Tivdak (tisotumab vedotin) is a targeted antibody-drug conjugate (ADC) consisting of an antibody that specifically recognizes cervical cancer cells and a potent chemotherapy drug. Tivdak can deliver chemotherapy drugs directly into cancer cells, thereby killing cancer cells while reducing damage to normal cells. Currently, Tivdak is used to treat adult patients with recurrent or metastatic cervical cancer.

Who Makes Tivdak?

Tivdak was first jointly developed by Seagen and Genmab and received accelerated approval from the FDA on September 20, 2021. In April 2024, it was fully approved for the treatment of recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. It is the first ADC approved for cervical cancer and the only ADC currently on the market that targets tissue factor (TF). TF is a protein involved in tumor signal transduction and angiogenesis. It is overexpressed in most cervical cancer patients and many other solid tumors, with a positive rate of 100% in cervical cancer, 34%-88% in non-small cell lung cancer, 14%-100% in endometrial cancer, 47%-75% in prostate cancer, 75%-100% in ovarian cancer, 43%-91% in esophageal cancer, and 78% in bladder cancer. This high expression of TF may contribute to the growth and survival of tumor cells, angiogenesis, and metastasis. Therefore, it is considered to be a highly potential target for tumor treatment.

Tivdak Reviews

• Tivdak Drug

The active pharmaceutical ingredient of Tivdak is tisotumab vedotin, which is composed of human anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable vc (valine-citrulline) linker. The monoclonal antibody is produced in a mammalian cell cline (Chinese hamster ovary). MMAE and the linker are produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 4 MMAE molecules. Tivdak has an approximate molecular weight of 153 kDa.

Fig. 1. The structure of Tivdak..

• Tisotumab: Humanized anti-TF IgG1κ monoclonal antibody, produced in the mammalian cell population Chinese hamster ovary.
• Vedotin (MMAE): It is a natural microtubule inhibitor, a derivative of Dolastatin 10, monomethyl auristatin E, which has the effect of destroying cell microtubules.
• Linker: The protease-sensitive cleavable linker valine-citrulline (Val-Cit) is used.

*Tivdak related products:

• Tivdak Mechanism of Action

Tivdak travels through the bloodstream and binds to cancer cells expressing TF. Once bound, the entire complex enters the cancer cell via receptor-mediated endocytosis. Inside the cell, the acidic environment of the endosome causes the linker to break, releasing the cytotoxic MMAE into the cytoplasm. MMAE is a potent anti-mitotic agent that disrupts microtubule dynamics necessary for cell division. By binding to tubulin, MMAE inhibits microtubule polymerization, leading to cell cycle arrest at the G2/M phase and subsequent induction of apoptosis, or programmed cell death. This targeted approach minimizes the impact on normal healthy cells, resulting in reduced systemic toxicity compared to traditional chemotherapy.

Fig. 2. Mechanism of action of Tivdak (Image source: immunopaedia.org.za).

Tivdak Cervical Cancer

Cervical cancer originates in the cells of the cervix and is one of the leading causes of cancer death among women worldwide. It is estimated that in 2018, approximately 13,000 women in the United States will be diagnosed with cervical cancer and approximately 4,000 patients will die. Globally, more than 311,000 women die from cervical cancer each year, the vast majority of whom are in developing countries. In developed countries, routine medical screening and human papillomavirus (HPV) vaccines have reduced the incidence of cervical cancer. TF is a transmembrane glycoprotein that is not expressed in endothelial cells lining the blood vessels of normal tissues. However, TF is highly expressed in many different types of tumors, such as cervical cancer, breast cancer, prostate cancer, colon cancer, esophageal cancer, and pancreatic cancer. Drugs targeting TF can be delivered to tumor cells without targeting normal tissue cells, so TF can be used as an ideal target for ADC drugs. ADCs targeting tumor cells with high TF expression can selectively kill tumor cells expressing TF and inhibit tumor growth in vivo. By targeting TF, tumor growth, angiogenesis, and metastasis can be inhibited, thereby improving patient survival. Therefore, Tivdak is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer that has progressed during or after chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

* Common ADC targets include:

Tivdak FDA Approval

Initial clinical studies began in 2010, focusing on evaluating the safety, tolerability and preliminary efficacy of Tivdak in patients with recurrent or metastatic cervical cancer who have limited treatment options and poor prognosis. Early clinical trials showed strong potential, demonstrating manageable safety and promising anti-tumor activity.

The breakthrough came from the results of the innovaTV 204 trial, a pivotal Phase II study. The study was conducted in 101 patients with recurrent or metastatic cervical cancer to evaluate the efficacy and safety of Tivdak. These patients had previously received no more than two systemic treatment regimens, including at least one platinum-containing chemotherapy regimen. Clinical studies showed that Tivdak had an objective response rate (ORR) of 24% and a median duration of response (DOR) of 8.3 months. Based on the above results, on September 20, 2021, the FDA accelerated the approval of Tivdak for the treatment of adult patients with recurrent or metastatic cervical cancer who had progressed during or after chemotherapy.

Fig. 3. OS curve of innovaTV301.

In October 2023, Seagen and Genmab announced the results of a global, randomized, open-label Phase 3 clinical trial (innovaTV 301). In patients with recurrent or metastatic cervical cancer whose disease progressed during or after first-line treatment, patients treated with Tivdak had a 30% lower risk of death than chemotherapy alone, showing significant statistical and clinical significance. The study data was announced at the President's Session of the 2023 European Society for Medical Oncology (ESMO) Annual Meeting. The trial included 502 patients with recurrent or metastatic cervical cancer who had previously received one or two systemic treatment regimens. The study showed that the median overall survival (OS) was 11.5 months in the Tivdak group and 9.5 months in the chemotherapy group. The median progression-free survival (PFS) was 4.2 months in the Tivdak group and 2.9 months in the chemotherapy group. The objective response rate (ORR) was 17.8% and 5.2% in the Tivdak group and chemotherapy group, respectively. Based on the above results, in April 2024, the FDA fully approved Tivdak for the treatment of patients with recurrent or metastatic cervical cancer whose disease progressed during or after chemotherapy.

Tivdak Manufacturer

Currently, there are not many TF-targeting ADC drugs under clinical investigation. Including Tivdak, there are a total of three such drugs. The other two are Miracogen's MRG004A and Exelixis's XB-002. The linkers and toxins for these three TF-targeting ADCs all use valine-citrulline-MMAE. Miracogen's MRG004A employs the GlycoConnectTM site-specific conjugation technology to enhance molecular stability. Unlike the other two TF-targeting ADCs, MRG004A uses site-specific conjugation at the antibody's Asn297 residue, eliminating the binding of the Fc region to CD16a expressed on NK cells, thereby removing ADCC activity and potentially improving safety.

*Common antibody conjugation technologies in ADC: