Results today from the Phase 3 innovaTV 301 randomized global trial, which showed treatment with tisotumab vedotin (Tivdak®; Seagen/Genmab)* demonstrated a statistically significant and clinically meaningful 30% reduction in the risk of death in recurrent or metastatic cervical cancer patients with disease progression on or after front-line therapy, compared with chemotherapy (HR: 0.70, 95% CI: 0.54-0.89, p=0.0038).
Recurrent and/or metastatic cervical cancer is a particularly devastating and mostly incurable disease; up to 16% of adults with cervical cancer are diagnosed with metastatic disease at diagnosis and, for adults diagnosed at earlier stages who receive treatment, up to 61% will experience disease recurrence and progress to metastatic cervical cancer.  It is estimated that in 2023, more than 13,960 new cases of invasive cervical cancer will be diagnosed in the U.S. and 4,310 adults will die from the disease. 
Among available, novel treatment options is tisotumab vedotin, 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.
Topline results from innovaTV 301 were disclosed earlier this year following a pre-specified interim analysis conducted through an independent data monitoring committee. The additional results were presented during the Presidential Symposium at the European Society of Medical Oncology (ESMO) Congress 2023.
“Patients with cervical cancer have few treatment options once their cancer comes back or spreads after initial treatment,” explained Ignace B. Vergote, M.D., Ph.D., co-founder of European Network of Gynaecological Oncological Trial groups (ENGOT), and lead investigator on the innovaTV 301/ENGOT cx-12/GOG 3057 clinical trial.
“The positive data, seen in a representative patient population of recurrent or metastatic cervical cancer, demonstrate the potential for tisotumab vedotin to reshape clinical practice and provide hope for patients who need a new treatment option,” Vergote said.
Across primary and key secondary efficacy endpoints compared with chemotherapy, tisotumab vedotin demonstrated showed:
- Overall survival (OS) was statistically significantly prolonged with tisotumab vedotin , demonstrating a 30 percent reduction in the risk of death compared with chemotherapy (Hazard ratio [HR]: 0.70 [95% CI: 0.54, 0.89], p=0.0038).
- Progression-free survival (PFS) results were statistically significant with tisotumab vedotin , demonstrating a 33 percent reduction in the risk of disease worsening or death compared with chemotherapy (HR: 0.67 [95% CI, 0.54-0.82], p<0.0001).
- The confirmed objective response rate (ORR) was also statistically significantly improved with tisotumab vedotin (17.8 percent) compared with chemotherapy (5.2%); odds ratio: 4.0 [95% CI, 2.1-7.6], p<0.0001). All the complete responses were seen in the tisotumab vedotin arm (2.4%), defined as patients with no detectable evidence of a tumor over a specified time period.
- The disease control rate (DCR), defined as the percentage of patients who achieved complete response, partial response or stable disease, was 75.9% in the tisotumab vedotin arm compared with 58.2% in the chemotherapy arm.
The safety profile of tisotumab vedotin in innovaTV 301 was consistent with its known safety profile as presented in the U.S. prescribing information, and no new safety signals were observed.
In innovaTV 301, treatment-related adverse events (TRAEs) occurring in patients with tisotumab vedotin were generally low grade and manageable with supportive care or dose modifications. The proportion of patients who experienced TRAEs of Grade 3 or higher with chemotherapy was 45.2% compared with tisotumab vedotin (29.2%), and the most frequent adverse events of special interest of Grade 3 and higher with tisotumab vedotin include peripheral neuropathy (5.2%), ocular events (3.2%), and bleeding events (0.8%).
The results of innovaTV 301, a global, randomized, open-label Phase 3 trial, add to the previous results of innovaTV 204, which served as the basis for the accelerated approval of tisotumab vedotin in the U.S. Subject to discussions with regulatory authorities, the results from innovaTV 301 are intended to serve as the pivotal confirmatory trial for the U.S. accelerated approval and support potential global regulatory applications.
“We are excited to share the additional results of the innovaTV 301 trial, which demonstrated benefit in prolonging survival in patients with recurrent or metastatic cervical cancer compared with chemotherapy,” said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab.
“Together with our partners at Seagen, we look forward to discussing the results of this pivotal confirmatory trial with regulatory authorities with a view to potentially delivering tisotumab vedotin to more patients in need of alternative treatment options in the future,” Winkel added.
The innovaTV 301 trial (NCT04697628) is a global, randomized, open-label Phase 3 trial evaluating tisotumab vedotin-tftv versus investigator’s choice of single agent chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in 502 patients (n=253 TIVDAK; n=249 chemotherapy) with recurrent or metastatic cervical cancer who received no more than two prior systemic regimens, with a median survival follow-up of 10.8 months (95% CI, 10.3-11.6). The treatment arms were balanced for demographics and disease characteristics, and reflective of the real-world patient population in advanced cervical cancer.
Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with a standard of care systemic chemotherapy doublet or platinum-based therapy (if eligible) are included. The main efficacy outcome measure is overall survival. The key secondary endpoints are progression-free survival and objective response rate, as assessed by the investigator, as well as safety and quality of life outcomes.
Note: *In September 2021, the U.S. Food and Drug Administration granted accelerated approval for tisotumab vedotin in adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tisotumab vedotin is the first and only approved ADC for the treatment of these patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The drug, approved under accelerated approval based on tumor response rate and durability of response in confirmatory trials, is indicated in the U.S. for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
Tisotumab Vedotin vs Chemotherapy in Recurrent or Metastatic Cervical Cancer (innovaTV 301) – ClinicalTrials.gov ID NCT04697628
Highlights of Prescribing information
Tisotumab vedotin (Tivdak®; Seagen/Genmab) [Prescribing Information]
 The threshold for statistical significance is 0.0226 (2-sided).
 National Cancer Institute. SEER Cancer Stat Facts: Cervical Cancer. 2020. Online. Last accesses on October 22, 2023
 McLachlan J, Boussios S, Okines A, et al. The impact of systemic therapy beyond first-line treatment for advanced cervical cancer. Clin Oncol (R Coll Radiol). 2017;29(3):153-60.
 Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214(1):22-30.
 Key Statistics for Cervical Cancer. American Cancer Society. Atlanta, GA. 2023. Online. Last accesses on October 22, 2023.
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