Preliminary data from the innovaTV 207 global, open-label, multicenter phase 2 trial of tisotumab vedotin (Tivdak®; Seagen and Genmab) as a monotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN) who experienced disease progression on or after a first-line platinum-containing regimen and a checkpoint inhibitor.
Early results showed tisotumab vedotin demonstrated a manageable safety profile and promising preliminary antitumor activity in this patient population with the primary endpoint of confirmed objective response rate (ORR) per investigator, achieved by 16 percent of patients (95% CI: 5.5 to 33.7).
Findings of the trials were presented as part of a plenary session at the American Society for Radiation Oncology (ASTRO) Multidisciplinary Head and Neck Cancers Symposium on February 25, 2022.
“There is a significant unmet need for additional treatment options for patients diagnosed with squamous cell carcinoma of the head and neck that has progressed despite the use of chemotherapy,” said David S. Hong, M.D., deputy chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and lead investigator of the innovaTV 207 clinical trial.
“These preliminary data provide important insight into the safety of tisotumab vedotin in this tumor type and demonstrate the value of exploring this potential use further in the innovaTV 207 trial.”
The phase 2 innovaTV 207 study was designed to evaluate the activity, safety, and tolerability of tisotumab vedotin in selected solid tumors with high tissue factor (TF) expression.
Tissue Factor or TF is a transmembrane glycoprotein that localizes the coagulation serine protease factor VII/VIIa (FVII/VIIa) to the cell surface. The primary function of TF is to activate the clotting cascade.
The TF:FVIIa complex also activates cells by cleavage of a G-protein coupled receptor called protease-activated receptor 2 (PAR2). TF is expressed by tumor cells and contributes to a variety of pathologic processes, such as thrombosis, metastasis, tumor growth, and tumor angiogenesis. 
In cancer biology, tissue factor can promote tumor growth, angiogenesis, and metastasis.  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.
Tisotumab vedotin is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody.
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. 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.
The trial is a global, multicenter, open-label basket trial that will enroll an estimated 532 adult patients with relapsed, locally advanced, or metastatic disease in separate tumor-specific cohorts. The primary endpoint of the trial is confirmed ORR per investigator, defined as the proportion of patients who achieve a confirmed complete or partial response. Key secondary endpoints include confirmed and unconfirmed ORR, DCR, duration of response, PFS, OS, safety, and tolerability.
Squamous cell carcinoma of the head and neck cohort
The squamous cell carcinoma of the head and neck (SCCHN) cohort of the innovaTV 207 trial enrolled 31 patients with a median age of 65 (range 47 to 78) years whose disease progressed on or after systemic therapy. Patients received 2 milligrams (mg)/kilogram (kg) tisotumab vedotin (maximum dose: 200 mg per infusion) intravenously on day one of each 21-day cycle. The secondary endpoints included disease control rate or DCR, progression-free survival (PFS) per investigator, and overall survival (OS).
Disease control rate (DCR) per investigator was 58.1 percent (95% CI: 39.1 to 75.5), median PFS was 4.2 months (95% CI: 2.7 to 4.8), median follow-up was 10.0 months (95% CI: 8.5 to 13.1) and median OS was 9.4 months (95% CI: 8.1 to 11.8). Adverse events were consistent with the known safety profile of tisotumab vedotin: twenty-one (67.7%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and incidence of treatment-related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post-procedural hemorrhage [n=1]).
“We recognize the high medical need for additional treatment options for patients with head and neck cancers,” said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab.
“These initial data results are encouraging and underscore the importance of our ongoing clinical trial program that will assess the potential utility of tisotumab vedotin in various cancers.”
“The presentation of these preliminary data represents another step forward in our work to advance the tisotumab vedotin development program,” said Roger Dansey, M.D., Chief Medical Officer, Seagen. “In partnership with Genmab, we will continue to recruit additional patients for trials to further investigate tisotumab vedotin in patients with squamous cell carcinoma of the head and neck, including its potential use as a combination therapy.”
Efficacy and Safety Study of Tisotumab Vedotin for Patients With Solid Tumors (innovaTV 207) – NCT03485209
Highlights of prescribing information
Tisotumab vedotin-tftv (Tivdak®; Seagen and Genmab)(Prescribing Information)
 Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009 Oct 10;27(29):4834-8. doi: 10.1200/JCO.2009.22.6324. Epub 2009 Sep 8. PMID: 19738116; PMCID: PMC2764391.
 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.
Featured Image: Genmab’s bioreactor laboratory. Photo Courtesy: 2020 – 2022 Genmab.