Tisotumab vedotin, an investigational agent is being developed by Seattle Genetics and Genmab, shows meaningful clinical activity as monotherapy in patients with previously treated recurrent and/or metastatic cervical cancer

That is the conclusion based on results from the ongoing, multicenter innovaTV 204 pivotal phase II, single-arm clinical trial of tisotumab vedotin, conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups (ENGOT) and Gynecologic Oncology Group (GOG), and presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Tisotumab vedotin 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 innovaTV 204 and a number of other clinical studies are evaluating tisotumab vedotin as monotherapy in a range of solid tumors, including recurrent and/or metastatic cervical cancer, ovarian cancer, and other solid tumors and in combination with commonly used therapies in recurrent or metastatic cervical cancer. These trials are evaluating tisotumab vedotin on a weekly or every three-week dosing schedule.

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Tissue factor
Tissue factor (TF) a transmembrane glycoprotein with a 219-amino acid extracellular domain, a 23-residue transmembrane region, and a 21-residue intracellular domain. It is found on the surface of many extravascular cells, including vascular smooth muscle cells and adventitial cells, which form an integral part of the blood vessel wall. As a cellular receptor for coagulation factor VII (FVII), and its activated form, factor VIIa, tissue factor is part of the coagulation pathway.

In cancer biology, tissue factor can promote tumor growth, angiogenesis, and metastasis. [2] Based on its high expression on many solid tumors, including cervical cancer, and its rapid internalization, tissue factor was selected as a target for an ADC approach.

Robert L. Coleman, M.D., Chief Scientific Officer for US Oncology Research and lead investigator of the innovaTV 204 clinical trial. Photo courtesy: © 2020 Texas Oncology. Used with permission.

Trial results
Patients participating in the trial had previously received doublet chemotherapy and, if eligible, bevacizumab (Avastin®; Genentech/Roche), an antibody that functions as an angiogenesis inhibitor, as first-line therapy.

Additionally, patients were eligible if they had received up to two prior lines of therapy in the recurrent and/or metastatic setting. 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.

Results from the trial showed a 24% confirmed objective response rate (ORR) by independent central review [95% Confidence Interval (CI): 15.9%-33.3%], including 7 patients (7%) with a complete response and 17 patients (17%) with a partial response. After a median follow-up of 10 months, the median duration of response (DOR) was 8.3 months (95% CI: 4.2, not reached). The study also results showed a median time to response was 1.4 months (range, 1.1-5.1), with activity generally observed within the first two treatment cycles. A subgroup analysis demonstrated responses that were generally consistent across subgroups regardless of tumor histology, lines of prior therapy, responses to a prior systemic regimen, and doublet chemotherapy with bevacizumab as first-line treatment. Overall, the median PFS was 4.2 months (95% CI: 3.0, 4.4) and the six-month PFS rate was 30% (95% CI: 20.8, 40.1) while the median OS was 12.1 months (95% CI: 9.6, 13.9) and the six-month OS rate was 79% (95% CI: 69.3, 85.6).

Adverse events
The most common treatment-related adverse events (TRAEs; greater than or equal to 20%) included alopecia (Grade 1/2 at 38%), epistaxis (nose bleeds, Grade 1/2 at 30%), nausea (Grade 1/2 at 27%), conjunctivitis (Grade 1/2 at 26%), fatigue (Grade 1/2 at 24%, Grade 3 or higher at 2%) and dry eye (Grade 1/2 at 23%).

Most treatment-related adverse events were Grade 1 or 2 and no new safety signals were reported. One death due to septic shock was considered by the investigator to be related to therapy.

Pre-specified adverse events of interest with tisotumab vedotin treatment included ocular events, bleeding, and peripheral neuropathy. Ocular adverse events considered to be related to therapy that occurred in patients were mostly mild to moderate (Grade 1 at 25%, Grade 2 at 27%, Grade 3 at 2%) of which a majority of the events resolved (86%) and were managed with an eye care plan. Bleeding events considered to be related to therapy that occurred in patients were mostly mild (Grade 1 at 34%, Grade 2 at 3%, Grade 3 at 2%) of which a majority of the events resolved (90%). The most common bleeding events included Grade 1 epistaxis (28%). Peripheral neuropathy events considered to be related to therapy were mostly mild to moderate (Grade 1 at 17%, Grade 2 at 9%, Grade 3 at 7%) and managed with dose modifications. The resolution of peripheral neuropathy was limited by the follow-up period.

Current 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. [2][3][4][5][6][7][8][9]

Meaningful and encouraging clinical activity
“Following resistance to, or progression on the first-line standard of care therapy, there are currently limited treatment options for women with metastatic cervical cancer,” explained Robert L. Coleman, M.D., Chief Scientific Officer for US Oncology Research and lead investigator of the innovaTV 204 clinical trial.

“The current treatment approaches for this disease setting have low objective response rates with poor outcomes. The results of the tisotumab vedotin phase 2 clinical trial are encouraging as they demonstrate clinically meaningful, durable responses with a manageable side effect profile,” Coleman added.

“Tisotumab vedotin has demonstrated meaningful clinical activity in patients with recurrent and/or metastatic cervical cancer for whom there is a high unmet need for new therapies,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

“Based on these results, we look forward to submitting a Biologics License Application to the FDA under the accelerated approval pathway,” Dansey further noted.

Important option
“We are encouraged by the innovaTV 204 trial results, which suggests that tisotumab vedotin as a monotherapy could potentially become an important option for women with metastatic and or recurrent cervical cancer,” noted Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

“Seattle Genetics and Genmab are committed to making a difference in the lives of cancer patients, and we look forward to working with the FDA with a goal to make this potential treatment option available to women as quickly as possible.”

Data presented at ESMO include the primary endpoint of confirmed ORR as assessed by independent central review in 101 patients treated with tisotumab vedotin in the trial. Secondary endpoints included DOR, time to response, progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Why important
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.[10]

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.[11] 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.

The current treatment options of recurrent and/or metastatic cervical cancer following disease progression on or after first-line therapy are limited, offer only minimal benefits and there is no current second-line standard of care.

Based on the study results from the innovaTV 201 study, tissue factor is a potential therapeutic target and tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in this advanced, previously treated patient population. It’s interesting to notice that treatment responses with tisotumab vedotin were observed across histologic types and prior types of treatment type received. The study results presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 provide clear evidence to support the continued investigation of tisotumab vedotin as a potential treatment option for the patients with cervical cancer who, today, lack an effective therapy option, may have a high risk of relapse, and, overall, have a low survival expectancy after first-line treatment.

Note
* The innovaTV 204 trial is also known as GCT1015-04 or innovaTV 204/GOG-3023/ENGOT-cx6

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

References
[1] Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract #LBA32/Abstract #3435, late-breaking proffered paper oral presentation)
[2] 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 Jan 26;119(4):924-32. doi: 10.1182/blood-2011-06-317685. Epub 2011 Nov 7. PMID: 22065595..
[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] Cancer Stat Facts: Cervix Uteri Cancer. National Cancer Institute SEER. Online. Last accessed on September 20, 2020.
[11] Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 countries. Online. Last accessed on September 20, 2020.

Featured image: Genmab’s Functional Characterization & Bioassays Laboratory. Photo courtesy: © 2020 Genmab. Used with permission.

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