Tisotumab Vedotin for Recurrent or Metastatic Cervical Cancer

  • Tisotumab vedotin represents a promising development for women with recurrent or metastatic cervical cancer.
  • It is a tissue factor-directed antibody-drug conjugate that delivers a cytotoxic agent directly to cancer cells, disrupting their growth and division.
  • The efficacy of Tisotumab vedotin was established in the innovaTV 301 trial, a phase 3 study involving patients with recurrent or metastatic cervical cancer who had already undergone one or two lines of systemic therapy.
  • The trial demonstrated that Tisotumab vedotin significantly improved overall survival (OS) and progression-free survival (PFS) compared to chemotherapy. The confirmed objective response rate (ORR) was 17.8% for patients treated with Tisotumab vedotin compared to just 5.2% for those receiving chemotherapy

Cervical cancer, particularly in its advanced stages, presents significant challenges in terms of treatment. Although early-stage cervical cancer can often be successfully treated with surgery or radiation, recurrent or metastatic cervical cancer has a poor prognosis.

For many patients who experience recurrence after initial treatment, chemotherapy is the standard approach, often combined with agents like bevacizumab or immune checkpoint inhibitors. There remains a substantial need for effective second- or third-line therapies when patients experience progression following these treatments — and there has been some exciting progress with Tisotumab vedotin (brand name Tivdak).

“Chemotherapy has been largely disappointing for the treatment of cervix cancer. Cervix cancer is resistant to conventional cytotoxic chemotherapy and has very difficult, often quality of life reducing, side effects. And so I think the major advances that have been made over the last five years or so are really introducing some novel therapies or novel therapeutic approaches,” Dr. Marta Crispens, Director of the Gynecologic Oncology Division at Vanderbilt University Medical Center, tells SurvivorNet Connect.

Tisotumab vedotin represents a promising development in this space. It is a tissue factor-directed antibody-drug conjugate that delivers a cytotoxic agent directly to cancer cells, disrupting their growth and division. Tissue factor, which is over-expressed in many types of cancer, including cervical cancer, is the target of this therapy, making it a novel and precise approach.

“I think we’ve seen introduction of new drug classes that have changed the responsiveness and also the tolerability of therapy for patients with advanced or recurrent disease,” Dr. Crispens adds. 

Mechanism of Action

Tisotumab vedotin is composed of a monoclonal antibody that targets tissue factor and is linked to the cytotoxic drug monomethyl auristatin E (MMAE). Once the drug binds to tissue factor on the surface of cancer cells, the antibody-drug conjugate is internalized, and MMAE is released. MMAE interferes with microtubule formation, a critical process in cell division, effectively killing the cancer cells.

This mechanism of action is particularly relevant for advanced cervical cancer, as tissue factor is often highly expressed in these tumors.​

Efficacy of Tisotumab Vedotin

The efficacy of Tisotumab vedotin was established in the innovaTV 301 trial, a phase 3, randomized, open-label study involving 502 patients with recurrent or metastatic cervical cancer who had already undergone one or two lines of systemic therapy. Patients were randomized to receive either Tisotumab vedotin or the investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed).

Overall Survival and Progression-Free Survival

The trial demonstrated that Tisotumab vedotin significantly improved overall survival (OS) compared to chemotherapy. Patients in the Tisotumab vedotin group had a median OS of 11.5 months compared to 9.5 months in the chemotherapy group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.54 to 0.89; P = 0.004).

Furthermore, the median progression-free survival (PFS) was also longer with Tisotumab vedotin, at 4.2 months versus 2.9 months in the chemotherapy group (HR, 0.67; 95% CI, 0.54 to 0.82; P < 0.001).

Objective Response Rate

The confirmed objective response rate (ORR) was 17.8% for patients treated with Tisotumab vedotin compared to just 5.2% for those receiving chemotherapy, representing a substantial improvement (odds ratio, 4.0; 95% CI, 2.1 to 7.6; P < 0.001).  This increase in response rates suggests that Tisotumab vedotin not only extends survival but also enhances the likelihood of a tumor response.

Safety Profile

The safety profile of Tisotumab vedotin, while generally manageable, includes notable adverse effects. In the innovaTV 301 trial, 52% of patients in the Tisotumab vedotin group experienced grade 3 or higher adverse events, compared to 62.3% in the chemotherapy group. The most common adverse events associated with Tisotumab vedotin included conjunctivitis (31.2%), peripheral sensory neuropathy (28.4%), and anemia (23.2%).

Ocular toxicity, in particular, is a well-known side effect of Tisotumab vedotin, with 52.8% of patients reporting some form of ocular event. While most were mild to moderate, 4.0% of patients experienced grade 3 or higher ocular toxicity​. This side effect requires monitoring and, in some cases, may necessitate treatment discontinuation.

Peripheral neuropathy is another significant concern, with 38.4% of patients reporting this side effect, including 5.6% who experienced grade 3 or higher neuropathy. These toxicities highlight the importance of close monitoring and potential dose adjustments during treatment.

Patient Selection and Treatment Considerations

Tisotumab vedotin is typically used as a second- or third-line therapy in patients with recurrent or metastatic cervical cancer who have already undergone systemic therapy. Patients who are candidates for Tisotumab vedotin often have limited treatment options, having already received chemotherapy and, in some cases, immune checkpoint inhibitors. Given the relatively high rates of adverse events, it is essential that patients are carefully monitored, and supportive care is provided as needed.

One of the key considerations in using Tisotumab vedotin is the potential for ocular and neurological side effects. Patients should undergo regular ophthalmologic evaluations, and dose modifications should be considered if peripheral neuropathy or ocular toxicities become severe​.