The 12th ADC Drug Approved by the FDA

Seagne and Genmab announced on September 20, 2021 that Tisotumab Vedotin has received accelerated approval from the FDA for the treatment of recurring or metastatic cervical cancer.

Tivdak (Tisotumab vedotin-tftv) is an ADC produced by combining Genmab’s tissue factor (TF) monoclonal antibody with Seagen’s ADC technology, which binds the cytotoxic drug MMAE to the monoclonal antibody via a protease-cleavable linker. The antigen tissue factor is found on the surface of cervical cancer cells. When tivdak is endocytosed, it releases MMAE that disrupts the microtubule network in dividing cells, causing cell cycle arrest and death.

Tivdak is the first FDA-approved antibody-drug conjugate targeting tissue factor (TF), which is a membrane protein expressed in the tumor cells of many solid tumors and is associated with poorer tumor growth, angiogenesis, metastasis, and clinical prognosis.

Tisotumab Vedotin demonstrated excellent efficacy in phase II clinics Innovatv 204 (also known as GCT1015–04 or Innovatv 204/GOG-3023/ENGOT-CX6), an ongoing single-arm, global, multicenter study in patients with recurrent or metastatic cervical cancer who have previously received double combination chemotherapy with or without Bevac monotherapy. Patients were also eligible if they had previously had up to two therapies for relapsed or metastatic cancer. In this study, 101 patients were treated with Tisotumab Vedotin at multiple centers in the United States and Europe. The independent central review assessed that the primary endpoint of the trial was the objective response rate for each response evaluation criterion in solid tumors (RECRIST) V1.1. Key secondary endpoints included time to response, progression-free survival, overall survival, safety, and tolerability.

The overall response rate (ORR) was 24% in phase II clinical trial of innovaTV204, with a complete remission rate of 7%. The average time in remission was 8.3 months, the average time without advancement was 4.2 months, and the average total survival was 12.1 months.

Cervical cancer originates in the cells lining the cervix and is one of the leading causes of cancer death in women worldwide, with more than 311,000 cases dying each year. It is estimated that more than 13,500 women were diagnosed with invasive cervical cancer in 2020 in the United States, with approximately 4,200 deaths. Routine medical screening and HPV vaccines have reduced the incidence of cervical cancer in developed countries, but patients diagnosed with cervical cancer often have recurrence or metastasis. Treated patients with recurrent or metastatic cervical cancer have limited objective remission rates at follow-up treatment, usually less than 15%, with a median overall survival of 6.0 to 9.4 months.

Currently, Tisotumab Vedotin is in a global phase 3 randomized clinical trial, called Innovatv 301, of which the primary endpoint is overall survival, with secondary endpoints including progression-free survival, response time, objective response rate, safety, and tolerability. The study is presently recruiting volunteers and is set up to enable a global registry. Tisotumab Vedotin is also being tested as a monotherapy for recurrent or metastatic cervical cancer, ovarian cancer, and other solid tumors in conjunction with routinely used therapies., which is being tested on a weekly or tri-weekly dose schedule in several trials.