Genmab and Seagen have submitted a Biologics Licence Application or BLA to the U.S. Food and Drug Administration (FDA) for tisotumab vedotin.

The companies are codeveloping the tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The submission is based on the results of the innovaTV 204 pivotal phase II single-arm clinical trial evaluating tisotumab vedotin as monotherapy in this setting.

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

The trial, which is also known as GCT1015-04 or GOG-3023/ENGOT-cx6, is an ongoing single-arm, global, multicenter study in patients with recurrent or metastatic cervical cancer who were previously treated with doublet chemotherapy with or without bevacizumab. Additionally, patients were eligible if they had received up to two prior lines of therapy in the recurrent or metastatic setting.

“This BLA submission is an important step toward our goal of improving the lives of women with recurrent or metastatic cervical cancer. I would like to thank the patients, nurses, physicians and researchers who participated in the innovaTV 204 trial, which is the basis of this submission,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

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“We believe, if approved, tisotumab vedotin as monotherapy has the potential to become an important treatment option for women with recurrent or metastatic cervical cancer, who have disease progression on or after chemotherapy,” Winkel added.

“In the pivotal phase 2 study, tisotumab vedotin induced clinically meaningful and durable responses in this difficult to treat cervical cancer patient population, with a manageable and tolerable safety profile. Today’s submission marks an important milestone for tisotumab vedotin and a potential advance for patients with recurrent or metastatic cervical cancer for whom there is a high unmet need for effective new therapies,” noted Roger Dansey, M.D., Chief Medical Officer at Seagen.

“We look forward to working with the FDA on the review of the application,” Dansey further said.

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.

The study was conducted by Genmab in collaboration with Seagen, European Network of Gynaecological Oncological Trial Groups (ENGOT) and the Gynecologic Oncology Group (GOG) Foundation. For more information about the phase II innovaTV 204  clinical trial and other clinical trials with tisotumab vedotin, please visit

The topline results from the phase II study were announced in June 2020 and data were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Antibody-drug Conjugate
Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell-surface protein expressed on multiple solid tumors including cervical cancer and is associated with tumor growth, angiogenesis, metastasis, and poor prognosis. [1]

The investigational drug is composed of Genmab’s fully human monoclonal antibody specific for tissue factor and Seagen’s ADC technology that uses 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.

In cancer biology, tissue factor is a cell-surface protein and associated with tumor growth, angiogenesis, metastasis and poor prognosis. [1]

Based on its elevated expression in multiple solid tumors and its rapid internalization, tissue factor was selected as a target for an ADC approach.

Cervical cancer
Cervical cancer originates in the cells lining the cervix. Over 13,500 women are expected to be diagnosed with invasive cervical cancer in the U.S. in 2020, with approximately 4,200 deaths. [2]

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.[3]

Routine medical examinations and human papillomavirus (HPV) vaccines 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. 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 [4][5][6][7][8][9][10]

Clinical trials
A Trial of Tisotumab Vedotin in Cervical Cancer – NCT03438396
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
Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors – NCT02552121
A Study of Weekly Tisotumab Vedotin for Patients With Platinum-Resistant Ovarian Cancer With Safety Run-in (innovaTV 208) – NCT03657043
Safety and Efficacy of Tisotumab Vedotin Monotherapy & in Combination With Other Cancer Agents in Subjects With Cervical Cancer – NCT03786081
Tisotumab Vedotin vs Chemotherapy in Recurrent or Metastatic Cervical Cancer (innovaTV 301) – NCT04697628
Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors – NCT02001623
A Trial of Tisotumab Vedotin in Japanese Subjects With Advanced Solid Malignancies (innovaTV 206) – NCT03913741

Reference
[1] 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.
[2] National Cancer Institute SEER. Cancer Stat Facts: Cervix Uteri Cancer. Online. Last accessed on February 8, 2021.
[3] Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 countries Online. Last accessed on February 9, 2021.
[4] 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..
[5] 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..
[6] 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..
[7] 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..
[8] 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..
[9] 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.
[10] 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.

Featured Image: Research associate at Genmab, Cell culturing. Photo courtesy: 2020 Genmab/Tuala Hjarnø and Torkil Stavdal

 

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