Each year more than 13,500 women in the United States are diagnosed with invasive cervical cancer and approximately 4,200 will die of the disease. deaths. [1] Globally, the disease, which originates in the cells lining the cervix, remains one of the leading causes of cancer death in women globally, with over 311,000 women dying annually. The vast majority of these women are living in the developing world. [2]

Approximately two-thirds of women diagnosed with the disease are diagnosed with locally metastatic or advanced cervical cancer, which has a poor prognosis and generally shows disappointing survival rates despite correct multidisciplinary management.

Overall risk
All women are at risk for cervical cancer which, in the majority of cases occurs in women over age 30. One of the established causes of the long-lasting infection with certain types of human papillomavirus (HPV) is the main cause of cervical cancer. HPV is a common virus that is passed from one person to another during sex, and at least half of sexually active people will, at some point in their lives, be infected with HPV.

Routine medical screening examinations, including the Pap smear, and human papillomavirus (HPV) vaccines have lowered the incidence of cervical cancer in the developed world. And when treated early, the disease is highly treatable and associated with long survival and a good health-related quality of life (hrQoL).

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In addition to HPV, other risk factors for the disease include having HIV, smoking, using birth control pills for a long time (five or more years), having given birth to three or more children, and having multiple sexual partners.

Today, the mainstay of treatment includes surgery, chemotherapy or radiation therapy. However, despite advances in diagnosis and treatment, women are still diagnosed with cervical cancer, which often recurs or becomes metastatic. Current therapies for previously treated recurrent or metastatic cervical cancer generally result in limited objective response rates of typically less than 15% with median overall survival ranging from 6.0 to 9.4 months. As a result, there remains a major unmet medical need for the treatment of women diagnosed with cervical cancer. [3][4][5][6][7][8][9]

Standard treatment
Platinum-based chemotherapy has been the backbone treatment of metastatic cervical cancer for many years. However, treatment results changed dramatically when antiangiogenic agents, including bevacizumab, an antiangiogenic agent that targets vascular endothelial growth factor 2 (VEGF-2), added to standard chemotherapy showed significant improvement on survival; therefore, the combination of carboplatin, paclitaxel, and bevacizumab is currently the standard frontline treatment in cervical cancer.[10]

A new treatment option
Earlier this month, the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the Biologics License Application (BLA) seeking accelerated approval for tisotumab vedotin. The investigational drug is an investigational antibody-drug conjugate (ADC) composed of a human antibody targeted to tissue factor (TF), a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody.

The drug’s target, tissue factor, is a cell-surface protein expressed on multiple solid tumors including cervical cancer, and is associated with tumor growth, angiogenesis, metastasis, and poor prognosis. [11]

his BLA requests FDA approval of tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of October 10, 2021.

“The FDA’s filing of the tisotumab vedotin BLA with Priority Review marks an important step forward for this ADC as a potential treatment for patients with recurrent or metastatic cervical cancer,” said Roger Dansey, M.D., Chief Medical Officer at Seagen. “We are collaborating closely with the FDA throughout the review process to make this important therapy available to patients.”

“We are pleased that the tisotumab vedotin BLA has been accepted with Priority Review by the FDA as there is an unmet need for effective therapies for women with recurrent or metastatic cervical cancer, who have disease progression on or after chemotherapy,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. “This is an important milestone for Genmab as it brings us closer to our goal of bringing differentiated therapies to patients and transforming cancer treatment.”

The BLA for tisotumab vedotin was submitted in February 2021. The submission is based on the results of the innovaTV 204 pivotal phase 2 single-arm clinical trial (also known as GCT1015-04 or innovaTV 204/GOG-3023/ENGOT-cx6) evaluating tisotumab vedotin as monotherapy in patients with previously treated recurrent or metastatic cervical cancer. The ongoing single-arm, global, multicenter study includes patients with recurrent or metastatic cervical cancer who were previously treated with doublet chemotherapy with or without bevacizumab. In the study, 101 patients were treated with tisotumab vedotin at multiple centers in the U.S. and Europe. The primary endpoint of the trial was confirmed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by independent central review. Key secondary endpoints included duration of response, progression-free survival, overall survival, safety and tolerability.

These data were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Clinical trials
A Trial of Tisotumab Vedotin in Cervical Cancer – [NCT03438396]

[1] National Cancer Institute SEER. “Cancer Stat Facts: Cervix Uteri Cancer.” Online. Last accessed on April 1, 2020.
[2] Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 countries [Online]
[3] Miller DS, Blessing JA, Bodurka DC, Bonebrake AJ, Schorge JO; Gynecologic Oncology Group. Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2008 Jul;110(1):65-70. doi: 10.1016/j.ygyno.2008.03.009. Epub 2008 May 5. PMID: 18455781.
[4] Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA. Topotecan in squamous cell carcinoma of the cervix: A Phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000 Jun;77(3):446-9. doi: 10.1006/gyno.2000.5807. PMID: 10831357.
[5] Garcia AA, Blessing JA, Vaccarello L, Roman LD; Gynecologic Oncology Group Study. Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Am J Clin Oncol. 2007 Aug;30(4):428-31. doi: 10.1097/COC.0b013e31803377c8. PMID: 17762444.
[6] Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2009 Mar 1;27(7):1069-74. doi: 10.1200/JCO.2008.18.9043. Epub 2009 Jan 12. PMID: 19139430; PMCID: PMC2667811.
[7] Santin AD, Sill MW, McMeekin DS, Leitao MM Jr, Brown J, Sutton GP, Van Le L, Griffin P, Boardman CH. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2011 Sep;122(3):495-500. doi: 10.1016/j.ygyno.2011.05.040. PMID: 21684583; PMCID: PMC3152667.
[8] Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2005 Jan;96(1):103-7. doi: 10.1016/j.ygyno.2004.09.027. PMID: 15589587.
[9] Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. doi: 10.1200/JCO.18.01265. Epub 2019 Apr 3. PMID: 30943124.
[10] Marquina G, Manzano A, Casado A. Targeted Agents in Cervical Cancer: Beyond Bevacizumab. Curr Oncol Rep. 2018 Apr 2;20(5):40. doi: 10.1007/s11912-018-0680-3. PMID: 29611060.
[11] Rondon AMR, Kroone C, Kapteijn MY, Versteeg HH, Buijs JT. Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis. Semin Thromb Hemost. 2019 Jun;45(4):396-412. doi: 10.1055/s-0039-1687895. Epub 2019 May 16. PMID: 31096312.

Featured Image: Genmab’s bioreactor laboratory. Photo Courtesy: © 2020 Genmab.

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