Tisotumab for Advanced Cervical Cancer: A Comprehensive Overview of Benefits, Risks, and Data from New Study

Cervical cancer, especially when recurrent or metastatic, presents significant treatment challenges. For patients who progress after first-line therapy, treatment options are limited. Tisotumab vedotin (brand name Tivdak), a novel antibody-drug conjugate (ADC), has emerged as a potential option for second- or third-line treatment in these cases. Recent data, particularly from a study published in the New England Journal of Medicine (NEJM), sheds light on the efficacy and safety of this therapy.

What is Tisotumab?

Tisotumab is an ADC that targets tissue factor, a protein overexpressed in various cancers, including cervical cancer. Tissue factor is involved in cancer cell growth and metastasis. Tisotumab binds to tissue factor on the cancer cells, delivering a cytotoxic agent (monomethyl auristatin E, or MMAE) that interferes with cell division by disrupting microtubules. This leads to cancer cell death. The ability of Tisotumab to target tissue factor makes it a promising option for patients with advanced cervical cancer.

“People who were treated with Tisotumab had about a 12 month overall survival as compared to about nine months in patients who were treated with physician’s choice chemotherapy. So that has really changed our ability to treat patients with cervix cancer,” Dr. Marta Crispens, Director of the Gynecologic Oncology Division at Vanderbilt University Medical Center, tells SurvivorNet Connect.

What’s the Research Show?

The NEJM published results from a phase 3, open-label, randomized clinical trial (innovaTV 301) that evaluated the efficacy and safety of Tisotumab in patients with recurrent or metastatic cervical cancer. This study included 502 patients who had previously undergone one or two systemic therapies.

The trial compared Tisotumab to the investigator’s choice of chemotherapy, which included drugs like topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed.

Patients were randomly assigned in a 1:1 ratio to either Tisotumab (2 mg/kg every three weeks) or chemotherapy. The primary endpoint of the study was overall survival (OS), with progression-free survival (PFS) and objective response rate (ORR) as secondary endpoints.

Key Findings:

• Overall Survival (OS): The median OS for patients treated with Tisotumab was 11.5 months, compared to 9.5 months in the chemotherapy group. This represented a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.89; P = 0.004)
• Progression-Free Survival (PFS): Patients receiving Tisotumab had a median PFS of 4.2 months, compared to 2.9 months in the chemotherapy group (HR, 0.67; 95% CI, 0.54-0.82; P < 0.001)
• Objective Response Rate (ORR): The ORR was significantly higher in the Tisotumab group at 17.8%, compared to just 5.2% in the chemotherapy group. This indicated a fourfold higher chance of a positive tumor response with Tisotumab (odds ratio, 4.0; 95% CI, 2.1-7.6; P < 0.001).

The Benefits of Tisotumab

The NEJM study demonstrates several key benefits of Tisotumab for patients with advanced cervical cancer, making it a valuable second- or third-line option:

1. Extended Survival: The significant increase in overall survival (from 9.5 months with chemotherapy to 11.5 months with Tisotumab) suggests that this treatment offers patients more time, which is critical in recurrent or metastatic settings where treatment options are limited.
2. Improved Progression-Free Survival: Tisotumab’s ability to extend PFS by an additional 1.3 months compared to chemotherapy means patients can experience longer periods without disease progression, which can directly affect their quality of life.
3. Higher Response Rates: With an objective response rate of 17.8%, Tisotumab significantly outperforms chemotherapy in shrinking tumors, which can lead to symptom relief and potential reductions in tumor burden.

Risks and Side Effects

While Tisotumab offers clear benefits, it also comes with risks. As with any treatment, healthcare professionals must weigh these risks when considering it for their patients.

“I’m not going to say that Tisotumab doesn’t have its set of side effects. It does, but I think it is overall better tolerated because of the targeting,” says Dr. Crispens.

“You certainly will see myelosuppression — that absolutely is the case. You can see nausea and vomiting; those things are very manageable. Of course you can see fatigue, malaise, but again, I think less so than perhaps with conventional chemotherapy,” she adds.

“In terms of ocular toxicity, we need to manage that appropriately by having the patient be seen by an ophthalmologist prior to each cycle and using the drops appropriately”

Common Adverse Effects

The NEJM trial identified several adverse events, most of which were manageable. Some were more severe, including:

• Ocular Toxicity: A notable risk with Tisotumab is ocular toxicity, with 52.8% of patients experiencing some form of eye-related side effects. This includes conjunctivitis, dry eye, and blurred vision. While most events were mild to moderate, 4% of patients experienced grade 3 ocular toxicity.
• Peripheral Neuropathy: Another common side effect is peripheral neuropathy, affecting 38.4% of patients. Peripheral neuropathy involves damage to the nerves outside of the brain and spinal cord, which can cause pain, tingling, or numbness, particularly in the hands and feet. Severe (grade 3 or higher) neuropathy occurred in 5.6% of patients.
• Other Adverse Events: Additional common side effects included nausea (33.2%), fatigue (12.8%), and anemia (23.2%). The chemotherapy group, in comparison, had higher rates of grade 3 or greater adverse events (62.3%) versus the Tisotumab group (52.0%)

Discontinuation Due to Toxicity

Due to the nature of some of the adverse events, 14.8% of patients receiving Tisotumab discontinued treatment because of toxicity. This highlights the importance of close monitoring during treatment and the need for dose adjustments or supportive care measures to manage side effects.