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.

1st Faculty of Medicine Bulovka University Hospital Charles University Prague Czech Republic

Baskent University Ankara Turkey

Beatson West of Scotland Cancer Centre Gartnavel General Hospital Glasgow United Kingdom

Belgium and Luxembourg Gynaecological Oncology Group Leuven Cancer Institute Leuven Belgium

BGOG Centre Hospitalier de l'Ardenne Site de Libramont Libramont Chevigny Belgium

BGOG Centre Hospitalier Universitaire de Liège Liège Belgium

BGOG Ghent University Hospital Ghent Belgium

Centre for Cancer and Organ Diseases Rigshospitalet University Hospital of Copenhagen Copenhagen Denmark

Cliniques Universitaires Saint Luc and Université Catholique de Louvain and BGOG Brussels Belgium

Department of Medical Oncology Cancer Trials Ireland Cork University Hospital Cork Ireland

Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Obstetrics and Gynecology Augusta University Augusta GA

Department of Obstetrics and Gynecology University of Cincinnati Cancer Center Cincinnati OH

Dutch Gynaecological Oncology Group Amsterdam University Medical Centers Amsterdam the Netherlands

Erasmus MC Cancer Institute Rotterdam the Netherlands

Fondazione Policlinico Universitario Agostino Gemelli IRCCS Catholic University of Sacred Heart Rome Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Genmab A S Copenhagen Denmark

Genmab US Princeton NJ

HonorHealth Research Institute University of Arizona College of Medicine Creighton University School of Medicine Phoenix AZ

Memorial Sloan Kettering Cancer Center Weill Cornell Medical College New York NY

Merck and Co Inc Rahway NJ

Program in Women's Oncology Women and Infants Hospital Legorreta Cancer Center at Alpert Medical School of Brown University Providence RI

Radboudumc Nijmegen the Netherlands

Royal Marsden National Health Service Foundation Trust Institute of Cancer Research London United Kingdom

School of Medicine Virginia Commonwealth University Richmond VA

Seagen Bothell WA

University Medical Center Utrecht Utrecht the Netherlands

University of California Irvine CA

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ClinicalTrials.gov
NCT03786081