer., Methods: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important., Results: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%)., Conclusions: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).

Angiogenesis plays a fundamental role in the pathogenesis of ovarian cancer. Vascular endothelial growth factor (VEGF) expression has been associated with the development of malignant ascites and tumor progression. Bevacizumab (Avastin(®); Genentech, South San Francisco, CA, USA), a humanized anti-VEGF monoclonal antibody, is the most widely studied antiangiogenesis agent across tumor types and specifically in epithelial ovarian cancer (EOC). With the recent reporting of four consecutive positive randomized trials adding bevacizumab to chemotherapy in the treatment of both front-line (GOG 218 and ICON7) and recurrent EOC ['platinum-resistant' (AURELIA Trial) or 'platinum-sensitive' (OCEANS Trial)], the most debatable question today is thus not IF we should treat ovarian cancer patients with bevacizumab, but WHEN. As bevacizumab is active in both settings, it seems appropriate to carefully consider this clinical controversy: 'what is the optimal setting for bevacizumab treatment?' A fine balance of efficacy, toxicity, quality of life, and symptom control is the main crux of this controversy. The cost effectiveness of bevacizumab in EOC is also controversial.

Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To explore feasibility of measuring tumor blood flow as marker for antiangiogenic activity using DCE-MRI (Dynamic Contrast-Enhanced Magnetic Resonance Imaging) in women with recurrent EOC/PPC treated with bevacizumab., Methods: In a phase II study, 62 patients with recurrent/persistent EOC/PPC were treated with bevacizumab (15 mg/kg IV q21 days) until disease progression. DCE-MRI was performed pre-cycle 1 and 4 of bevacizumab. Images were analyzed retrospectively by a single experienced blinded radiologist. Tumor and muscle contrast enhancement was measured by region of interest signal intensity within the same DCE-MRI images. Flow rates were obtained with concentration of dye as a function of time. Relative blood flow (RBF) was calculated as a ratio of average blood flow into tumor to muscle tissue. Associations between RBF and characteristics/outcomes were explored., Results: Sixty-two patients were eligible for study. Unfortunately, only 14 (23%) patients had imaging data available for analysis at baseline and 13 of those same patients (21%) had imaging data available for analysis pre-cycle 4. The RBF distribution was similar from pre-cycle 1 to 4. RBF remained stable for the majority of the cases (median change -0.21). Baseline RBF was not significantly associated with being progression-free at 6 months, microvessel density, 17 month overall survival, tumor response, or platinum sensitivity. However, increases in blood flow rates were associated with likelihood to be progression-free at 6 months., Conclusion: Functional imaging of tumor blood flow is a potential research endpoint that may be explored further. Consideration should be given to timing of endpoint and standardizing the technique., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To compare two methods of determining therapeutic response and disease progression - modified Gynecologic Cancer Intergroup (GCIG) criteria based on CA-125 and Radiographic Evaluation Criteria in Solid Tumors (RECIST), in a phase II trial of bevacizumab for patients with recurrent or persistent epithelial ovarian and peritoneal carcinoma., Methods: Patients were treated with bevacizumab 15 mg/kg every 21 days. Modified GCIG definitions of progression and response were retrospectively applied and compared to RECIST-defined progression and response. The prognostic significance of CA-125- and RECIST-defined responses and progressions were explored., Results: Sixty-two patients were evaluable by RECIST, 59 for progression by CA-125, and 45 for response by CA-125. Median progression-free survival (PFS) by RECIST and progression-free interval (PFI) by CA-125 were 4.7 and 5.2 months respectively. However, 12.9% of those with CA-125 defined progression remained progression-free according to RECIST for at least 8 months. Thirteen of 62 patients (21%) had response by RECIST and 14/45 (31%) by CA-125. Time dependent analyses indicated that progression by CA-125 was associated with a 5.2 fold increased risk of progression by RECIST, and response by CA-125 had a 5 fold decrease in risk of progression by RECIST. Landmark and time dependent analyses showed prognostic value of responses by CA-125 and RECIST., Conclusions: In this study, disease assessment by RECIST and CA-125 appears to correlate in general. However, approximately 10% of patients might demonstrate progression earlier by CA-125., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy., Methods: In our double-blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks' duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. The primary end point was progression-free survival., Results: Overall, 1873 women were enrolled. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P<0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively., Conclusions: The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.).