The U.S. Food and Drug Administration (FDA) has granted accelerated approval to tisotumab vedotin-tftv (Tivdak™; Seagen/GenMab; previously known as HuMax®-TF-ADC), a first-in-class and only approved antibody-drug conjugate (ADC) for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
Tisotumab vedotin is approved under the FDA’s Accelerated Approval Program based on tumor response and the durability of the response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.
Incidence of cervical cancer
It is estimated that in 2021, more than 14,480 new cases of invasive cervical cancer will be diagnosed in the U.S., and 4,290 women will die from the disease.  Cervical cancer remains one of the leading causes of cancer death in women globally, with over 311,000 women dying of the disease in 2018, making the disease the third leading cause of cancer-related death in women worldwide. 
Recurrent or metastatic cervical cancer has a poor prognosis, with an average 5-year survival rate of 17% .
Current standard of care
Over the past 5 years, bevacizumab and doublet chemotherapy, a combination of paclitaxel and cisplatin or paclitaxel and topotecan, were adopted as first-line standard-of-care therapy for recurrent or metastatic cervical cancer.  However, upon disease progression on or after first-line therapy provides minimal benefit with no current second-line standard of care. As a result, there remains a major unmet medical need for the treatment of the disease.
Early trial results
Early on, in the InnovaTV 201 study (N = 55), tisotumab vedotin showed a manageable safety profile and encouraging antitumor activity in the treatment of patients diagnosed with advanced, previously treated cervical cancer. Interestingly, responses with tisotumab vedotin were observed across histologic types and prior treatment type received, including bevacizumab in combination with doublet chemotherapy, providing evidence that tisotumab vedotin would be a treatment option for the patients with cervical cancer that, until today, lacked effective therapies, with a high risk of relapse and has low survival after first-line treatment.
“Once recurrent or metastatic cervical cancer progresses, there is a need for more options for these patients,” said Robert L. Coleman, M.D., Chief Scientific Officer, US Oncology Research and lead investigator of the innovaTV 204 clinical trial.
“This is an important development for patients with recurrent or metastatic cervical cancer.”
Tisotumab vedotin is composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody.
Tissue factor (TF), also called platelet coagulation factor III, is an important member of the human coagulation factor family. TF initiates the blood coagulation cascade in vivo by binding with coagulation factor VII/VIIa  The expression of TF is a biomarker for preoperative diagnosis and the prognosis of malignant tumors. Tissue factor also affects the clinical progression of malignant tumors, including the proliferation, infiltration, and metastasis of cancer cells, making it a target for the treatment of cancer.
In cervical cancer, tissue factor (TF) is frequently highly expressed and associated with poor prognosis.
Nonclinical data suggests that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
In the innovaTV 204 study, an open-label, multicenter, single-arm Phase 2 clinical trial conducted by Genmab in collaboration with Seagen, European Network of Gynaecological Oncological Trial Groups (ENGOT), and the GOG Foundation (GOG), tisotumab vedotin was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen.
Patients were excluded if they had active ocular surface disease, any prior episode of cicatricial conjunctivitis or Stevens-Johnson syndrome, Grade ≥2 peripheral neuropathy or known coagulation defects leading to an increased risk of bleeding.
Results from the trial showed a 24 percent confirmed objective response rate (ORR) (95% CI; 15.9-33.3), as assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. The median duration of response (DOR) was 8.3 months (95% CI; 4.2 to not reached).
“We are thrilled to see this new treatment approved by the FDA. We are grateful to have another option for this devastating disease,” said Tamika Felder, Founder, Cervivor.
A long journey to approval
“[The] approval of tisotumab vedotin as a monotherapy in the U.S. is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them,” said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab.
“The journey towards the approval of tisotumab vedotin started nearly two decades ago with innovative research by scientists at Genmab and Seagen and reflects on our purpose of making an impact in the lives of cancer patients and their families. Today’s announcement marks Genmab’s evolution into a fully integrated biotechnology company and we would like to thank patients, caregivers, investigators, and our collaborators for their participation in our clinical studies.”
“We are pleased with the accelerated approval of tisotumab vedotin, Seagen’s third FDA-approved antibody-drug conjugate, and fourth approved medicine. Our mission at Seagen is to develop medicines that make a difference for people impacted by cancer,” said Roger Dansey, M.D., Chief Medical Officer, Seagen.
The Biologics License Application (BLA) for tisotumab vedotin was submitted in February 2021 and accepted with Priority Review in April 2021. The submission was based on the results of the innovaTV 204 trial.
The FDA’s Accelerated Approval Program allows for approval of a medicine based on a surrogate endpoint that is reasonably likely to predict clinical benefit, if the medicine fills an unmet medical need for a serious condition. A global, randomized phase 3 clinical trial (InnovaTV 301) is underway and is also intended to support global registrations.
Tisotumab vedotin is being co-developed by Genmab and Seagen, under an agreement in which the companies share costs and profits for the product on a 50:50 basis.
Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors – NCT02001623
A Trial of Tisotumab Vedotin in Cervical Cancer – NCT03438396/GOG-3023/ENGOT-cx6.
Tisotumab Vedotin vs Chemotherapy in Recurrent or Metastatic Cervical Cancer (InnovaTV 301) – NCT04697628
Highlights of Prescribing Information
Tisotumab vedotin-tftv (Tivdak™; Seagen/GenMab)[Prescribing Information]
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Featured image: Research associate at Genmab, Cell culturing. Photo courtesy: © 2020 Genmab/Tuala Hjarnø and Torkil Stavdal