Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer

Background: Advanced recurrent or metastatic cervical cancer has a 5-year survival of only 17% and no current second-line standard-of-care, representing a significant unmet need. Tissue factor (TF) is a potential therapeutic target in cervical cancer as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class antibody-drug conjugate targeting TF, has successfully demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201. 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. This trial is registered with Clinicaltrials.gov, number NCT02001623. Findings: Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% received prior bevacizumab+doublet chemotherapy. 51% 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% 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). TF expression was confirmed in most patients; no significant association with response was observed. Interpretation: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer. Funding: Genmab A/S. Declaration of Interest: D.S.H. has received research grants from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO Oncology, Medimmune, Merck, Mirati, Mirna Therapeutics, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, and Takeda; has been a consultant/advisor for Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Molecular Match, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics; has received travel accommodations from LOXO Oncology, Genmab, and Mirna Therapeutics; and has ownership interest in MolecularMatch, OncoResponse, and Presagia Inc. N.Con. has been a consultant/advisor for AstraZeneca and Seattle Genetics; and has received travel accommodations/expenses from Amgen, Genmab, and Roche. I.V. has received research grants from Amgen, Roche, and Stichting Tegen Kanker; has performed contracted research with Genmab A/S, Genmab BV, and Oncoinvent A/S; has been a consultant advisor for Advaxis, AstraZeneca NV, Clovis Oncology, Eisai, F. Hoffmann-La Roche Ltd, Genmab A/S, Genmab US, Immunogen, Millennium Pharmaceuticals, MSD Belgium, Oncoinvent A/S, PharmaMar, Roche NV, Tesaro Bio GmbH, and Tesaro; and has received travel accommodations from AstraZeneca, Genmab, PharmaMar, Roche, Takeda Oncology, and Tesaro. J.S.d.B. has participated in advisory boards for Astellas, AstraZeneca, Genentech, Genmab, GlaxoSmithKline, Merck, Pfizer, Roche, and Sanofi-Aventis. Y.D. has participated in advisory boards for Genmab. J.-P.M. has participated in advisory boards for Debio, INNATE, MSD, and Nanobiotix. M.D.F. is supported by the UCL/UCLH NIHR Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility supported by the UCL ECMC. C.G. has received research support from Lilly, Ipsen, Novartis, PharmaMar, Pfizer, and Roche; has received personal fees from AstraZeneca, Bristol-Myers Squibb, Lilly, Ipsen, Janssen, Novartis, PharmaMar, Pfizer, and Roche; has received non-financial support from AstraZeneca, Ipsen, Pfizer, PharmaMar, and Roche; and served as principal investigator at her institution for Genmab. M.L.J. has received research funding from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Array BioPharma, AstraZeneca, BeiGene, BerGenBio, Birdie, Boehringer Ingelheim, Bristol-Myers Squibb, Checkpoint Therapeutics, Clovis, Corvus, CytomX, Daiichi Sankyo, Dynavax, EMD Serono, G1 Therapeutics, Genmab, Genocea, Gritstone, Guardant Health, Hengrui Therapeutics, Incyte, Janssen, Kadmon, Lilly, LOXO, Lycera, Merck, Mirati Therapeutics, Neovia, Novartis, OncoMed, Pfizer, Regeneron, Roche/Genentech, Sanofi, Stemcentrx, Syndax, and Tarveda; has been a consultant/advisor for Araxes Pharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera, Celgene, Guardant Health, Incyte, LOXO, Merck, Mersana Therapeutics, Mirati, Pfizer, Ribon Therapeutics, Roche/Genentech, and Sanofi; has received travel support from AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol-Myers Squibb, Exelixis, Genentech, Incyte, Merck, Pfizer, Sysmex Inostics, and Vapotherm; and has a spouse who is a contract lobbyist for Astellas and Otsuka Pharmaceuticals. F.C.T. has received research support from Novartis; has been a consultant/advisor for Achilles Therapeutics, BristolMyers Squibb, Evelo Biosciences, Novartis, and Pfizer; has received travel support from BristolMyers Squibb and Ipsen; and has received non-financial support from Pfizer. R.A.R., S.G., K.W., and J.R.H. are employees of Genmab. R.L.C. has received grants from the Gateway Foundation, NIH, and V Foundation; has received research support from AstraZeneca, Clovis, Genmab, Janssen, Merck, and Roche/Genentech; and has been a consultant/advisor for Agenus, AstraZeneca, Clovis, GamaMabs, Genmab, Janssen, Medivation, OncoQuest, Regeneron, Roche/Genentech, and Tesaro. The following authors declare no conflicts of interest: N.Cor, B.M.S., H.-T.A., J.F.S., R.J., M.D.F., and U.N.L. Ethical Approval: The trial protocol was approved by an independent ethics committee or institutional review board prior to initiation.