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Competing Interests: I took part in an advisory board and in a health economics interview regarding the progression-free survival data from the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study previously published,(7) but was not involved in the current Article.(3) I report grants from AstraZeneca, Deciphera, and GSK; consulting fees from GSK, Ipsen, and MSD; speakers fees from AstraZeneca, BMS, GSK, Ipsen, MSD, Pfizer, and Pharmamar; support for meetings or travel from AstraZeneca, GSK, Ipsen, MSD, Pfizer, and Pharmamar; and participation on data safety monitoring board or advisory boards for AstraZeneca, BMS, Eisai, GSK, Ipsen, and MSD.

Background: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy., Methods: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival., Results: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects., Conclusions: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.)., (Copyright © 2024 Massachusetts Medical Society.)

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.

Purpose: To develop machine learning models to predict para-aortic lymph node (PALN) involvement in patients with locally advanced cervical cancer (LACC) before chemoradiotherapy (CRT) using 18 F-FDG PET/CT and MRI radiomics combined with clinical parameters., Methods: We retrospectively collected 178 patients (60% for training and 40% for testing) in 2 centers and 61 patients corresponding to 2 further external testing cohorts with LACC between 2010 to 2022 and who had undergone pretreatment analog or digital 18 F-FDG PET/CT, pelvic MRI and surgical PALN staging. Only primary tumor volumes were delineated. Radiomics features were extracted using the Radiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Different prediction models were trained using a neural network approach with either clinical, radiomics or combined models. They were then evaluated on the testing and external validation sets and compared., Results: In the training set (n = 102), the clinical model achieved a good prediction of the risk of PALN involvement with a C-statistic of 0.80 (95% CI 0.71, 0.87). However, it performed in the testing (n = 76) and external testing sets (n = 30 and n = 31) with C-statistics of only 0.57 to 0.67 (95% CI 0.36, 0.83). The ComBat-radiomic (GLDZM&#95;HISDE&#95;PET&#95;FBN64 and Shape&#95;maxDiameter2D3&#95;PET&#95;FBW0.25) and ComBat-combined (FIGO 2018 and same radiomics features) models achieved very high predictive ability in the training set and both models kept the same performance in the testing sets, with C-statistics from 0.88 to 0.96 (95% CI 0.76, 1.00) and 0.85 to 0.92 (95% CI 0.75, 0.99), respectively., Conclusions: Radiomic features extracted from pre-CRT analog and digital 18 F-FDG PET/CT outperform clinical parameters in the decision to perform a para-aortic node staging or an extended field irradiation to PALN. Prospective validation of our models should now be carried out., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This monocentric study aimed to assess the impact of technical advancement in brachytherapy (BT) on local control (LC) and cancer-specific survival (CSS) in locally advanced cervical cancer (LACC)., Methods: Since 2010, 211 patients with LACC have been treated with 45/50.4 Gy or 60 Gy radiochemotherapy (RTCT) followed by image-guided adaptive brachytherapy (IGABT) at the authors' institution. In 2013, combined intracavitary and interstitial brachytherapy (BT IC/IS) was implemented and in 2018, pulsed-dose-rate BT (PDR-BT) was replaced by high-dose-rate BT (HDR-BT). LC, CSS, and morbidity according to the RTOG/EORTC scoring system were analyzed. Dose-volume parameters for the high-risk clinical target volume (HRCTV) and organs at risk (OAR) were reported., Results: While 27 (12.8%) patients died of LACC, complete local remission was achieved in 199 (94.3%). Local relapse decreases with a high D95 in the HRCTV (hazard ratio, HR = 0.85, p = 0.0024). D95 in the HRCTV is lower after 60 Gy even if interstitial BT is used. Mean D95 in the HRCTV is 78.2 Gy, 83.3 Gy, and 83.4 Gy with PDR-BT IC, PDR-BT IC/IS, and HDR-BT IC/IS, respectively, after 45/50.4 Gy. D2 cc of OARs is significantly reduced by using interstitial BT. The mean rectum and sigmoid D2 cc are about 61.5 Gy with PDR-BT IC/IS and significantly decreased with HDR-BT IC/IS. This translates into a low fistula incidence. A very low rate of severe gastrointestinal (3.4%) and genitourinary (2.3%) toxicity was observed with HDR-BT IC/IS., Conclusion: This large monocentric study provides further evidence that implementation of BT IC/IS has an impact on D95 in the HRCTV, LC, and CSS. There are no differences between HDR and PDR in terms of efficacy, D95 in the HRCTV, and toxicity grade ≥ 3., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction : Locally advanced cervical cancer (LACC) (International Federation of Gynecology and Obstetrics (FIGO) 2009/2018 - stages IB2-IVA/IB3-IVA, respectively) is treated using a multimodal approach that includes chemoradiotherapy followed by brachytherapy. Areas covered : This review provides an overview of the progress made over the past decade in the treatment of LACC. Prognostic factors, FIGO classification and the role of imaging staging will be discussed. Efficacy of external-beam radiotherapy, brachytherapy and chemotherapy will be detailed. Indications for para-aortic staging lymphadenectomy and adjuvant hysterectomy, as well as follow-up and special population, will be covered. Expert opinion : The initial workup is one of the most crucial steps in the optimal care of patients, which should be realized by a multidisciplinary expert team. With the implementation of modern conformal radiotherapy techniques, the local control rate has been optimized. Nevertheless, 40% of patients experience recurrence with distant metastasis and a dismal prognosis. Currently, a clear benefit of neo- and adjuvant chemotherapy has not been established. The future likely involves (1) improved selection of patients for whom treatment intensification is justified, (2) a combination of new drugs with chemoradiation that are currently being tested in trials, and (3) the development of tailored treatment based on molecular characteristics.

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.)

Background: Hemoglobin (Hb), white blood cell (WBC), and polymorphonuclear neutrophil (PMN) blood counts may be correlated with outcomes in patients with locally advanced cervical cancer., Methods: Hb, WBC, and PMN counts were measured at diagnosis and during concomitant cisplatin-based chemoradiotherapy (CCRT) in a retrospective sample of 103 patients between 2010 and 2017. Red blood cell (RBC) transfusions were also recorded. The associations between hematological variables and patient overall survival (OS) and recurrence-free survival (RFS) were assessed by Cox regression models., Results: The 3-year OS and RFS rates were 81.4% and 76.8%, respectively. In addition to tumor size and smoking, OS and RFS were found to be significantly associated with changes in WBC and PMN counts from the first to the last cisplatin cycle. Hb count throughout the treatment and RBC transfusions were not predictive of outcome., Conclusions: This study found no association between Hb count or RBC transfusions and outcome. The daily practice of maintaining the Hb count above 12 g/dL during CCRT should be weighed against the potential risks of transfusions. Drops in WBC and PMN counts during treatment positively impacted OS and RFS and could, therefore, serve as biomarkers during CCRT to adapt the follow-up and consider the need for adjuvant systemic treatments., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to investigate the prognostic value of metabolic parameters obtained at pretreatment [ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) in patients with locally advanced cervical cancer. We hypothesize that these metabolic parameters could optimize the treatment decision and thus favor the outcome of patients suffering locally advanced cervical cancer., Methods: Patients with locally advanced cervical cancer underwent pretreatment PET/CT. Standard uptake values (maximum, mean, peak), metabolic tumor volume, and total lesion glycolysis were measured in the tumor and in the hypermetabolic pelvic lymph nodes. The relationship between clinical, pathological, and PET/CT metabolic parameters with recurrence-free survival and overall survival was assessed by Cox regression analysis., Results: 115 patients with a median age of 52 years (range 23-77) presented with locally advanced cervical cancer. After a mean follow-up of 33.0 months after initiation of therapy, 26 patients (22.6%) recurred of which 17 patients had distant metastasis; 18 (15.7%) patients died. Recurrence-free survival at 2 and 5 years was 79.2% and 72.2%, respectively. The total lesion glycolysis of the tumor and the delay between diagnosis and treatment were significantly associated with recurrence-free survival in the multivariate analysis (HR 1.00, p=0.004, and HR 2.04, p=0.02, respectively). Only the total lesion glycolysis of the tumor ≥373.54 (HR 2.49, 95% CI 1.15 to 5.38; p=0.02) remained significant after log rank testing. Overall survival at 2 and 5 years was 91.7% and 68.8%, respectively. The number of PET-positive pelvic lymph nodes was the only independent prognostic factor for overall survival in the multivariate analysis (HR 1.43, 95% CI 1.13 to 1.81; p=0.003)., Conclusion: Tumor total lesion glycolysis and the number of positive pelvic lymph nodes on pretreatment PET/CT appear to be independent prognostic factors for recurrence and survival in patients with locally advanced cervical cancer. This may help to select patients who may benefit from therapeutic optimization and closer surveillance., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Extended field chemoradiation is recommended for patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) metastases. The radiation planning may be based on PET/CT while others recommend to rely on surgical staging. We report the rate of patients for whom the radiation field defined on PET/CT was modified by the histological PALN status., Methods: Between March 2010 and December 2016, 168 consecutive patients with LACC underwent a pre-therapeutic PET/CT and PALN dissection. The data were reviewed retrospectively. The diagnostic performance of the PET/CT for definition of PALN status was calculated. We determined the percentage of patients for whom PALN dissection altered the external beam radiotherapy (EBRT) field defined on the PET/CT basis., Results: Of 151 patients with negative PALNs on PET/CT, 26 had histological PALN metastases. Of 17 patients with positive PALNs on PET/CT, 9 were negative on histology of which 7 were located in the common iliac region. Sensitivity, specificity, positive and negative predictive value of PET/CT were 23.5, 93.3, 47.1 and 82.8% respectively. In total, 35 out of 168 patients underwent EBRT - field adaptation (pelvic vs extended field). The rate of radiation field modification (27,7%) was particularly high in the subgroup of patients with metastatic pelvic lymph nodes (PLNs) on PET/CT., Conclusion: Para-aortic surgical staging contributes significantly to individualize the radiation treatment of patients with LACC, particularly for those with positive PLNs at PET/CT. Indication of surgical staging deserves particular attention when the PET/CT suggests positive LNs in the common iliac region., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623)., Patients and Methods: Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity., Results: Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%-37%]. Median duration of response (DOR) was 4.2 months (range: 1.0 + -9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%-43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%-35%), median DOR of 6.0 months (range: 1.0 + -9.7), and 6-month PFS rate of 40% (95% CI: 24%-55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed., Conclusions: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer., (©2019 American Association for Cancer Research.)

Background: To evaluate efficacy and toxicity of radio-chemotherapy (RCT) and MR-guided pulsed-dose-rate (PDR) adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC)., Material and Methods: Between 2007 and 2014 85 patients with FIGO stage 1B1 N+ or ≥ 1B2 cervical cancer were treated with RCT+ IGABT. The treatment consisted of a pelvic± paraaortic external beam radiotherapy (EBRT) (45-50.4 Gy ± 10 Gy boost to primary tumor and/or to pathologic lymph nodes) with concurrent cisplatin followed by 25-35 Gy of PDR IGABT in 30-50 pulses. The ratio of 3D-CFRT/IMRT was 61/24 patients. Dose-volume parameters of high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume (IR-CTV) and D2cm(3) organs at risk (OARs) were reported. Local control (LC), cancer-specific survival (CCS) and overall survival (OS) were analyzed actuarially and morbidity crude rates were scored using CTCAEv4.0., Results: Mean follow-up was 36 months (range 6-94). The mean D90 and D98 for HR-CTV was 84.4 ± 9 Gy and 77 ± 8.1 Gy, while for IR-CTV was 69.1 ± 4.3 Gy and 64.8 ± 4.3 Gy, respectively. The mean D2cm(3) for OARs was the following: bladder: 77.3 ± 10.5 Gy, rectum: 65 ± 6.8 Gy, sigmoid: 63 ± 7.9 Gy and intestine: 64.0 ± 9.1 Gy. Three year LC, CSS and OS were: 94%, 85% and 81%. The three-year regional- and distant control rates were 95% and 74%. Node negative patients had significantly higher three-year CSS (100 vs. 72%, p = 0.016) and OS (92 vs. 72%, p = 0.001) compared to node positive ones. Three-year actuarial late Grade ≥ 3 morbidity was the following: GI: 8%, GU: 5%, Vaginal: 8%. The frequency of Grade ≥ 3 hematological toxicities including anemia/leukopenia/neutropenia/thrombocytopenia were 8.6%/34.7%/24.3%/24.3%, respectively., Conclusion: This large mono-institutional experience builds up further evidences that IGABT in conjunction with RCT should be the standard of care for patients suffering LACC.

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.