FDA Approves Newest Antibody-Drug Conjugate for Cervical Cancer

Health-System Edition, January 2022 , Volume 11, Issue 01

Tisotumab vedotin-tftv is used as antitumor therapy for patients with disease progression during or after chemotherapy.

Cervical cancer is a rare type of cancer that originates from the cellular lining of the cervix, representing approximately 0.8% of all new cancer cases and 0.7% of all cancer deaths each year in the United States.1

In 2021, there were 14,440 new cases of cervical cancer and approximately 4290 deaths from cervical cancer in the United States, according to data from the National Cancer Institute.1 The 5-year relative survival rate for patients with cervical cancer is 66.3%, with a lower 5-year survival rate of 17.6% for patients with distant metastatic disease.1

Along with lower survival rates, recurrence rates for metastatic cervical cancer remain high, despite the implementation of newer therapies. Platinum-doublet chemotherapy alone was initially seen as a preferred first-line treatment option for patients with metastatic cervical cancer. Over time, however, the addition of newer agents such as the VEGF inhibitor bevacizumab (Avastin, Genentech) to first-line cervical cancer regimens has improved overall survival for patients who have metastatic disease.2 Regardless, patients with metastatic disease will ultimately fail treatment in the first-line setting because of chemotherapy intolerance or disease progression. National Comprehensive Cancer Network guidelines recommend numerous second- and subsequent-line therapies for metastatic cervical cancer.2 Therefore, there has been a general push for the development of newer, more effective, and safer treatments in this setting.

Antibody-drug conjugates (ADCs) are targeted agents that have shown promise in the treatment of certain cancers, including acute leukemias, breast cancer, and Hodgkin lymphoma. An ADC comprises a cytotoxic drug (“payload”) that has been artificially combined with a monoclonal antibody designed to carry, selectively target, and bind to tumor antigens. It then delivers the cytotoxic payload to the tumor sites, which results in cell death. Once the payload is internalized by a tumor cell, a phenomenon known as “bystander killing” can occur, where the cytotoxic payload is diffused to adjacent cells. By itself, the cytotoxic payload is incredibly potent. ADCs have been theorized to be more efficacious and safer than standard chemotherapy because of the lower incidence of systemic chemotherapy exposure through localized delivery.3 Even though ADCs are more selective than other chemotherapy agents, risks for off-target toxicities exist, oftentimes involving major organs.

Tissue factor (TF), also known as platelet coagulation factor III, is normally found within the body and is involved with the initiation of the coagulation cascade.4 Unfortunately, in cervical and many other cancers, malignant cells have developed mechanisms to manipulate TF. Some cancer cells can increase overall TF levels in the bloodstream, resulting in surges of tumor cell angiogenesis, metastasis, growth, and risks for thrombosis.4 Specifically in cervical cancer, higher levels of TF expression have been associated with higher-stage disease and an increased rate of invasion and metastasis.5

The FDA approved tisotumab vedotin-tftv (Tivdak, Seagen/Genmab) in September 2021 for patients with metastatic or recurrent cervical cancer with disease progression during or after prior treatment with chemotherapy. As the first ADC approved to target TF on tumor cells, tisotumab vedotin comprises a TF-directed antibody attached to a cytotoxic microtubule inhibitor, monomethyl auristatin E (MMAE). After selectively binding to extracellular TF, the ADC complex becomes internalized and MMAE is released intracellularly, leading to cell death.

The innovaTV 204 clinical trial (NCT03438396) was a multicentered, open-label, single-arm, phase 2 trial where 101 patients with either metastatic or recurrent cervical cancer were treated with tisotumab vedotin.6 Eligible patients had to have disease progression either during or after treatment involving doublet chemotherapy (paclitaxel, plus either platinum or topotecan) plus bevacizumab. Patients received tisotumab vedotin at a dose of 2 mg/kg (maximum 200 mg/dose) intravenously every 3 weeks until either disease progression or unacceptable toxicities.

After a median follow-up of 10 months at the time of data cutoff, 24% of patients had a confirmed disease response.6 The data were supported by a 6-month survival rate of 79% and a median overall survival rate of 12.1 months. With approximately 79% of patients having reductions in target lesion size and a median time to response of 1.4 months, the rapid antitumor effects of tisotumab vedotin may be clinically attractive as a subsequent-line treatment option.

Numerous toxicities were seen in the innovaTV 204 trial, including alopecia, bleeding events, fatigue, nausea, and peripheral neuropathy.6 Ocular toxicities have been seen with tisotumab vedotin, as well, reported in 53% of patients in the trial. These ocular toxicities include conjunctivitis, dry eye, keratitis, and vision changes, with rare cases of corneal ulceration and severe vision loss. The FDA label for tisotumab vedotin includes a boxed warning for ocular toxicities, and it is recommended that patients undergo ophthalmic exams at baseline and prior to each cycle.7 In addition, it is recommended that patients premedicate each infusion of tisotumab vedotin with corticosteroid and vasoconstrictor eye drops and ocular lubricants and use cooling eye pads during the infusion.

Tisotumab vedotin is one of the newest subsequent-line treatment options for patients with recurrent metastatic cervical cancer, who have generally poorer prognoses. As an ADC, tisotumab vedotin is among a growing class of antitumor therapies with more than 100 others under investigation.3

Don V. Scigliano is a PharmD candidate at St. John Fisher College of Wegmans School of Pharmacy in Rochester, New York.

Bryan Fitzgerald, PharmD, BCOP, is an oncology clinical pharmacy specialist at UR Medicine/Wilmot Cancer Institute at the University of Rochester Specialty Pharmacy in New York.


  1. Cancer stat facts: cervical cancer. National Cancer Institute. Accessed December 3, 2021. https://seer.cancer.gov/statfacts/html/cervix.html
  2. NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 1.2022. Accessed December 3, 2021. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
  3. Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019;394(10200)793-804. doi:10.1016/S0140-6736(19)31774-X
  4. Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009;27(29):4834-4838. doi:10.1200/JCO.2009.22.6324
  5. Zhao X, Cheng C, Gou J, et al. Expression of tissue factor in human cervical carcinoma tissue. Exp Ther Med. 2018;16(5):4075-4081. doi:10.3892/etm.2018.6723
  6. Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety o f tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5
  7. Tivdak (tisotumab vedotin-tftv). Prescribing information. Seagen Inc; 2021. https://www. seagen.com/medicines/tivdak