Tisotumab vedotin

Summary

Tisotumab vedotin (brand name Tivdak) is an antibody‑drug conjugate approved for intravenous use in adults with recurrent or metastatic cervical cancer that has progressed after prior systemic therapy. The drug combines a monoclonal antibody that binds tissue factor, a protein over‑expressed on many solid tumours, with a cytotoxic payload that kills the targeted cancer cells. It is given as an infusion every three weeks and is intended to improve survival and tumour response where standard chemotherapy offers limited benefit.

Mechanism of Action

The antibody component of tisotumab vedotin specifically recognizes tissue factor (TF) on the surface of tumour cells. Binding triggers internalisation of the ADC, where intracellular proteases cleave the linker and release monomethyl auristatin E (MMAE), a potent microtubule‑disrupting agent. MMAE blocks tubulin polymerisation, leading to cell‑cycle arrest and apoptosis of the TF‑expressing cancer cell. By directing the toxin to TF‑positive cells, the ADC aims to spare normal tissue while delivering potent cytotoxicity.

What the Research Shows

Early phase 1‑2 studies (InnovaTV 201) enrolled 174 heavily pre‑treated patients with a variety of TF‑positive solid tumours, establishing a recommended dose of 2.0 mg/kg every 3 weeks and reporting a 15.6% confirmed objective response rate with manageable toxicity, the most common AEs being epistaxis, conjunctivitis, fatigue and alopecia. A single‑arm phase 2 trial (InnovaTV 204) in 101 women with previously treated recurrent/metastatic cervical cancer showed a 24% confirmed response rate, including 7% complete responses, and grade ≥ 3 treatment‑related events in 28% of patients. The pivotal phase 3 trial (innovaTV 301) randomised 502 patients to tisotumab vedotin versus physician‑chosen chemotherapy, demonstrating a median overall survival of 11.5 months versus 9.5 months (HR 0.70) and a progression‑free survival of 4.2 months versus 2.9 months, with response rates of 17.8% versus 5.2%. Grade ≥ 3 adverse events occurred in 52% of the ADC arm versus 62.3% of chemotherapy, and 14.8% discontinued the drug due to toxicity.

Reported Benefits

Randomised data show that tisotumab vedotin extends overall survival and progression‑free survival compared with standard chemotherapy in recurrent/metastatic cervical cancer, and yields higher objective response rates. Across multiple tumour types, early‑phase studies indicate activity in TF‑expressing cancers, providing a therapeutic option where few alternatives exist. Responses can be durable, and the targeted delivery of MMAE may allow efficacy with a tolerable safety profile relative to conventional cytotoxics.

Limitations of the Evidence

Evidence of benefit is currently limited to cervical cancer; other solid tumours have only early‑phase, non‑comparative data. Overall response rates, while superior to chemotherapy, remain modest, and many patients experience adverse events requiring dose modifications or discontinuation. Long‑term safety beyond the trial periods is not fully characterised, and the requirement for intravenous infusion every three weeks may affect convenience. Further studies are needed to define efficacy in additional TF‑positive cancers and to optimise management of ocular and bleeding toxicities.

Safety Considerations

Adverse events are common, with ≥98% of patients reporting any‑grade toxicity. The most frequent include epistaxis, conjunctivitis, dry eye, alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥ 3 events occur in roughly half of treated patients, notably fatigue, neutropenia, ulcerative keratitis, and neuropathy. Serious treatment‑related events were reported in 13% of patients, and 14.8% discontinued therapy due to toxicity. Ocular complications such as conjunctivitis and keratitis, as well as bleeding tendencies, are notable and may require specialist monitoring. Emergency physicians should be aware of potential severe bleeding and ocular emergencies.

How It Is Administered

Tisotumab vedotin is administered as an intravenous infusion at a dose of 2.0 mg per kilogram of body weight (maximum 200 mg) once every three weeks. The infusion is given in a clinical setting, with patients monitored for infusion‑related reactions and ocular or bleeding side effects. No oral formulation or alternative routes are currently approved.

Routes of Administration

Goals & Uses

• Treatment of endometrial cancerOncologyModerate
• Treatment of bladder/urothelial cancerOncologyLow
• Treatment of head and neck squamous cell carcinomaOncologyLow
• Treatment of recurrent or metastatic cervical cancerOncologyHigh

Contraindications

• Hypersensitivity to tisotumab vedotin or excipientsAllergy/immunologicHigh
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Severe ocular surface diseaseOphthalmologicHigh

Adverse Effects

• Peripheral neuropathyNeurologicalCommon
• AlopeciaDermatologicCommonHair loss
• Nausea and fatigueGastrointestinal/constitutionalCommon
• Ocular toxicity (conjunctivitis, keratitis, dry eye, corneal ulceration)OphthalmologicCommon
• Infusion-related reactionsHypersensitivityUncommon
• Hemorrhage / bleeding eventsHematologic/vascularCommon

Drug Interactions

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine)Moderate
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole)Moderate
• Anticoagulants / antiplatelet agentsModerate

Population Constraints

• Pregnant or lactating individualsReproductiveAbsolute
• Pediatric patientsAgeRelative
• Patients with active or severe ocular diseaseOphthalmologicRelative
• Patients with severe hepatic impairmentHepaticRelative

Regulatory Status

• European UnionApprovedApproved: Recurrent or metastatic cervical cancer in adults who have received prior platinum-based chemotherapyEuropean Commission granted conditional marketing authorization in 2022; subsequently converted to full approval.
• United StatesApprovedApproved: Recurrent or metastatic cervical cancer with disease progression on or after chemotherapy (adults)Initially granted accelerated approval September 2021; converted to regular approval November 2023 based on innovaTV 301 overall survival data.
• United KingdomApprovedApproved: Recurrent or metastatic cervical cancer with disease progression on or after prior chemotherapyApproved by MHRA; NICE technology appraisal conducted for NHS reimbursement consideration.

FDA accelerated approval granted September 2021 for recurrent or metastatic cervical cancer; regular approval granted November 2023 based on confirmatory trial (innovaTV 301). Carries a Boxed Warning for ocular toxicity (conjunctival and corneal adverse reactions). Risk Evaluation and Mitigation Strategy (REMS) program not required but ophthalmologic monitoring mandated.

Evidence & Sources

• Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer
  Journal ArticleModerateVergote I, et al.2024-01-01T00:00:00.000000Z
• Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial
  Journal ArticleModeratede Bono JS, et al.2019-01-01T00:00:00.000000Z
• Antibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know
  Journal ArticleModerateMarkides DM, et al.2025-01-01T00:00:00.000000Z
• Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study
  Journal ArticleModerateColeman RL, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions