SUMMARY: The FDA on April 29, 2024, granted traditional approval to Tisotumab vedotin-tftv (TIVDAK®) for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tisotumab vedotin previously received accelerated approval for this indication in September 2021.
The American Cancer Society estimates that for cervical cancer in the US for 2024, about 13,820 new cases of invasive cervical cancer will be diagnosed and about 4,360 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to develop cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.
Patients with persistent, recurrent, or metastatic cervical cancer in the past often received Platinum-based chemotherapy, (Cisplatin or Carboplatin along with Paclitaxel) plus Bevacizumab. The addition of Bevacizumab to chemotherapy improved the median Overall Survival from 13.3 months to 17 months in a randomized study. Anti-PD1 and anti-PD-L1 therapies such as Pembrolizumab and Atezolizumab, (respectively) in combination with a doublet of platinum and Paclitaxel with or without Bevacizumab have demonstrated an Overall Survival benefit in Phase III studies. Despite these advances, the prognosis for patients with cervical cancer is poor, with 5-year Overall Survival less than 19% among patients with distant disease. There is an unmet need for additional treatment options.
Tissue Factor is a transmembrane glycoprotein highly expressed in multiple cancers including cervical, pancreatic, esophageal, gastric, colorectal cancers and hepatocellular carcinoma. Tissue Factor is the primary initiator of the extrinsic blood coagulation signaling pathway. Tisotumab vedotin is a tissue factor directed Antibody Drug Conjugate (ADC) which consists of a fully humanized IgG1 monoclonal antibody covalently linked to the microtubule-disrupting agent MonoMethyl Auristatin E (MMAE). Tisotumab vedotin selectively binds to tissue factor-expressing cells, internalized, and releases payload MMAE via proteolytic cleavage. Upon binding of MMAE to tubulin, it disrupts the microtubule network of actively dividing cells, resulting in cell cycle arrest and apoptotic death of the tumor cells. Additionally, Tisotumab vedotin also mediates Antibody-Dependent Cellular Phagocytosis and Antibody-Dependent Cellular Cytotoxicity.
The present FDA approval was based on efficacy, evaluated in innovaTV 301 trial. This study is a pivotal, multinational, open-label, randomized Phase III trial, conducted to evaluate the efficacy and safety of Tisotumab vedotin compared to standard chemotherapy regimens in patients with recurrent or metastatic cervical cancer. This study enrolled 502 patients (N=502) with recurrent or metastatic cervical cancer who had previously received up to two systemic regimens, including chemotherapy with or without Bevacizumab and/or an anti-PD-(L)-1 agent. Participants were randomly assigned in a 1:1 ratio to receive either Tisotumab vedotin 2 mg/kg IV every three weeks (N=253) or Investigators choice of chemotherapy which included either Topotecan, Vinorelbine, Gemcitabine, Irinotecan, or Pemetrexed (N=249). Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced with respect to demographic and disease characteristics. This study excluded patients with active ocular surface disease, a history of cicatricial conjunctivitis or ocular Stevens-Johnson syndrome, Grade 2 or more peripheral neuropathy, or significant bleeding risks. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR).
The median OS for the Tisotumab vedotin group was 11.5 months compared to 9.5 months for the chemotherapy group. This difference represented a 30% reduction in the risk of death with Tisotumab vedotin, with a Hazard Ratio (HR) of 0.70 (P=0.0038). The median PFS was 4.2 months for the Tisotumab vedotin group versus 2.9 months for the chemotherapy group. The HR for PFS was 0.67 (P<0.0001). The ORR was 17.8% in the Tisotumab vedotin group compared to 5.2% in the chemotherapy group, demonstrating a significant therapeutic benefit with a P-value <0.0001.
Grade 3 or higher adverse events occurred in 52.0% of the Tisotumab vedotin group compared to 62.3% of the chemotherapy group. Additionally, 14.8% of patients on Tisotumab vedotin discontinued treatment due to adverse effects. Despite these side effects, no new safety signals were identified, and ocular adverse events were generally manageable with dose modifications.
In conclusion, the innovaTV 301 trial established that Tisotumab vedotin significantly improves survival and response rates in patients with recurrent or metastatic cervical cancer compared to standard chemotherapy regimens. Future research is underway combining Tisotumab vedotin with other therapies such as checkpoint inhibitors, as well as its utilization in earlier lines of treatment.
Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. Vergote I, González-Martín A, Fujiwara K, et al. for the innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. N Engl J Med 2024;391:44-55.
