The U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) for tisotumab vedotin (Tivdak®; Genmab and Pfizer) seeking to convert the accelerated approval to full approval, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after first-line therapy. The application has been granted Priority Review. The Prescription Drug User Fee Act (PDUFA) action date of May 9, 2024.

Cervical cancer remains a disease with high unmet need despite advances in effective vaccination and screening practices to prevent and diagnose pre- and early-stage cancers for curative treatment. Recurrent and/or metastatic cervical cancer is a particularly devastating and mostly incurable disease; up to 15% of adults with cervical cancer are diagnosed with metastatic disease at diagnosis. [1][2] and, for adults diagnosed at earlier stages who receive treatment, up to 31.5% will experience disease recurrence.[3]

It was estimated that, in 2023, more than 13,960 new cases of invasive cervical cancer were diagnosed in the U.S. and 4,310 adults would die from the disease.[4]

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Tisotumab vedotin is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Pfizer’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Determination of TF expression is not required.

Nonclinical data suggest 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. In turn, 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.

Positive results
The sBLA is supported by positive efficacy and safety data from the global, randomized Phase 3 innovaTV 301 trial (NCT04697628), in which tisotumab vedotin demonstrated superior overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR), as assessed by the investigator, in patients with recurrent or metastatic cervical cancer compared to chemotherapy.

The safety profile of tisotumab vedotin in innovaTV 301 was consistent with its known safety profile as presented in the U.S. prescribing information. In October 2023, results from the innovaTV 301 study were presented during the Presidential Symposium at the European Society of Medical Oncology (ESMO) Congress.[5]

Jan van de Winkel, Chief Executive Officer of Genmab. Photo courtesy: 2020 Genmab/Tuala Hjarnø and Torkil Stavdal. Used with permission

Survival advantage
“Therapeutic options for metastatic cervical cancer that not only demonstrate a survival advantage but also include a novel approach to treating this condition are needed,” said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab.

“This milestone underscores our commitment to continuing to deliver tisotumab vedotin as a treatment option to women in the U.S. diagnosed with cervical cancer whose disease has progressed after first-line treatment,” Winkel said.

“The Phase 3 innovaTV 301 trial demonstrated a favorable benefit/risk profile, including improvement in overall survival, and adds to the overall data supporting TIVDAK as a treatment option for people with recurrent and metastatic cervical cancer who have limited treatment options,” said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer.

“The FDA acceptance of our sBLA for review is important progress toward continuing to offer an option that can extend the lives of more adults with cervical cancer,” Dansey added.

innovaTV 301 Study Design
The innovaTV 301 trial (NCT04697628) is a global, randomized, open-label Phase 3 trial evaluating tisotumab vedotin versus investigator’s choice of chemotherapy alone (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in 502 patients with recurrent or metastatic cervical cancer who received no more than two prior systemic regimens in the recurrent or metastatic setting.

Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with chemotherapy doublet +/- bevacizumab and an anti-PD-(L)1 agent (if eligible) are included. The primary endpoint is overall survival. The main secondary outcomes are progression-free survival, confirmed objective response rate, time to response, and duration of response, as assessed by the investigator, as well as safety and quality of life outcomes.

The study was conducted by Seagen, which was recently acquired by Pfizer, in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the Gynecologic Oncology Group (GOG) Foundation (study number GOG 3057). For more information about the Phase 3 innovaTV 301 clinical trial and other clinical trials with tisotumab vedotin, please visit


Note: * Tisotumab vedotin (branded as Tivdak®; Genmab and Pfizer) was granted accelerated approval in the U.S. by the FDA in September 2021. The accelerated approval is based on tumor response and durability of response from the innovaTV 204 pivotal Phase 2 single-arm clinical trial evaluating tisotumab vedotin as monotherapy in patients with previously treated recurrent or metastatic cervical cancer. The data from innovaTV 301 will support global regulatory submissions. Tisotumab vedotin is being co-developed by Genmab and Pfizer, under an agreement in which the companies share costs and profits for the product on a 50:50 basis.

Clinical trials
Tisotumab Vedotin vs Chemotherapy in Recurrent or Metastatic Cervical Cancer (innovaTV 301) – ID NCT04697628

Highlights of Prescribing information
Tisotumab vedotin (Tivdak®; Seagen/Genmab) [Prescribing Information]

[1] National Cancer Institute. SEER Cancer Stat Facts: Cervical Cancer. 2023. Online. Lasr accesses on January 9, 2024
[2] McLachlan J, Boussios S, Okines A, et al. The impact of systemic therapy beyond first-line treatment for advanced cervical cancer. Clin Oncol (R Coll Radiol). 2017;29(3):153-60.
[3] de Foucher T, Bendifallah S, Ouldamer L, et al. Patterns of recurrence and prognosis in locally advanced FIGO stage IB2 to IIB cervical cancer: retrospective multicentre study from the FRANCOGYN Group. Eur J Surg Oncol. 2019;45:659–665. doi: 10.1016/j.ejso.2018.11.014.
[4] Key Statistics for Cervical Cancer. American Cancer Society. Atlanta, GA. 2023. Online. Last accesses on January 9, 2023
[5] Garcia D. Tisotumab Vedotin Significantly Prolongs Overall Survival in Patients with Recurrent/Metastatic Cervical Cancer Compared with Chemotherapy, JADC October 22, 2023 [Article]

Featured Image: Genmab’s bioreactor laboratory. Photo Courtesy: 2020 Genmab. Used with permission.

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