The phase II innovaTV 204 trial, a single-arm clinical trial also known as GCT1015-04 or GOG-3023/ENGOT-cx6 (NCT03438396), evaluating tisotumab vedotin administered every three weeks (Q3W) for the treatment of patients who have relapsed or progressed on or after prior treatment for recurrent or metastatic cervical cancer, has shown positive topline results.

Preliminary data from the trial, which is sponsored by Genmab in collaboration with Seattle Genetics, the European Network of Gynaecological Oncological Trial Groups (ENGOT), the Belgian Gynaecological Oncology Group and the Gynecologic Oncology Group, showed a 24% confirmed objective response rate (ORR) by independent central review [95% Confidence Interval: 15.9%-33.3%] with a median duration of response (DOR) of 8.3 months. The most common treatment-related adverse events (greater than or equal to 20 percent) included alopecia, epistaxis (nose bleeds), nausea, conjunctivitis, fatigue and dry eye. The investigators confirmed that that the data will be submitted for presentation at an upcoming medical meeting.

Investigational ADC
Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) directed to tissue factor, which is expressed on cervical cancer and can promote tumor growth, angiogenesis, and metastases.[1]

Tisotumab vedotin is composed of Genmab’s fully human monoclonal antibody specific for tissue factor and Seattle Genetics’ ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody and releases it upon internalization, inducing target cell death.

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In cancer biology, tissue factor is a protein that can promote tumor growth, angiogenesis, and metastases.[1] Based on its high expression on many solid tumors and its rapid internalization, tissue factor was selected as a target for an ADC approach.

Standard therapies for previously treated recurrent and/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, in an all-comers population.[1][2][3][4][5][6][7][8]

Tisotumab vedotin is being developed by Genmab in collaboration with Seattle Genetics, under an agreement in which the companies share all costs and profits for the product on a 50:50 basis.

Meeting a major unmet medical need
“Available therapies [followng] progression after first-line chemotherapy in recurrent or metastatic cervical cancer are limited,” noted Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

“[And as a result] … there is a high unmet need for new effective and tolerable treatment options for women with advanced cervical cancer, regardless of biomarkers and histology,” added Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

“Tisotumab vedotin has demonstrated clinically meaningful and durable objective responses with a manageable safety profile,” Dansey observed.

“These promising topline data from innovaTV 204 will be the basis of further engagement with the U.S. Food and Drug Administration (FDA) as we continue to progress and expand our tisotumab vedotin development program in solid tumors with our partners at Seattle Genetics,” Van de Winkel concluded.

Cervical cancer originates in the cells lining the cervix. Over 13,500 women are expected to be diagnosed with cervical cancer in the U.S. in 2020, with approximately 4,200 deaths. [9] Cervical cancer 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 being in the developing world. [10]

Routine medical examinations and the human papillomavirus (HPV) vaccine have lowered the incidence of cervical cancer in the developed world. Despite these advances, women are still diagnosed with cervical cancer, which often recurs or becomes metastatic.

Additional clinical trials of tisotumab vedotin are currently enrolling patients, including in combination with pembrolizumab, carboplatin or bevacizumab, and with a weekly dosing schedule in patients with locally advanced or metastatic cervical cancer. Tisotumab vedotin is also being evaluated in other tissue factor expressing tumor types, including ovarian and other solid tumors.

Ongoing research
Tisotumab vedotin is, in addition to cervical cancer, being evaluated in ongoing clinical trials as a monotherapy in a range of solid tumors, including recurrent and/or metastatic cervical cancer, ovarian cancer, and in combination with other commonly used therapies in recurrent or metastatic cervical cancer. These trials are evaluating tisotumab vedotin on a weekly or every three weeks dosing schedule.

Clinical trials
A Trial of Tisotumab Vedotin in Cervical Cancer – NCT03438396
A Trial of Tisotumab Vedotin in Japanese Subjects With Advanced Solid Malignancies (innovaTV 206) – NCT03913741
Tisotumab Vedotin Continued Treatment in Patients With Solid Tumors – NCT03245736
Efficacy and Safety Study of Tisotumab Vedotin for Patients With Solid Tumors (innovaTV 207) – NCT03485209
A Study of Weekly Tisotumab Vedotin for Patients With Platinum-Resistant Ovarian Cancer With Safety Run-in (innovaTV 208) – NCT03657043
Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors – NCT02552121
Safety and Efficacy of Tisotumab Vedotin Monotherapy & in Combination With Other Cancer Agents in Subjects With Cervical Cancer – NCT03786081
Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors – NCT02001623

[1] Van den Berg YW, Osanto S, Reitsma PH, Versteeg HH. The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood. 2012;119(4):924-932. doi:10.1182/blood-2011-06-317685
[2] 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;110(1):65-70. doi:10.1016/j.ygyno.2008.03.009
[3] 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;77(3):446-449. doi:10.1006/gyno.2000.5807
[4] 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;30(4):428-431. doi:10.1097/COC.0b013e31803377c8
[5] 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;27(7):1069-1074. doi:10.1200/JCO.2008.18.9043
[6] Santin AD, Sill MW, McMeekin DS, et al. 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;122(3):495-500. doi:10.1016/j.ygyno.2011.05.040
[7] 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;96(1):103-107. doi:10.1016/j.ygyno.2004.09.027
[8] Chung HC, Ros W, Delord JP, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019;37(17):1470-1478. doi:10.1200/JCO.18.01265
[9] National Cancer Institute SEER. Cancer Stat Facts: Cervix Uteri Cancer. Online. Last accessed on June 27, 2020.
[10 Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 countries. Online. Last accessed on June 27, 2020.

An edited version of this article was published in Onco’Zine.

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

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