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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.)

Objective: Stage IVA patients comprise a small proportion of participants in cervical cancer trials, yet survival outcomes are disproportionately poor. We aim to perform a systematic review evaluating stage IVA cervical cancer., Methods: This systematic review was completed via PRISMA 2020 guidelines using two databases. Inclusion criteria comprised Phase III trials (2004-2024) assessing stage IVA cervical cancer including patients by stage. Searches had MeSH terms: ((cervical cancer) AND (stage IVA) AND (locally advanced)). 761 were articles identified, including books, trials, reviews, and meta-analyses. Of the articles identified, 12 met inclusion criteria., Results: A total of 133 (3.8% of study populations) stage IVA and 818 (40% of study populations) stage III-IVA cervical cancer patients were analyzed. Two studies (stage IVA n = 15; 3.1%) established cisplatin as chemoradiotherapy agent of choice, while one study (stage IVA n = 2; 1%) showed no benefit with cisplatin versus radiotherapy alone. Four studies (stage IVA n = 32; 3.6%; stages IIIB-IVA n = 220; 24%) found no benefit with adjuvant chemotherapy, with one analyzing stage IIIB-IVA patients (progression-free survival (PFS) hazard ratio (HR) = 0.84; 95% confidence interval (CI): 0.57-1.23). Three studies (stage IVA n = 71; 5%) found no benefit adding immunomodulator (stage IVA overall survival HR = 3.48; 95% CI: 0.52-23.29), hypoxic cell sensitizer, or immunotherapy (stage III-IVA PFS HR = 0.71; 95% CI: 0.49-1.03) to chemoradiotherapy. One study (stages III-IVA n = 598; 56%) found benefit adding immunotherapy to chemoradiotherapy (stage III-IVA PFS HR = 0.58; 95% CI: 0.42-0.8). One study (stage IVA n = 13; 3.5%) showed benefit with induction chemotherapy., Conclusion: Trials have not included substantial IVA patients to draw reasonable conclusions. Despite mixed results for immunotherapy, adjuvant chemotherapy, and induction chemotherapy, the exact benefit for stage IVA patients remains unknown. Future clinical trials should include a greater number of stage IVA cervical cancer patients and analyze them individually., Competing Interests: Declaration of competing interest There are no conflicts of interest for this systematic review., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: KST and BJM report consultancy on advisory boards for Merck focused on clinical trial design in cervical cancer.

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: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC)., Methods: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR)., Results: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E)., Conclusion: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III, double-blind KEYNOTE-826 trial of pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with or without bevacizumab, showed statistically significant survival benefits with the addition of pembrolizumab for patients with persistent, recurrent, or metastatic cervical cancer (primary data cutoff: May 3, 2021). This article reports the protocol-specified final overall survival (OS) results tested in the PD-L1 combined positive score (CPS) ≥1, all-comer, and CPS ≥10 populations. At the final data cutoff (October 3, 2022), the median study follow-up duration was 39.1 months (range, 32.1-46.5 months). In the PD-L1 CPS ≥1 (N = 548), all-comer (N = 617), and CPS ≥10 (N = 317) populations, median OS with pembrolizumab-chemotherapy versus placebo-chemotherapy was 28.6 months versus 16.5 months (hazard ratio [HR] for death, 0.60 [95% CI, 0.49 to 0.74]), 26.4 months versus 16.8 months (HR, 0.63 [95% CI, 0.52 to 0.77]), and 29.6 months versus 17.4 months (HR, 0.58 [95% CI, 0.44 to 0.78]), respectively. The incidence of grade ≥3 adverse events was 82.4% with pembrolizumab-chemotherapy and 75.4% with placebo-chemotherapy. These results show that pembrolizumab plus chemotherapy, with or without bevacizumab, continued to provide clinically meaningful improvements in OS for patients with persistent, recurrent, or metastatic cervical cancer.

Background: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer., Methods: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m 2 ) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866., Findings: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy)., Interpretation: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care., Funding: AstraZeneca., Competing Interests: Declaration of interests BJM reports institutional research funding from Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, Tesaro, Morphotek, Pfizer Advaxis, AstraZeneca, ImmunoGen, Regeneron, and Nucana. Honoraria from Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology, Eisai, Genmab/Seattle Genetics, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, TESARO/GKS, Vascular Biogenics, GOG Foundation, Elevar Therapeutics, Novocure, Gradalis, Karyopharm Therapeutics, Bayer, EMD Merck, Macrogenics, Sorrento Therapeutics, US Oncology, and Myriad Pharmaceuticals; a leadership position for US Oncology; speakers’ bureau participation for Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, TESARO/GSK, and Merck; served in a consulting or advisory role for Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology, Eisai, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Myriad Pharmaceuticals, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, TESARO/GSK, Vascular Biogenics, Gradalis, Karyopharm Therapeutics, Sorrento Therapeutics, Novocure, Bayer, Elevar Therapeutics, EMD Merck, Gradalis, and US Oncology. TT reports personal fees from AstraZeneca, Chugai, JGOG, and Zeria, outside the submitted work. JCVL reports funding, provision of study material, medical writing, and processing charges for the present work and grants from AstraZeneca; consulting fees and honoraria from AstraZeneca and Bristol Myers Squibb outside the submitted work; travel support from AstraZeneca, Merck Sharp and Dohme, Novartis, and Pfizer; served as an advisor for AstraZeneca; grants for clinical research from AstraZeneca, Bristol Myers Squibb, Janssen, Merck Sharp and Dohme, Novartis, Roche, and Sanofi, outside the submitted work. RS-F received an institutional research grant from Merck Sharp and Dohme and served at an advisory board for Merck Sharp and Dohme; and received lecture honoraria from AstraZeneca, Bristol Myers Squibb, Medison, Merck Sharp and Dohme, Neopharm, Novartis, and Roche, outside the submitted work. UM reports institutional grants from Varian Medical Systems and was a RT Steering Committee member for CALLA study. MdPED reports institutional funding from AstraZeneca for the present work and served as an advisor for AstraZeneca, outside the submitted work. SL has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events and participated on a data safety monitoring board or advisory board for AstraZeneca, Bristol Myers Squibb Boehringer Ingelheim, Merck, Roche, and Novartis, and has a leadership or fiduciary role for Iylon Precision Oncology. FJRG reports support for the present work from AstraZeneca, grants from AstraZeneca, Janssen, Lilly Company, Merck Sharp and Dohme, Roche, and Sanofi; travel support from BioGentec, and an unpaid leadership role with the Comite de Etica e Investigacion del Hospital Civil de Guadalajara, outside the submitted work. NV reports personal research funding from AstraZeneca, Merck Sharp and Dohme, and Roche; Consulting fees or honoraria from Tecnofarma, MSD, and Roche; and is currently the Vice President of the Peruvian Mastology society, outside the submitted work. DA reports funding for this clinical trial was made to his institute from AstraZeneca; an institutional grant from Takeda Pharmaceutical; consulting fees from AbbVie; honoraria from AstraZeneca, AbbVie, MSD, Takeda Pharmaceutical, and Chugai; participated in an advisory board for Takeda Pharmaceutical, AstraZeneca, and MSD; and was the president of the Asian Society of Gynecologic Oncology, the Chairperson of the Japan Society of Gynecologic Oncology, and the Vice President of the Japan Gynecologic Oncology Group. ML reports grants for clinical research from AstraZeneca, Bristol Myers Squib, Merck Sharp and Dohme, and Roche; consulting fees, honoraria, and travel support from Roche, outside the submitted work. J-YL reports personal research funding from AstraZeneca and Merck Sharp and Dohme; institutional funding from Clovis Oncology, Immunogen, Janssen Oncology, Merck, Merck Sharp and Dohme, and Synthon; served an advisory role for AstraZeneca, Merck Sharp and Dohme, Roche, and Takeda. FR reports personal fees from AstraZeneca. YR reports subcontract funding from NIH SBIR grant R44CA254844, compensation from Medical Physics Journal Editorial as the Deputy Editor, and personal fees from AstraZeneca for case review. SW is an employee and shareholder at AstraZeneca and has patents at GlaxoSmithKline UK Ltd and AstraZeneca. AL and HD are employees and shareholders at AstraZeneca. ATN received medical writing support for this manuscript funded by AstraZeneca, is a shareholder and was an employee of AstraZeneca during this study; and is a current employee at Merck. JM reports honoraria and consulting fees from AstraZeneca, Varian Medical Systems, Merck, Primmune, Agenus Bio; grants from NRG Oncology; royalties from Springer Medical Books for published work; and support for attending meetings and travel from NRG Oncology. XW, RT, MM, QZ, COK, SV, RS, YK, W-FC, and GK have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cervical cancer is the most commonly diagnosed gynecologic cancer worldwide. Although the incidence has declined with increased screening and higher uptake of human papillomavirus (HPV) vaccination in high-income countries, this disease remains the second highest cause of cancer mortality among women in low- and middle-income countries. In this clinical practice statement, we describe therapies for cervical cancer by treatment setting, as well as quality of life, financial toxicity, and disparities associated with this disease. In addition to chemotherapy and radiation, therapeutic strategies for cervical cancer include immune checkpoint blockade, antiangiogenics, and antibody-drug conjugates. Optimal treatment for recurrent cervical cancer remains an area of unmet need, necessitating further exploration of rational and innovative treatment approaches, including cell and immune-based therapies. Importantly, development of effective therapies for cervical cancer must incorporate strategies to ensure universal equitable access to HPV vaccination, screening, and treatment. Important consequences of the disease and treatment that impact quality of life must also be addressed. Patients with cervical cancer are at increased risk for financial toxicity, which can lead to downstream detrimental effects on physical, financial, and career outcomes. Underrepresentation of racial and ethnic minorities in gynecologic oncology clinical trials highlights the urgent need for collaborative and focused initiatives to bridge the significant divide and alleviate inequalities in the prevention and treatment of cervical cancer., Competing Interests: Declaration of Competing Interest Dr. Girda reports personal fees from Merck. Dr. Randall reports personal fees from Seagen for an educational webinar at drug launch and speaker's bureau and personal fees from Merck for an unbranded educational video for cervical cancer. Her institute receives research funding for clinical research from Seagen and Merck. She reports personal fees from BluPrint Oncology, PER, CurioScience, Projects in Knowledge, AstraZeneca, Tesaro, Merck, Mersana, Agenus, Rubius Therapeutics, Myriad Genetics, EMD Serono, Genentech/Roche, Seattle Genetics, Novartis, and Eisai, all outside the submitted work. Dr. Chino reports grants from NIH/NCI, during the conduct of the study. Dr. Monk reports personal fees from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis, Easai, Elevar Therapeutics, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Karyopharm, Iovance, Merck, Mersana, Novocure, Myriad, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, all outside the submitted work. Dr. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech. She reports grants from NIH/NCI. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma, and Gynecologic Oncology Foundation. Dr. Farley has nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tisotumab vedotin (TV) is an antibody-drug conjugate used for the treatment of adult patients with recurrent or metastatic cervical cancer. TV comprised of a monoclonal antibody against tissue factor and monomethyl auristatin E (MMAE), a potent inhibitor of cell division. The innovaTV-201 and innovaTV-204/GO30xx/ENGOT-cx6 trials showed that TV has clinically meaningful and durable antitumor activity in pretreated patients with recurrent or metastatic cervical cancer. The innovaTV-204 trial showed that TV monotherapy resulted in an objective response rate of 24% (including 7% and 17% complete and partial responses, respectively). In September 2021, the US Food and Drugs Administration (FDA) granted accelerated approval to TV for the treatment of recurrent or metastatic cervical cancer patients with disease progression on or after chemotherapy. The ongoing randomized, open-label Phase 3 innovaTV-301/ENGOTcx12/GOG-30xx trial will assess the effect of TV in pre-treated recurrent or metastatic cervical cancer. Meanwhile, the phase 1b/2 trial ENGOT Cx8/GOG 3024/innovaTV-205 is testing other possible combination between TV and other treatments. TV is characterized by a promising antitumor activity and an acceptable safety profile. Moreover, the preliminary data highlighted the feasibility of using TV in first line. In the first line, TV in combination with carboplatin or pembrolizumab provides an ORR of 55% and 41%, respectively Although the effect of adding TV to the current standard of care in first-line (carboplatin plus pembrolizumab) is still under evaluation, we expected to observe impressive results in the cervical cancer population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy., Methods: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m 2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m 2 ) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088., Findings: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths., Interpretation: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting., Funding: National Health and Medical Research Council and National Cancer Institute., Competing Interests: Declaration of interests LRM reports grant from National Health and Medical Research Council (NHMRC) Australia for support for the present manuscript. KNM reports research funding to institution outside of submitted work from PTC Therapeutics, Lilly, Merck, and GSK/Tesaro; participation on an Advisory Board for AstraZeneca, Aravive, Alkemeres, Addi, Blueprint Medicines, Eisai, EMD Serono, Elevar Therapeutics, GSK/Tesaro, Genentench/Roche, Hengrui, Immunogen, INXmed, IMab, Lilly, Mereo, Mersana Therapeutics, Merck, Myriad, Novartis, Novocure, OncXerna, Onconova Therapeutics, Tarveda Therapeutics, VBL Therapeutics, and Verastem Oncology; and leadership role as Associate Director of Gynecological Oncology Group Partners and on the Board of Directors for GOG Foundation. WSJ reports honoraria for invited talks from Carl Zeiss; payments made for participation on a data and safety monitoring board from Novocure; and Co-Chair of Gynaecological Committee until June 2020 with NRG Oncology. DKG reports grants and contracts from Elekta; payment or honoraria from ANZGOG, payment for expert testimony from in a Montana court case, participating on a DSMB or Advisory Board for Merck; and leadership role in NRG Oncology as Co-Chair of the Gyn Committee. PK reports funding outside of this submitted work from ANZGOG Fund for New Research and Medical Research Future Fund Reproductive Cancers Grant; is the Deputy Chair of Treatment Pillar for the National Cervical Cancer Elimination Strategy; is on the Board Director for ANZGOG and AMA Victoria. WKH reports consulting fee payments from AstraZeneca and SeaGen and payment for participation on a DSMB from Syneos and Inovio. CAM reports support for the present manuscript from National Cancer Institute, and funding to their institution from Syros, Deciphera, Astellas Pharma GlaxoSmithKline/Tesaro, Seagen, Genmab, EMD Serono, Merck, Regeneron, Moderna, Astra Zeneca, and Genentech, outside of the submitted work. TEL reports support for the present manuscript from the National Cancer Institute Community Research Program and support for attending meetings and travel from SHCC MU NCORP Grant. CHH reports support for the present manuscript from GOG and NRG, and leadership role in the Executive Board, Western Association of Gynecologic Oncology, and the 2023 Program Committee Chair, Western Association of Gynecologic Oncology. MQ reports personal payment as Chair of an independent data and safety monitoring committee for the Garnet Study and Tesaro Study from GSK, and Chair of DSMB for the COMPASS Study. DR reports trial funding all to institution outside of submitted work from MSD, GSK, Regeneron, Roche, Bristol Myers Squibb, Kura, ALX Oncology and participation on a DSMB for MSD, Regeneron, Sanofi. BJM reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, 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, and VBL Therapeutics, Verastem, Zentalis and payment or honoraria from AstraZeneca, Merck, Myriad, TESARO/GSK, Roche/Genentech, Clovis, and Easai. MRS reports grant to institution from NHMRC Australia for support for the present manuscript, and grants to their institution from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Tilray. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In the KEYNOTE-826 study, the addition of the anti-PD-1 monoclonal antibody pembrolizumab to chemotherapy with or without bevacizumab improved overall survival and progression-free survival (primary endpoints) versus placebo plus chemotherapy with or without bevacizumab, with manageable toxicity, in patients with persistent, recurrent, or metastatic cervical cancer. In this Article, we report patient-reported outcomes (PROs) from KEYNOTE-826., Methods: KEYNOTE-826 is a multicentre, randomised, phase 3 trial in 151 cancer treatment centres in 19 countries. Eligible patients were aged 18 years or older with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy (previous radiosensitising chemotherapy was allowed) and not amenable to curative treatment and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) centrally by means of an interactive voice response system in a double-blind manner to receive either pembrolizumab 200 mg or placebo every 3 weeks intravenously for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m 2 plus cisplatin 50 mg/m 2 or carboplatin area under the curve 5 mg/mL per min, intravenously) with or without bevacizumab 15 mg/kg every 3 weeks intravenously. Randomisation (block size of 4) was stratified by metastatic disease at diagnosis, planned bevacizumab use, and PD-L1 combined positive score. Patients, investigators, and other study personnel involved in study treatment administration or clinical evaluation of patients were unaware of treatment group assignments. PRO instruments were the EORTC Quality-of-Life-Core 30 (QLQ-C30), the EORTC cervical cancer module (QLQ-CX24), and the EuroQol-5 dimension-5 level (EQ-5D-5L) visual analogue scale, each collected before treatment at cycles 1-14 and every other cycle thereafter. Primary endpoints were overall survival and progression-free survival per RECIST version 1.1 by investigator review. Change from baseline in QLQ-C30 global health status (GHS)-quality of life (QoL) was a prespecified secondary endpoint and was assessed in the PRO full analysis population (all patients who received at least one dose of study treatment and completed at least one post-baseline PRO assessment). Other PRO analyses were protocol-specified exploratory endpoints. The study is registered with ClinicalTrials.gov, NCT03635567, and is ongoing., Findings: Between Nov 20, 2018, and Jan 31, 2020, of 883 patients screened, 617 were randomly assigned (pembrolizumab group, n=308; placebo group, n=309). 587 (95%) of 617 patients received at least one dose of study treatment and completed at least one post-baseline PRO assessment and were therefore included in the PRO analyses (pembrolizumab group, n=290; placebo group, n=297). Median follow-up was 22·0 months (IQR 19·1-24·4). At week 30, QLQ-C30 completion was 199 (69%) of 290 patients in the pembrolizumab group and 168 (57%) of 297 patients in the placebo group; compliance was 199 (94%) of 211 and 168 (90%) of 186, respectively. The least squares mean change in QLQ-C30 GHS-QoL score from baseline to week 30 was -0·3 points (95% CI -3·1 to 2·6) in the pembrolizumab group and -1·3 points (-4·2 to 1·7) in the placebo group, with a between-group difference in least squares mean change of 1·0 point (95% CI -2·7 to 4·7). Median time to true deterioration in GHS-QoL was not reached (NR; 95% CI 13·4 months-NR) in the pembrolizumab group and 12·9 months (6·6-NR) in the placebo group (hazard ratio 0·84 [95% CI 0·65-1·09]). 122 (42%) of 290 patients in the pembrolizumab group versus 85 (29%) of 297 in the placebo group had improved GHS-QoL at any time during the study (p=0·0003)., Interpretation: Addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect health-related quality of life. Along with the efficacy and safety results already reported from KEYNOTE-826, these data support the benefit of pembrolizumab and the value of immunotherapy in patients with recurrent, persistent, or metastatic cervical cancer., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests All authors' institutions received research funding from Merck Sharp & Dohme, a subsidiary of Merck (Rahway, NJ, USA), for the conduct of this study. BJM was a consultant to or received honoraria from AbbVie, Agenus, Akeso Biopharma, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, EMD Serono, Genentech, Genmab–Seattle Genetics, GlaxoSmithKline, GOG Foundation, Gradalis, ImmunoGen, Incyte Corporation, Iovance Biotherapeutics, Janssen Biotech, Karyopharm Therapeutics, Merck, Mersana Therapeutics, Myriad Genetic Laboratories, Novocure, Pfizer, Pfizer International, Puma Biotechnology, Regeneron Pharmaceuticals, Sorrento Therapeutics, Takeda Development Center Americas, US Oncology, and VBL Therapeutics. KST received research grant to institution, and consultant–speaker's bureau fees from Merck. CD was on an endpoint review committee for Merck. KH was a scientific advisory board member and received honoraria, contracted research and study funding to their institution from Merck Sharp & Dohme. RS-F received speaker honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Roche, Medison, and Neopharm; a research grant to their institution from Merck Sharp & Dohme, and was an advisory board member for Merck Sharp and Dohme, VBL Therapeutics, and Clovis Oncology. PS received research support from Merck and participated in advisory boards for BMS, AstraZeneca, Janssen, and Novartis. MG received speaker's bureau–advisory board fees from Amgen, and received advisory board fees (institutional) from from AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Merck, Novartis, Pfizer, and Takeda Oncology, and travel fees from F Hoffmann-La Roche. VS was a consultant or advisory board member for GlaxoSmithKline and Merck. VC received a grant to institution from AstraZeneca, Bayer, Bayer Healthcare, Bristol Myers Squibb, Merck, Seagen; consultant–advisory board fees from Bristol Myers Squibb, Ipsen Biopharmaceuticals, Merck, Pfizer Canada, and Seagen; and consultant fees from AstraZeneca Canada and Pfizer Canada. CT, KL, AMN, and MJM are employees of Merck Sharp & Dohme and own stock in Merck. NC reports fees for advisory board membership from AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, Mersana, Merck Sharp & Dohme–Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris, Roche; fees as an invited speaker for AstraZeneca, Novartis, Clovis Oncology, GlaxoSmithKline, and Merck–Merck Sharp & Dohme; institutional research grants from AstraZeneca, PharmaMar, and Roche; and non-remunerated activities as member of the ESMO Guidelines Steering Committee and chairs for of the Scientific Committee of Alleanza contro il tumore ovarico. DL was a consultant for Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Gynecological Cancer InterGroup, Merck Sharp and Dohme, Pharma Mar; received a research grant to institution from AstraZeneca, Clovis Oncology, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, ImmunoGen, Incyte Corporation, Merck, Merck Sharp and Dohme, PharmaMar; and was a data and safety monitoring board member for Novartis. MVC, EY, MOHdM, and AA declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma., Methods: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m 2 plus topotecan 0.75 mg/m 2 days 1-3 (n = 223) vs cisplatin 50 mg/m 2 plus paclitaxel 135 or 175 mg/m 2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS., Results: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones., Conclusions: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062., Competing Interests: Declaration of Competing Interest Dr. Tewari reports receiving honoraria for lectures, presentations, speakers' bureaus for Merck, Astra Zeneca, Eisai, Seagen, Tesaro and Clovis. He also reports serving on Data Safety Monitoring Board/Advisory Board for Iovance. Dr. Penson reports grants received from Array BioPharma Inc., AstraZeneca, Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, Tesaro Inc. and Vascular Biogenics Ltd. Dr. Penson also reports receiving consulting fees from AstraZeneca, Eisai, GSK Inc., ImmunoGen Inc., Merck & Co, Mersana, Novacure, Roche Pharma, Sutro Biopharma, and Vascular Biogenics Ltd. and reports participating on Advisory Boards for AstraZeneca and Roche Pharma. Dr. Oaknin reports grants to her institution from the following: Abbvie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, AstraZeneca AB, BeiGene USA, Inc., Belgian Gynecological Oncology Group (BGOG), Bristol-Myers Squibb International Corporation (BMSM Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann-La Roche, Grupo Española de Investigación en Cáncer de Ovario (GEICO)), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Unipharm Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem. Dr. Oaknin also reports receiving consulting fees from: Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc., and GEICO. Dr. Oaknin reports personally receiving honoraria for lectures, presentations and Speakers bureaus from ESMO, Edizioni Minerva Medica SpA, Doctaforum Servicios S.L and received support for travel from Roche, AstraZeneca, PharmaMar as well as Clovis. Dr. Oaknin participated on Data Safety Monitoring Board/Advisory Board for Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, GOG, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs and Sutro Biopharma. Dr. Leitao reports receiving consulting fees from Medtronic, honoraria for lectures from Intuitive Surgical, Inc. as an Ad-hoc Speaker and participating on an Advisory Board for JnJ/Ethicon. Dr. Monk reports receiving consulting fees from the following: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, UmmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pleris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem and Zentalis. He also reports receiving honoraria from: AstraZeneca, Merck, Myriad, Tesaro/GSK, Roche/Genentech, Clovis and Easai. All other authors had no conflicts of interest to disclose with regard to this Study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate outcomes and cost-effectiveness of targeted therapy sequencing for metastatic and recurrent cervical cancer., Method: Models were simulated based on phase II and III trials on bevacizumab (bev) from GOG-240, cemiplimab (cemi) from GOG 3016, pembrolizumab (pembro) from KEYNOTE-826, and tisotumab vedotin (tiso) from GOG 3023. Costs were based on IBM Micromedex RED BOOK™ and company listed costs., Results: For [chemo + bev → chemo], total cost was $125,918.04, with median overall survival (mOS) of 21.8 months, and cost-effectiveness ratio (CER) of $119,835.79. For [chemo + bev → cemi], total cost was $187,562.99 with mOS of 28.5 months and CER of $162,039.16. For [chemo + bev + pembro → chemo], total cost was $319,963.78 with mOS 32.9 months and CER of $249,930.10. For [chemo + bev + pembro → tiso], total cost was $455,204.45, with mOS 36.5 months and CER of $320,072.99., Conclusion: The combination of immunotherapies and biologics have significantly increased overall survival, but with associated higher costs, primarily related to drug costs.

Background: Optimal treatment of cervical cancer is based on disease stage; therefore, an understanding of the global epidemiology of specific stages of locally advanced disease is needed., Objective: This systematic literature review was conducted to understand the global and region-specific proportions of patients with cervical cancer with locally advanced disease and to determine the incidence of the locally advanced disease., Methods: Systematic searches identified observational studies published in English between 2010 and June 10, 2020, reporting the proportion of patients with, and/or incidence of, locally advanced stages of cervical cancer (considered International Federation of Gynecology and Obstetrics (FIGO) IB2-IVA). Any staging criteria were considered as long as the proportion with locally advanced disease was distinguishable. For each study, the proportion of locally advanced disease among the cervical cancer population was estimated., Results: The 40 included studies represented 28 countries in North or South America, Asia, Europe, and Africa. Thirty-eight studies reported the proportion of locally advanced disease among populations with cervical cancer. The estimated median proportion of locally advanced disease among all cervical cancer was 37.0% (range 5.6-97.5%; IQR 25.8-52.1%); estimates were generally lowest in North America and highest in Asia. Estimated proportions of ≥50% were reported in nine studies from Asia, Europe, Brazil, and Morocco; estimates ≤25% were reported in six studies from Asia, United States, Brazil, and South Africa. Locally advanced disease was reported for 44% and 49% of women aged >70 and ≥60 years, and 5-100% of younger women with cervical cancer. A greater proportion of locally advanced disease was reported for Asian American (19%) versus White women (8%) in one United States study. Two of five studies describing the incidence of locally advanced disease reported rates of 2-4/100 000 women among different time frames., Conclusion: This review highlights global differences in proportions of locally advanced cervical cancer, including regional variance and disparities according to patient race and age., Competing Interests: Competing interests: BJM reports personal fees from Abbvie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson & Johnson, Mateon (formally Oxigene), Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma, Roche/Genentech, Samumed, Takeda, TESARO, Inc., and VBL, outside the submitted work. DT is supported by grants from the Singapore Ministry of Health’s National Medical Research Council and Pangestu Family Foundation Gynaecological Cancer Research Fund. He also reports personal fees from AstraZeneca, Roche, MSD, Merck Serono, GSK, Tessa Therapeutics, Eisai, and Genmab; research funding and support from AstraZeneca, Roche, Bayer, BMS, MSD, Eisai, and Karyopharm; stock ownership in the Asian Microbiome Library (AMiLi). All of these have been received outside the submitted work. JT has nothing to disclose. ATN, JDHC, and MP are employees and shareholders of AstraZeneca. EP-L reports personal fees and non-financial support from AstraZeneca, Tesaro/GSK, Roche; personal fees from Clovis, Incyte, and Pfizer; and other from ARCAGY-Research, outside the submitted work., (© IGCS and ESGO 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Survival outcomes for cervical cancer differ between countries and world regions. Locally advanced cervical cancer (LACC) is associated with poorer outcomes than early-stage disease. Country-specific variations in diagnostic and treatment recommendations might contribute to differences in LACC outcomes among countries., Objective: We compared international and country-specific guidelines for LACC diagnostic imaging and treatment recommendations., Methods: A systematic literature review and targeted search were used to identify cervical cancer treatment guidelines published between January 1999-August 2021. Guidelines were identified via literature databases, health technology assessment databases, disease-specific websites, and health organization websites. The targeted search included guidelines from countries in regions known to have high cervical cancer prevalence or mortality. Non-English guidelines were translated by native speakers or online translation services., Results: Forty-six guidelines from 31 countries, regions, and international organizations were compared (41/46 using staging criteria, 27 of which used 2009 FIGO). Most guidelines recommended imaging tests for diagnosis and staging. Chest X-ray, intravenous pyelogram, CT, and MRI were commonly recommended for diagnosis and staging while MRI and PET-CT were recommended for the assessment of lymph node status and distant metastases, with a preference for PET-CT over MRI. There was global consensus for cisplatin-based concurrent chemoradiation as primary treatment for stages IIB to IVA, with few exceptions. Treatment recommendations for stages IB2 to IIA2 varied. Most guidelines agreed on adjuvant concurrent chemoradiation after radical hysterectomy when there is a high recurrence risk, and adjuvant radiotherapy when there is an intermediate recurrence risk. Recommendations for other adjuvant and neoadjuvant therapies varied among the guidelines., Conclusions: Differences among treatment guidelines by LACC stage might be influenced by staging criteria used, resource availability, and prevention program effectiveness. Addressing these areas may unify guidelines and improve global outcomes. Review and update of guidelines will be important as novel LACC therapies become available., Competing Interests: Declaration of Competing Interest E. Pujade-Lauraine reports personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Tesaro/GSK, personal fees from Clovis, personal fees and non-financial support from Roche, personal fees from Incyte, and personal fees from Pfizer, other from ARCAGY-Research, outside the submitted work. D.S.P. Tan is supported by grants from the Singapore Ministry of Health's National Medical Research Council and Pangestu Family Foundation Gynaecological Cancer Research Fund. He also reports personal fees from AstraZeneca, Roche, MSD, Merck Serono, GSK, Tessa Therapeutics, Eisai, and Genmab, and research funding and support from AstraZeneca, Roche, Bayer, BMS, MSD, Eisai, and Karyopharm. He also reports stock ownership in the Asian Microbiome Library (AMiLi). All of these have been received outside the submitted work. A. Leary reports grants, personal fees, and non-financial support from AstraZeneca, Tesaro, and Clovis; grants and personal fees from MSD and Ability; personal fees from Biocad, Seattle Genetics, and Zentalis; other support from Merck Serono; and grants, non-financial support, and other from GSK, outside the submitted work. M.R. Mirza reports personal financial interests for AstraZeneca, Biocard, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Mersana, MSD, Oncology Venture, Pfizer, Roche, SeraPrognostics, Tesaro-GSK, ZaiLab; leadership roles for Karyopharm Therapeutics and Sera Prognostics; institutional financial interests (study grants) for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Tesaro-GSK, Ultimovacs. T. Enomoto reports personal fees from AstraZeneca, Takeda, MSD, and Chugai, outside the submitted work. J. Takyar has nothing to disclose. A.T. Nunes, J.D.H. Chagüi, and M.J. Paskow are employees and shareholders at AstraZeneca. B.J. Monk reports personal fees from AbbVie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson & Johnson, Mateon, Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma, Roche/Genentech, Samumed, Takeda, Tesaro, and VBL, outside the submitted work., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study., Methods: Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1-16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy., Results: Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77-13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08-12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations., Conclusions: Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.O. reports serving on advisory boards for Roche, AstraZeneca, MSD/Merck, PharmaMar, Clovis Oncology, Tesaro, Immunogen, Genmab, Mersana Therapeutic, GSK, SUTRO, AGENUS and Deciphera Pharmaceuticals; and support for travel or accommodation from Roche, AstraZeneca and PharmaMar. B.J.M. reports consulting honoraria from Aravive, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Circulogene, Conjupro Biotherapeutics, Eisai, Geistlich, Genmab/Seattle Genetics, Gynecologic Oncology Group Foundation, Immunogen, Immunomedics, Incyte, Laekna Health Care, Mateon/Oxigene, Merck, Mersana, Myriad, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Precision Oncology, Puma, Regeneron, Samumed, Takeda, VBL and Vigeo; and consulting or speaker honoraria from AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech and Tesaro/GSK. I.V. reports consulting fees from AstraZeneca, Elevar Therapeutics, Genmab, GSK, Immunogen, Merck Sharp & Dohme and Oncoinvent; and contracted research from Genmab and Hoffmann-La Roche. A.C.M. has served on advisory boards for Merck Sharp & Dohme, Bristol-Myers Squibb and Libbs; has received support for travel or accommodation from AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb and Roche; and reports institutional research grant support from Clovis Oncology, Bristol-Myers Squibb, Roche, Novartis, Amgen, Merck Sharp & Dohme, Lilly, Pierre Fabre, Sanofi and Pfizer. Y.M.K. reports ownership of stock at Johnson & Johnson and Genolution for self and spouse; consulting or advisory role at Merck Sharp & Dohme; and research funding from Regeneron Pharmaceuticals, Inc., and Roche. A.S.L., V.S., H.S.K., E.A.G., F.D. and C.-L.C. declare no conflict of interest. S.T. reports honoraria from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, Merck Sharp & Dohme, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Nihonkayaku, Pfizer and Lilly Japan; advisory role at Bayer; research funding from Daiichi Sankyo, Sanofi, Eisai, Bayer, Taiho Pharmaceutical, Merck Sharp & Dohme, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb, Lilly, Ono Pharmaceutical, PharmaMar and Pfizer/EMD Serono; and travel, accommodation and expenses from Daiichi Sankyo and Novartis. J.L., M.M., M.G.F., I.L., J.H. and C.C. are employees and shareholders of Regeneron Pharmaceuticals, Inc. C.I. and M.R. report employment at IQVIA and institutional research funding from Regeneron Pharmaceuticals, Inc. P.R.L. is an employee of, and may hold shares and stock options in Sanofi. K.T. reports honoraria from Tesaro and Clovis Oncology; consulting or advisory roles for Genentech, Tesaro, Clovis and AstraZeneca; serving on a speaker's bureau for Genentech, AstraZeneca, Merck, Tesaro and Clovis; institutional research funding from AbbVie, Genentech, Morphotek, Merck and Regeneron Pharmaceuticals, Inc.; and travel, accommodation and expenses from Genentech., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Understanding real-world treatment patterns and proportions of eligible patients in each line of treatment is imperative to inform future clinical trial designs and multi-line treatment algorithm development., Methods: We conducted a retrospective observational cohort study of adult women who received first-line (1 L) therapy for r/mCC between 01 September 2014 and 31 December 2019, using The US Oncology Network electronic health records and chart review data. Patients were followed to 31 December 2020. Patient demographic and clinical characteristics, treatment patterns, and clinical outcomes were assessed descriptively., Results: A total of 262 patients with r/mCC met study inclusion criteria (mean age = 53 years). The majority of patients in 1 L received platinum-based chemotherapy doublet plus bevacizumab (66%) or chemotherapy doublet alone (24%). Nearly half the patients (48%) completing 1 L received 2 L therapy. Among these patients, there was no consistent 2 L treatment of choice. Overall median time to treatment discontinuation was 3.5 months from 1 L treatment initiation, and median overall treatment-free interval was 2.1 months from 1 L discontinuation. Besides elevated serum creatinine, abnormal BMI indicated a directional trend for lower likelihood of receiving 2 L. Other predictors may include no prior bevacizumab, worse ECOG, and earlier disease prevention., Conclusions: >50% of the patients who initiated 1 L treatment did not receive 2 L therapy, highlighting the need for novel and effective treatment options. As the treatment landscape continues to evolve, we anticipate that more patients will live longer with more treatment options across multiple lines of therapies in the r/mCC setting., Competing Interests: Declaration of Competing Interest Bradley J. Monk has received honorarium/consultant fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Karyopharm, Iovance, Macrogenics, Mersana, Novartis, Novocure, Myriad, OncoC4, Pieris, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, and honorarium/consulting/speaking fees from AstraZeneca, Clovis, Easai, Merck, Roche/Genentech, and Tesaro/GSK. Zachary Alholm has no financial conflicts of interest to disclose. Jie Ting is an employee of Seagen Inc. and owns stock in Seagen Inc. Yitong Zhang is an employee of Seagen Inc. and owns stock in Seagen Inc. Ding He is an employee of Ontada, which received consulting fees in connection with this study from Seagen, Inc. Lavanya Sudharshan is an employee of Ontada, which received consulting fees in connection with this study from Seagen, Inc. Traci Leong is an employee of Ontada, which received consulting fees in connection with this study from Seagen, Inc. Robert L. Coleman has received grants and personal fees from AstraZeneca, Merck, Clovis, Genmab, Roche/Genentech, Janssen, Zentalis, Immunogen, and personal fees from GSK, Agenus, Regeneron, OncoQuest, Oncxerna, Onxeo, Alkermes, Epsilogen, Novocure, outside the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tisotumab vedotin is a tissue factor-directed antibody-drug conjugate developed for treatment of recurrent or metastatic cervical cancer (r/mCC). In the pivotal phase 2 study innovaTV 204, 101 r/mCC patients received tisotumab vedotin. 138 ocular treatment-related AEs (TRAEs), predominantly Grade 1 or 2, were observed in 54 (53%) patients. The most common ocular TRAEs were conjunctivitis (26 patients [26%]), dry eye (23 patients [23%]), and keratitis (11 patients [11%]). Observed ocular TRAEs are hypothesized to be conjunctival and inflammatory in nature, resulting in signs and symptoms readily recognizable by patients and healthcare providers. Generally, ocular TRAEs were manageable with ophthalmic care (prophylactic and symptom management) and dose modifications. Of 138 ocular TRAEs, 118 (86%) resolved within 30 days after last dose of tisotumab vedotin. Median time to resolution was 0.7 months (interquartile range: 0.3-1.6). To help reduce the risk of ocular AEs, an eye care plan based on clinical trial experience was developed. This encompasses an oncology care team partnering with an eye care provider, incorporates eye exams at baseline (per trial mitigation measures) and prior to each dose, includes eye drops and cold packs, avoids contact lens use, and advises prompt referral for new or worsening ocular signs and symptoms. Moreover, dose modification guidelines have been developed to manage potential ocular AEs. Ocular AEs will require patient management strategies that may be new to oncology teams. Oncologists should become familiar with symptoms that typically arise, and eye care providers should be an integral part of the comprehensive care team treating patients receiving tisotumab vedotin. With diligent monitoring for early signs and symptoms, careful adherence to required eye care, pharmacologic intervention when ocular AEs arise, and dose modifications when needed, ocular AEs can be detected early and symptoms can be alleviated before any impact on vision, to ultimately help patients stay on therapy., Competing Interests: Declaration of Competing Interest Dr. Kim reports consulting/advisory roles for Seagen, ImmunoGen, Abbvie, Astellas, CytomX, and Zymeworks outside the submitted work. Dr. Ursell reports travel grants & fees from Alcon, Medisoft & Essilor outside the submitted work. Dr. Coleman reports grants and personal fees from AstraZeneca, grants from Merck, personal fees from GSK, grants and personal fees from Clovis, grants and personal fees from Genmab, grants and personal fees from Roche/Genentech, grants and personal fees from Janssen, personal fees from Agenus, personal fees from Regeneron, and personal fees from OncoQuest outside the submitted work. Dr. Monk reports personal fees from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Karyopharm, Iovance, Merck, Mersana, Novocure, Myriad, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, and VBL outside the submitted work. Dr. Vergote reports research funding from Amgen (Europe) GmbH and Roche and personal fees from AstraZeneca, Deciphera Pharmaceuticals, Elevar Therapeutics, F Hoffman-La Roche Ltd., Genmab, GSK, Immunogen Inc., Jazzpharma, Mersana, MSD, Novocure, Oncoinvent AS, and Sotio a.s. outside the submitted work., (Copyright © 2022. Published by Elsevier Inc.)

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.)

Balstilimab (anti-programmed death 1) and zalifrelimab (anti-CTLA-4) are two new checkpoint inhibitors that have emerged as promising investigational agents for the treatment of cervical cancer, particularly in the setting of previously-treated, recurrent/metastatic disease. Here we describe the rationale and design of RaPiDS (NCT03894215), a two-arm Phase II study evaluating the safety, tolerability and efficacy of balstilimab administered alone or in combination with zalifrelimab in patients with advanced cervical cancer who progressed after first-line, platinum-based chemotherapy. Patients will be randomized in a 1:1 ratio. The primary end point is objective response rate, and key secondary objectives include safety, duration of response, progression-free survival, overall survival and quality of life outcomes.

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: There is no standard systemic treatment for recurrent or metastatic cervical cancer (r/mCC) after failure of first-line (1L) therapy. This study characterizes the patient experience, treatment patterns, and clinical outcomes of patients who initiated second-line (2L) therapy for r/mCC in a US community oncology setting., Methods: This is an observational study of cervical cancer patients who failed 1L systemic treatment for r/mCC and initiated 2L systemic therapy between 2014 and 2019 within the US Oncology Network (USON). USON's electronic health records were used to identify eligible patients and abstract data. Overall survival (OS), time to treatment discontinuation (TTD), and time to first subsequent treatment (TFST) were estimated using Kaplan-Meier methods., Results: A total of 130 patients were identified (mean age 53 years). Over 60% of patients had Eastern Cooperative Oncology Group score of 0-1. Cytotoxic monotherapy was the most frequently prescribed regimen (N = 60, 46%) in 2L, followed by combination therapies (N = 45, 35%), pembrolizumab monotherapy (N = 19, 15%), and bevacizumab monotherapy (N = 6, 5%). Median OS was 9.1 months (95% CI: 7.2-12.2) after initiation of 2L therapy. Median TTD was 2.8 months (95% CI: 2.5-3.3), and median TFST was 4.9 months (95% CI: 4.2-5.7). No significant difference in outcomes was found when stratified by 2L treatments., Conclusions: The observed heterogeneity in 2L r/mCC therapy suggests no clear standard-of-care in this setting. Additionally, short duration of OS observed was consistent across 2L regimens. New, effective treatment options in this setting are needed., Competing Interests: Declaration of Competing Interest Bradley J. Monk has received honorarium/consultant fees from Agenus, Akeso Bio, Aravive, Elevar Therapeutics, Genmab/Seagen Inc., GOG Foundation, Gradalis, ImmunoGen, Karyopharm, Iovance, McKesson/US Oncology, Mersana, Novocure, Myriad, Pfizer, Puma, VBL, and honorarium/consulting/speaking fees from AstraZeneca, Clovis, Easai, Merck, Roche/Genentech, and Tesaro/GSK. Jie Ting is an employee of Seagen Inc. and owns stock in Seagen Inc. Sonia Pulgar is an employee of Seagen Inc. and owns stock in Seagen Inc. Marley Boyd is an employee of McKesson, which received consulting fees in connection with this study from Seagen, Inc. Lavanya Sudharshan is an employee of McKesson, which received consulting fees in connection with this study from Seagen, Inc., Savreet Bains is an employee of Genmab. Leonardo Nicacio is an employee of Seagen Inc. and owns stock in Seagen Inc. Robert L. Coleman has received research support and consulting fees from AstraZeneca, Clovis, Genmab, Roche/Genentech, Janssen, and Immunogen, research support from Merck, and consulting fees from GSK, Agenus, OncoQuest, and Gradalis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin + /anti-CD45 - cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker., (©2020 American Association for Cancer Research.)

Objective: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors., Methods: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety., Results: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations., Conclusions: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population., Trial Registration Number: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT)., Competing Interests: Declaration of Competing Interest A. Oaknin: has received advisory board honoraria from Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, and Deciphera and travel/accommodation support from Roche, AstraZeneca, and PharmaMar. C.F. Friedman: has received institutional research funding from Bristol-Myers Squibb, Merck, and Genentech, advisory board honoraria from AstraZeneca, and serves on steering committees for the Genentech MyPathway and the Merck LYNK-002 studies (compensation waived). L.D. Roman: has received advisory board honoraria from Tempus Labs and is a consultant for Quantgene. A. D'Souza: has no competing interests. I. Brana: has received institutional research funding from Puma Biotechnology Inc. F. Clement-Bidard: has received advisory board honoraria from Pfizer, Novartis, Eli Lilly, Amgen, and AstraZeneca. J. Goldman: has received institutional research funding from Puma Biotechnology Inc. E. A. Alvarez: has received advisory board honoraria from Eisai Co. Inc. and ArQule Inc. and has been a medical consultant for Tracon Pharmaceuticals, Inc. V. Boni: has received advisory board honoraria from Loxo Oncology and Ideaya. A.C. ElNaggar: has received institutional research funding from Caris Life Sciences and advisory board honoraria from AstraZeneca, Clovis Oncology, Leap Therapeutics, Tesaro/GSK, and AbbVie Pharmaceuticals. R. Passalacqua: has received advisory board/speaker honoraria from Amgen, Astellas, Bayer, BMS, Ipsen, Janssen, Novartis, Sanofi-Aventis, Roche, MSD, and Pierre-Fabre. K.T.M. Do: has received advisory board honoraria from QED Therapeutics. A.D. Santin: has received advisory board honoraria from Merck and Tesaro and has received institutional research funding from Puma Biotechnology Inc., Immunomedics, Tesaro, Boehringer Ingelheim, and Genentech. K. Keyvanjah: is an employee and shareholder of Puma Biotechnology Inc. F. Xu: is an employee and shareholder of Puma Biotechnology Inc. L.D. Eli: is an employee and shareholder of Puma Biotechnology Inc. A.S. Lalani: is an employee and shareholder of Puma Biotechnology Inc. R.P. Bryce: is an employee and shareholder of Puma Biotechnology Inc. D.M. Hyman: has acted in a consulting/advisory role for Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, and Genentech, and has received institutional research funding from Loxo Oncology, Puma Biotechnology Inc., and AstraZeneca. He is currently employed by Loxo Oncology/Eli Lilly. F. Meric-Bernstam: has received institutional research funding from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, Puma Biotechnology Inc., Curis, Millennium, Daiichi Sankyo, AbbVie, Guardant Health, Takeda, and GlaxoSmithKline, grants/travel-related fees from Taiho, Genentech, Debiopharm Group, and Pfizer, consultancy fees from Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, and Parexel International, advisory board fees from Inflection Biosciences, GRAIL, Darwin Health, Clearlight Diagnostics, Spectrum, Mersana, and Seattle Genetics. D.H. Solit: has acted in a consulting/advisory role for Loxo Oncology, Pfizer, Illumina, Vivideon Therapeutics, QED Therapeutics, and Lilly Oncology. B.J. Monk: has received consultancy fees from Puma Biotechnology Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Women with persistent, recurrent, and/or metastatic cervical cancer have a poor prognosis. Even with the availability of cisplatin plus paclitaxel and bevacizumab, median overall survival (OS) is only 17.0 months, with median post-progression survival of approximately seven months. We studied the therapeutic vaccine, Axalimogene filolisbac (ADXS-HPV), in women who had progressed following at least one prior line of therapy (Gynecologic Oncology Group protocol 265/NCT01266460)., Methods: Volunteers ≥18 years with advanced cervical cancer and GOG performance status score of 0 or 1 were eligible for participation in this 2-stage, phase II trial. In stage 1, women received up to three doses of ADXS-HPV (1 × 10 9 colony-forming units in 250 mL IV over 15 min every 28 days) and were monitored for tumor progression. In stage 2, women were treated until progression, intolerable adverse events (AEs), or voluntary withdrawal of consent. Co-primary endpoints were safety and proportion of volunteers surviving ≥12 months. An estimated, combined (stages 1 + 2) 12-month OS of 35% was calculated from historical GOG cohorts to declare ADXS-HPV sufficiently active in this platinum-pre-treated population. Secondary endpoints were OS and progression-free survival (PFS)., Results: Among 50 evaluable volunteers, the 12-month OS was 38% (n = 19). Median OS was 6.1 months (95% CI: 4.3-12.1) and median PFS was 2.8 months (95% CI: 2.6-3.0). The most common treatment-related AEs were fatigue, chills, fever, nausea, and anemia. The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment., Conclusion: At the dose and schedule studied, ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity required to warrant further investigation in volunteers with cervical carcinoma., Competing Interests: Declaration of Competing Interest Dr. Warner Huh received money for consultancy from Inovio and Antiva. Dr. William Brady's institution received grant funding from the NCI. He received support for travel to meetings for the study or other purposes from Advaxis. He also received money paid to him from Sarah Cannon Development Innovations. Dr. Paula Fracasso reports that she became an employee of Bristol-Myers Squibb Company (BMS) as of 5/1/14, and as such, she has stock with the company. Prior to her employment with BMS, she was a professor of Medicine and Obstetrics and Gynecology at the University of Virginia where she is now affiliated as a Visiting Professor of Medicine and Obstetrics and Gynecology. Her work on this clinical study was done while she was a Professor at the University of Virginia and no aactivities in this work have any relationship to her work at BMS. Dr. Don Dizon received monies for consultancy from Clovis, Regeneron and AstraZeneca. His institution received grants/pending grants from Bristol Myers Squibb, Kazia, Tesaro and Lilly. Dr. Matthew Powell received monies for consultancy from Merck, Tesaro, Clovis Oncology, AstraZeneca, Abbvie, Janssen and Eisai. He also received payment for lectures, including service on speakers bureaus from Merck, Tesaro, Clovis Oncology and AstraZeneca. Dr. Bradley Monk's institution received Grant money from Advasix and Genentech. He received money from Advaxis, Genentech and Genmab for consulting free or honorarium. He received fee for participation in review activities such as data monitoring boards, statistical analysis, end point committees and the like from Advaxis. Dr. Monk also received money paid to him for consultancy from Advaxis, Genentech and Genmab. His institution has grants/grants pending from Advaxis, Genentech and Genmab. He received payment for lectures, including service on speakers bureaus from Genentech as well as payment for development of educational presentations. He also has received money from Advaxis for stock/stock options. Dr. Charles Leath's institute received grant money from the NIH. His institution also received grants/grants pending for contracted research for recurrent cervical cancer from Agenus. Dr. Erin Crane received New Investigator Travel Award from NRG. She received money from Tesaro/GSK for Speaker's Bureau. Dr. Michael McHale received money for advisory board consultancy from Eisai. He also received money for payment for lectures, including speakers bureau, from Tesaro. Dr. Carol Aghajanian reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, personal fees from Mateon Therapeutics, grants from Genentech, grants from AbbVie, grants from AstraZeneca, personal fees from Eisai/Merck, outside the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BackgroundConcurrent chemoradiotherapy is the standard of care for locally advanced cervical cancer. Concurrent chemoradiotherapy with programmed blockade of the cell death-1/programmed cell death-ligand 1 pathway may promote a more immunogenic environment through increased phagocytosis, cell death, and antigen presentation, leading to enhanced immune-mediated tumor surveillance., Primary Objective: The CALLA trial is designed to determine the efficacy and safety of the programmed cell death-ligand 1 blocking antibody, durvalumab, with and following concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in women with locally advanced cervical cancer., Study Hypothesis: Durvalumab concurrent with and following concurrent chemoradiotherapy will improve progression-free survival in patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 to IVA cervical cancer compared with concurrent chemoradiotherapy alone., Trial Design: CALLA is a phase III, randomized, multicenter, international, double-blind, placebo-controlled study. Patients will be randomized 1:1 to receive either durvalumab (1500 mg intravenously (IV)) or placebo every 4 weeks for 24 cycles. All patients will receive external beam radiotherapy with cisplatin (40 mg/m 2 ) IV or carboplatin (area under the curve 2) IV once a week for 5 weeks, followed by image-guided brachytherapy., Major Inclusion/exclusion Criteria: The study will enroll immunotherapy-naïve adult patients with histologically confirmed cervical adenocarcinoma, cervical squamous, or adenosquamous carcinoma FIGO 2009 stages IB2-IIB node positive and stage IIIA-IVA with any node stage. Patients will have had no prior definitive surgical, radiation, or systemic therapy for cervical cancer., Primary Endpoint: The primary endpoint is progression-free survival (assessed by the investigator according to Response Evaluation Criteria in Solid Tumors v1.1, histopathological confirmation of local tumor progression or death)., Sample Size: Approximately 714 patients will be randomized 1:1 to receive either durvalumab + concurrent chemoradiotherapy or placebo + concurrent chemoradiotherapy., Estimated Dates for Completing Accrual and Presenting Results: Patient enrollment is continuing globally with an estimated completion date of April 2024., Trial Registration: NCT03830866., Competing Interests: Competing interests: Outside the submitted work, JM, reports personal fees from Varian Medical Systems, personal fees from GOG Foundation, personal fees from NRG Oncology, personal fees from AstraZeneca, grants from NRG Oncology, other from GOG Foundation. ATN, ML report personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca outside the submitted work. MM reports personal fees from AstraZeneca and personal fees from Incyte Corporation during the conduct of the study and personal fees from AstraZeneca and Incyte Corporation outside the submitted work. MCL reports personal fees from AZ/MedImmune during the conduct of the study and personal fees from AZ/MedImmune outside the submitted work. BJM reports personal fees from Abbvie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson&Johnson, Mateon (formally Oxigene), Merck, Myriad, Perthera, Pfizer, Precison Oncology, Puma, Roche/Genentech, Samumed, Takeda, TESARO, Inc. and VBL outside the submitted work. ATN, ML, MM and MCL are all employees of AstraZeneca., (© IGCS and ESGO 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Introduction: To describe patient-reported outcomes and toxicities at time of treatment discontinuation secondary to progression or toxicities in advanced/recurrent cervical cancer patients receiving chemotherapy with bevacizumab., Methods: Summarize toxicity, grade, and health-related quality of life within 1 month of treatment discontinuation for women receiving chemotherapy with bevacizumab in GOG240., Results: Of the 227 patients who received chemotherapy with bevacizumab, 148 discontinued study protocol treatment (90 for disease progression and 58 for toxicity). The median survival time from treatment discontinuation to death was 7.9 months (95% CI 5.0 to 9.0) for those who progressed versus 12.1 months (95% CI 8.9 to 23.2) for those who discontinued therapy due to toxicities. The most common grade 3 or higher toxicities included hematologic, gastrointestinal, and pain. Some 57% (84/148) of patients completed quality of life assessment within 1 month of treatment discontinuation. Those patients who discontinued treatment due to progression had a mean decline in the FACT-Cx TOI of 3.2 points versus 2.2 in patients who discontinued therapy due to toxicity. This was a 9.9 point greater decline in the FACT-Cx TOI scores than those who discontinued treatment due to progression (95% CI 2.8 to 17.0, p=0.007). The decline in quality of life was due to worsening physical and functional well-being. Those who discontinued treatment due to toxicities had worse neurotoxicity and pain., Discussion: Patients who discontinued chemotherapy with bevacizumab for toxicity experienced longer post-protocol survival but significantly greater declination in quality of life than those with progression. Future trial design should include supportive care interventions that optimize physiologic function and performance status for salvage therapies., Competing Interests: Competing interests: DC reports personal fees received from AstraZeneca, Clovis, Roche/Genentech, and Tesaro, outside of the submitted work. BJM reports personal fees received from Roche/Genentech, outside of the submitted work. RTP reports serving on a Scientific Advisory Board for Genentech/Roche. AO reports serving on advisory boards for Roche, AstraZeneca, PharmaMar, Clovis Oncology, and Tesaro and received support for travel/accommodation from Roche, AstraZeneca, and PharmaMar. WKH reports receiving personal fees as consultant for Antiva, PathoVax, and Li-Cor, outside of the submitted work. DR reports serving on the Advisory Board for Genentech and Ipsen and received personal fees, outside of the submitted report. RS reports serving on the Speaker Bureau for Genentech as well as serving on Advisory Boards for Tesaro, Clovis, AstraZeneca, and Ethicon, outside of the submitted work. KST reports serving on the Speaker’s Bureau, Advisory Board for Roche/Genentech., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Chemotherapy is the standard treatment in stage IVB cervical cancer (CC). However, given that many women have a significant pelvic disease burden, whole pelvic radiation (WPR) in addition to chemotherapy for primary treatment may have utility. The aim of this study was to compare the overall survival (OS) and complication rates between women who received both WPR and chemotherapy (CT) versus CT alone in the management of stage IVB CC., Methods: A multi-institutional, IRB-approved, retrospective review of patients (pts) with stage IVB CC, diagnosed between 2005 and 2015, was performed. Descriptive statistics of the demographic, oncologic, and treatment characteristics were performed. OS was estimated using the Kaplan Meier method., Results: A total of 126 pts met inclusion criteria. Thirty one patients elected for hospice care at diagnosis and were excluded from further analysis. In the remaining population, median age was 53 yrs. The majority (72%) had squamous cell carcinoma and 82% had FIGO grade 2 or 3 tumors. Thirty four patients (35.8%) received WPR in addition to CT as a part of planned primary therapy and 64.2% (n = 61) received CT alone, with 88.2% and 80.3% receiving a cisplatin-based chemotherapy regimen, respectively. The OS was significantly longer in the WPR with CT group (41.6 vs 17.6 mo, p < 0.01). The rates of ureteral obstruction, vaginal bleeding, pelvic infection, pelvic pain, and fistula were not significantly different between the 2 groups (all p > 0.05)., Conclusion: This study found WPR in addition to CT gives a significant OS benefit. Further study is warranted to determine which subgroups may benefit the most from this novel treatment strategy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Benefits of social support (SS) during cancer survivorship are complex. This study examines change in SS over time in cervical cancer (CXCA) survivors who have completed definitive treatment and how changing SS impacts quality of life (QOL) and T-helper type 2 (Th2) cytokines., Methods: We conducted a randomized trial in 204 CXCA survivors to test if psychosocial telephone counseling (PTC) could improve QOL compared to usual care (UC). Although PTC did not target SS, data were collected at baseline, 4 and 9 months post-enrollment using the Medical Outcomes Survey Social Support scale. Biospecimens were collected to investigate associations with patient-reported outcomes. Data were analyzed using multivariate linear models and stepwise regression., Results: Participants' mean age was 43. PTC participants experienced increasing SS compared to UC at 4 months (PTC-UC = 5.1; p = 0.055) and 9 months (PTC-UC = 6.0; p = 0.046). Higher baseline SS and increasing SS were independently associated with improved QOL at 4 and 9 months after adjusting for patient characteristics (p < 0.05). Differences between study arms were not statistically significant. Improvements in QOL at 4 months were observed with increases in emotional/informational and tangible SS. Increasing SS predicted significant longitudinal decreases in IL-4 and IL-13 at 4 months that were larger in the PTC arm (interactions p = 0.041 and p = 0.057, respectively)., Conclusion: Improved SS was significantly associated with improved QOL independent of patient characteristics and study arm. Decreasing Th2 cytokines with increasing SS and QOL are consistent with a biobehavioral paradigm in which modulation of the chronic stress response is associated with shifts in immune stance.

Purpose: To evaluate the practice patterns among centers and physicians worldwide regarding sentinel lymph node biopsies (SLNB) in cervical cancer (CC) patients., Method: A validated 35-item questionnaire regarding SLNB in CC supported by the Gynecologic Cancer Intergroup (GCIG), and sponsored by the North-Eastern German Society of Gynaecologic-Oncology (NOGGO) was sent to all major gynecological cancer societies across the globe for further distribution from October 2015 and continued for a period of 7 months., Results: One hundred and sixty-one institutions from around the world participated. One hundred and six (66%) of the participants were from university centers and 111 (69%) were gynecologic oncologists. One hundred and fifty-two (97%) performed lymphadenectomy (LNE) and 147 (94%) did so systematically; 97 (60%) used SLNB, due to lower morbidity (73%), reliability (55%) and time-saving (27%). In cases of positive SLNB (pN+), 39% of respondents stopped the operation and sent the patient for chemoradiation (CRT), 45% completed pelvic and paraaortic LNE, whereas 26% went on to perform a radical hysterectomy (RH) and systematic pelvic and paraaortic LNE. In case of negative SLNB (pN0), 39% of institutions still performed a systematic pelvic and paraaortic LNE., Conclusion: In this survey worldwide, SLNB adoption is an encouraging 60%, yet ample differences exist regarding strategy, and to a lower extent the techniques used. Lack of experience is the most common reason SLNB is not performed. Efforts to increase surgical education on SLNB technique and multicenter prospective trials providing evidence-based guidelines are warranted.

Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota (VMB). We enrolled women with ICC, high- and low-grade squamous intraepithelial lesions, as well as, HPV-positive and healthy HPV-negative controls. A broad range of cancer biomarkers was present in the local CVM and specifically elevated in ICC patients. The majority of cancer biomarkers were positively correlated to other biomarkers and linked to genital inflammation. Several cancer biomarkers were also negatively correlated to Lactobacillus abundance and positively correlated with abnormal vaginal pH. Finally, a hierarchical clustering analysis of cancer biomarkers and immune mediators revealed three patient clusters, which varied in levels of cancer biomarkers, genital inflammation, vaginal pH and VMB composition. Specific cancer biomarkers discriminated patients with features of the CVM, such as high genital inflammation, elevated vaginal pH and dysbiotic non-Lactobacillus-dominant VMB, that have been associated with HPV persistence, dysplasia and progression to ICC.

Since 1970, the Gynecologic Oncology Group (GOG) has been at the forefront of evaluating and helping to implement ground breaking and paradigm changing research in the management of cervical cancer. While the most dramatic example of this impact was a series of clinical trials published in 1999 that evaluated chemoradiation therapy versus radiation therapy alone for patients with various clinical scenarios, including both locally advanced as well as post radical hysterectomy patients, investigation has continued to further refine and improve therapy. In 2014, based on the results of GOG protocol 240, bevacizumab became the first approved targeted therapy in a gynecologic cancer in the United States. Most recently, clinical trial work from the GOG is changing the standard of care for all clinical scenarios. Finally, an emphasis on survivorship and special populations are now top priorities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Based primarily on studies concerning early-stage tumours (treated surgically), and locally advanced disease (treated with chemoradiation), the prognosis for women with adenocarcinoma (AC) or adenosquamous (AS) carcinoma has been reported to be poorer than those with squamous cell carcinoma (SCCA) of the cervix. It is unclear whether differences in prognosis also persist in the setting of recurrent or metastatic disease treated using chemotherapy doublets with or without bevacizumab., Methods: Cases were pooled from three Gynaecologic Oncology Group randomised phase III trials of chemotherapy doublets. Pearson's test was used to evaluate response rate (RR) of AC/AS vs SCCA, Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS), and Cox proportional hazards model to estimate the impact of histology on PFS and OS., Results: Of 781 evaluable patients, 77% (N=599) had SCCA and 23% (N=182) AC/AS. There were no significant differences in RRs between histologic subgroups. The adjusted hazard ratio (HR) for death for SCCA vs AC/AS was 1.13 (95% CI 0.93, 1.38 P=0.23). When comparing SC/AS (N=661, 85%) to AC alone (N=120, 15%), the adjusted HR for death was 1.23 (95% CI 0.97, 1.57, P=0.09)., Conclusions: AC/AS and SCCA have similar survival in recurrent or metastatic cervical carcinoma when treated with chemotherapy doublets.

Background: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m 2 on day 1 or 2) plus paclitaxel (135 mg/m 2 or 175 mg/m 2 on day 1) or topotecan (0·75 mg/m 2 on days 1-3) plus paclitaxel (175 mg/m 2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062., Findings: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death., Interpretation: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer., Funding: National Cancer Institute., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients., Methods: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response., Results: Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension., Conclusions: Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability., (Copyright © 2017. Published by Elsevier Inc.)

Cervical cancer is the fourth most common cause of cancer of women worldwide. In the developing world, it comprises 12% of all cancers of women. Since 1999, the mainstay of treatment for locally advanced cervical cancer (LACC) has been concurrent cisplatin-based chemoradiation. However, outcomes in this disease remain suboptimal, with long-term progression-free survival and overall survival rates of approximately 60%. There are several new strategies of combined modality treatment under evaluation in LACC, including chemotherapy before and after treatment as well as novel agents such as poly-adenosine diphosphate ribose polymerase inhibitors, antiangiogenic blockage, and immunotherapy. We provide a brief overview of these strategies and their potential in the treatment of women with LACC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Improvement in health behaviors following cancer diagnosis may contribute to better prognosis and well-being. This study examines the prevalence of health behaviors in cervical cancer survivors who have completed treatment, and associations between health behaviors and quality of life (QOL)., Methods: We recruited 204 women who had completed treatment for cervical cancer to participate in a randomized counseling intervention. Participants provided information on health behaviors (smoking, physical activity, and alcohol consumption); QOL (Functional Assessment of Cancer Therapy-Cervical questionnaire); and depression (Patient-Reported Outcomes Measurement Information System), anxiety (Patient-Reported Outcomes Measurement Information System), and distress (Brief Symptom Inventory) at baseline (9-30 months after diagnosis) and subsequent to the intervention. Data were analyzed using multivariate general linear models., Findings: Participants ranged in age from 20 to 72 years at diagnosis (mean = 43 years), 41% were Hispanic, and 52% were non-Hispanic white. Three-fourths were stage 1 at diagnosis and 51% were treated with radiation with or without chemotherapy. At baseline, 15% of patients were current smokers, 4% reported alcohol consumption of >10 drinks per week, and 63% reported exercising <3 hours per week. Overall, 67.4% of cervical cancer survivors did not meet recommended national guidelines for at least 1 of these health behaviors. QOL scores were significantly higher for patients with greater physical activity (128 vs 118; P = 0.002) and increased with the number of recommended guidelines met (P for trend = 0.030). Associations between patient-reported outcomes and smoking and alcohol consumption did not reach statistical significance. Participants who met guidelines for all health behaviors also had less depression (P = 0.008), anxiety (P = 0.051), and distress (P = 0.142). Participants who improved their aggregate health behaviors during the 4-month follow-up experienced a greater improvement in QOL than those who did not improve their health behaviors (10.8 vs 4.5; P = 0.026)., Implications: Results indicate that two-thirds of cervical cancer survivors are not meeting national guidelines for smoking, physical activity, and alcohol consumption following completion of definitive treatment. These adverse health behaviors were associated with impaired QOL and higher levels of depression and distress. Positive changes in health behaviors are associated with significant improvement in QOL., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Objective: Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries., Methods: The focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identifying national and international barriers for studies of cervix cancers. The second half of the meeting was concerned with achieving consensus on a path forward., Results and Conclusions: There were 5 principal outcomes as follows: first, a proposal to expand fertility-preserving options with neoadjuvant chemotherapy; second, validation of the assessment of sentinel lymph nodes using minimally invasive surgery with an emphasis on identification and management of low-volume metastasis, such as isolated tumor cells and micrometastasis; third, evaluation of hypofractionation for palliative and curative radiation under the umbrella of the GCIG Cervix Cancer Research Network; fourth, adding to the advances in antiangiogenesis therapy in the setting of metastatic disease; and fifth, developing a maintenance study among women at high risk of relapse. The latter 2 systemic interventions could study PI3K (phosphatidylinositol-3-kinase) inhibitors, immunotherapy, anti-human papillomavirus approaches, or novel antiangiogenic agents/combinations.

Purpose: In the randomized phase III trial, Gynecologic Oncology Group (GOG) protocol 240, the incorporation of bevacizumab with chemotherapy significantly increased overall survival (OS) in women with advanced cervical cancer. A major objective of GOG-240 was to prospectively analyze previously identified pooled clinical prognostic factors known as the Moore criteria., Experimental Design: Potential negative factors included black race, performance status 1, pelvic disease, prior cisplatin, and progression-free interval <365 days. Risk categories included low-risk (0-1 factor), mid-risk (2-3 factors), and high-risk (4-5 factors). Each test of association was conducted at the 5% level of significance. Logistic regression and survival analysis was used to determine whether factors were prognostic or could be used to guide therapy., Results: For the entire population (n = 452), high-risk patients had significantly worse OS (P < 0.0001). The HRs of death for treating with topotecan in low-risk, mid-risk, and high-risk subsets are 1.18 [95% confidence interval (CI), 0.63-2.24], 1.11 (95% CI, 0.82-1.5), and 0.84 (95% CI, 0.50-1.42), respectively. The HRs of death for treating with bevacizumab in low-risk, mid-risk, and high-risk subsets are 0.96 (95% CI, 0.51-1.83; P = 0.9087), 0.673 (95% CI, 0.5-0.91; P = 0.0094), and 0.536 (95% CI, 0.32-0.905; P = 0.0196), respectively., Conclusions: This is the first prospectively validated scoring system in cervical cancer. The Moore criteria have real-world clinical applicability. Toxicity concerns may justify omission of bevacizumab in some low-risk patients where survival benefit is small. The benefit to receiving bevacizumab appears to be greatest in the moderate- and high-risk subgroups (5.8-month increase in median OS). Clin Cancer Res; 21(24); 5480-7. ©2015 AACR., (©2015 American Association for Cancer Research.)