Clinical trialPhase 3Cervical cancer

Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer

N Engl J Med · 2024502 patients

Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, et al. N Engl J Med. 2024. 391:44-55

Study type: Clinical trial
Study name: innovaTV 301 (ENGOT-cx12/GOG-3057)
Phase: Phase 3
Design: Randomised, open-label, multinational trial
Sample size: 502 patients
Source: N Engl J Med · 2024
Trial registration: NCT04697628

In plain words

Tisotumab vedotin is an "antibody–drug conjugate": like a guided missile, it carries a chemotherapy drug straight to cancer cells that carry a protein called "tissue factor". In patients whose cervical cancer had grown after their first treatment, this drug helped them live longer than standard chemotherapy. Eye care (special eye drops and eye examinations) is essential during treatment.

Key results

11.5 vs 9.5 months

Median overall survival

HR 0.70 (95% CI 0.54–0.89); P=0.004

4.2 vs 2.9 months

Median progression-free survival

HR 0.67 (95% CI 0.54–0.82); P<0.001

17.8% vs 5.2%

Confirmed objective response rate

Odds ratio 4.0 (95% CI 2.1–7.6)

Drugs in this study:Gemcitabine (Gemzar)Irinotecan (Camptosar)Vinorelbine (Navelbine)

Dose and schedule cards

Single-agent chemotherapy (innovaTV 301 control-arm options)

Recurrent or metastatic disease after first-line combination therapyEach drug’s schedule in the tableOn the page “Cervical cancer” · Metastatic or recurrent disease: second line and beyond

Recurrent or metastatic disease after first-line combination therapy

Drug	Dose	Route	Schedule
One of the following
Topotecan	1 or 1.25 mg/m²	IV	Days 1–5, every 21 days
Vinorelbine	30 mg/m²	IV	Days 1 and 8, every 21 days
Gemcitabine	1000 mg/m²	IV	Days 1 and 8, every 21 days
Irinotecan	100 or 125 mg/m²	IV	Weekly for 4 weeks, every 42 days
Pemetrexed	500 mg/m²	IV	Day 1, every 21 days

Cycle schedule: Drug-dependent (see the days column)

Pemetrexed: folic acid 400 to 1000 mcg orally daily from 7 days before the first dose until 21 days after the last dose; vitamin B12 1 mg IM one week before the first dose and then every 3 cycles; and dexamethasone 4 mg orally twice daily on the day before, the day of and the day after the infusion. The objective response rate with these drugs in the trial was 5.2%. Source for dosing: protocol NCT04697628.

On the page “Cervical cancer” · Metastatic or recurrent disease: second line and beyond

Tisotumab vedotin (innovaTV 301)

Recurrent or metastatic cancer with progression on or after chemotherapy (second or third line)Cycle length: Every 3 weeksOn the page “Cervical cancer” · Metastatic or recurrent disease: second line and beyond

Recurrent or metastatic cancer with progression on or after chemotherapy (second or third line)

Drug	Dose	Route	Schedule
Tisotumab vedotin	2 mg/kg (maximum 200 mg for body weight of 100 kg or more), 30-minute infusion	IV	Day 1

Cycle length: Every 3 weeks
Duration: Until progression or unacceptable toxicity

Ocular toxicity warning: Eye examination (visual acuity and slit lamp) before initiation and before each cycle for the first 9 cycles; ophthalmic corticosteroid drops, one drop in each eye before each infusion and then three times daily for 72 hours; ocular vasoconstrictor drops immediately before the infusion; cold eye packs during the infusion; lubricating eye drops throughout treatment and for 30 days after the last dose; avoid contact lenses. Dose reductions: 1.3 mg/kg, then 0.9 mg/kg; permanently discontinue if 0.9 mg/kg is not tolerated. Grade 3 or higher adverse events occurred in 52.0% and treatment discontinuation due to toxicity in 14.8%.

On the page “Cervical cancer” · Metastatic or recurrent disease: second line and beyond

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Tisotumab vedotin (253 patients)

Single-agent tisotumab vedotin 2.0 mg/kg IV every 3 weeks. According to the FDA label: maximum 200 mg (body weight 100 kg or more), 30-minute infusion, until progression or toxicity; eye examination before starting and before each cycle for the first 9 cycles, corticosteroid eye drops (before the infusion and three times daily for 72 hours), vasoconstrictor eye drops before the infusion, cold eye pads during the infusion and lubricating eye drops until 30 days after the last dose; dose reduction to 1.3 and then 0.9 mg/kg.

2Investigator's choice of chemotherapy (249 patients)

One of the following at the investigator's choice (all IV): topotecan 1 or 1.25 mg/m² days 1 to 5 every 21 days; vinorelbine 30 mg/m² days 1 and 8 every 21 days; gemcitabine 1000 mg/m² days 1 and 8 every 21 days; irinotecan 100 or 125 mg/m² weekly for 4 weeks every 42 days; or pemetrexed 500 mg/m² day 1 every 21 days.

Source of the regimen details: Abstract of the paper, ClinicalTrials.gov NCT04697628 (dose and schedule of the control-group chemotherapy) and the FDA label for tisotumab vedotin (DailyMed; dose cap, infusion duration, eye care and dose reductions)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with recurrent or metastatic cervical cancer that had progressed after first-line combination therapy, receiving second-‎ or third-line treatment.

According to ClinicalTrials.gov: squamous, adenocarcinoma or adenosquamous histology; progression during or after a standard chemotherapy doublet (paclitaxel + cisplatin or carboplatin or topotecan, with bevacizumab and anti-PD-‎(L)1 where standard); 1 or 2 prior systemic regimens for recurrent or metastatic disease; measurable disease; ECOG 0 or 1; life expectancy of at least 3 months; no clinically significant bleeding risk.

Endpoints

Primary endpoint: overall survival. Secondary: progression-free survival, objective response rate and safety.

Safety and side effects

Grade 3 or higher adverse events occurred in 52.0% of the tisotumab vedotin group versus 62.3% of the chemotherapy group; 14.8% of patients discontinued tisotumab vedotin because of toxicity. Ocular adverse events (such as conjunctivitis and dry eye), peripheral neuropathy and haemorrhage are known adverse effects of this drug, and preventive eye care is required (FDA label).

Clinical significance and place in guidelines

The first phase 3 trial to show an overall survival advantage for an antibody–drug conjugate in second-line cervical cancer. In April 2024 the FDA granted full approval to tisotumab vedotin for recurrent or metastatic cervical cancer with progression on or after chemotherapy. The NCCN guideline (version 2.2026) lists it as a preferred second-line/subsequent option regardless of biomarker status.

Limitations

Open-label design; the control group received single-agent chemotherapy with limited activity; most patients had previously received immunotherapy, but the optimal sequence with other new therapies is unclear.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.