Introduction

Tisotumab vedotin-tftv, a tissue factor-directed antibody and microtubule inhibitor conjugate, is an antineoplastic agent.

Uses for Tisotumab Vedotin-tftv

Tisotumab vedotin-tftv has the following uses:

Tisotumab vedotin-tftv is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Tisotumab Vedotin-tftv Dosage and Administration

General

Tisotumab vedotin-tftv is available in the following dosage form(s) and strength(s):

For Injection: 40 mg as a lyophilized cake or powder in a single-dose vial for reconstitution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• For intravenous infusion only. Do not administer tisotumab vedotin-tftv as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products.

• The recommended dose of tisotumab vedotin-tftv is 2 mg/kg (up to a maximum of 200 mg for patients weighing ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Contraindications

None.

Warnings/Precautions

Ocular Adverse Reactions

Ocular adverse reactions occurred in 60% of patients with cervical cancer treated with tisotumab vedotin-tftv across clinical trials. The most common ocular adverse reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with tisotumab vedotin-tftv at the recommended dose.

The median time to onset of the first ocular adverse reaction was 1.2 months (range, 0 – 6.5). Of the patients who experienced ocular events, 55% had complete resolution and 30% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to discontinuation of tisotumab vedotin-tftv in 6% of patients with cervical cancer.

In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions

Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms.

Withhold, reduce the dose, or permanently discontinue tisotumab vedotin-tftv based on the severity of the adverse reaction.

Peripheral Neuropathy

Peripheral neuropathy occurred in 42% of patients with cervical cancer treated with tisotumab vedotin-tftv across clinical trials; 8% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with tisotumab vedotin-tftv at the recommended dose developed Guillain-Barre syndrome.

The median time to onset of peripheral neuropathy was 2.4 months (range, 0-11.3). Of the patients who experienced peripheral neuropathy, 17% had complete resolution and 17% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of tisotumab vedotin-tftv in 8% of patients with cervical cancer.

Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dose, then dose reduce, or permanently discontinue tisotumab vedotin-tftv based on the severity of peripheral neuropathy.

Hemorrhage

Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab vedotin-tftv across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.

The median time to onset of hemorrhage was 0.3 months (range, 0-6.5). Of the patients who experienced hemorrhage, 71% had complete resolution and 11% had partial resolution (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up.

Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue tisotumab vedotin-tftv. For grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue tisotumab vedotin-tftv.

Pneumonitis

Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody drug conjugates containing vedotin including tisotumab vedotin-tftv. Among patients with cervical cancer treated with tisotumab vedotin-tftv across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms indicative of pneumonitis. Symptoms may include hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations.

Withhold tisotumab vedotin-tftv for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue tisotumab vedotin-tftv in all patients with Grade 3 or 4 pneumonitis.

Embryo-fetal Toxicity

Based on the mechanism of action and findings in animals, tisotumab vedotin-tftv can cause fetal harm when administered to a pregnant woman. The small molecule component of tisotumab vedotin-tftv, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.

Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with tisotumab vedotin-tftv and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with tisotumab vedotin-tftv and for 4 months after the last dose.

Specific Populations

Pregnancy

Risk Summary: Based on the mechanism of action and findings in animals, tisotumab vedotin-tftv can cause fetal harm when administered to a pregnant woman. There are no available human data on tisotumab vedotin-tftv use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of tisotumab vedotin-tftv, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose. Advise patients of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Animal Data: No embryo-fetal development studies in animals have been performed with tisotumab vedotin-tftv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of tisotumab vedotin-tftv, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).

Lactation

Risk Summary: There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with tisotumab vedotin-tftv and for 3 weeks after the last dose.

Females and Males of Reproductive Potential

Tisotumab vedotin-tftv can cause fetal harm when administered to a pregnant woman.

Verify pregnancy status in females of reproductive potential prior to initiating tisotumab vedotin-tftv treatment.

Advise females of reproductive potential to use effective contraception during treatment with tisotumab vedotin-tftv and for 2 months after the last dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with tisotumab vedotin-tftv and for 4 months after the last dose.

Based on findings from animal studies, tisotumab vedotin-tftv may impair male fertility.

Pediatric Use

Safety and effectiveness of tisotumab vedotin-tftv in pediatric patients have not been established.

Geriatric Use

Of the 101 patients treated with tisotumab vedotin-tftv in innovaTV 204, 13% were ≥65 years of age. Grade ≥3 adverse reactions occurred in 69% patients ≥65 years and in 59% patients <65 years. Serious adverse reactions occurred in 54% patients ≥65 years and in 41% patients <65 years. No patients aged ≥65 years treated with tisotumab vedotin-tftv in innovaTV 204 experienced a tumor response.

Hepatic Impairment

Avoid use of tisotumab vedotin-tftv in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN).

In patients with mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin > 1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of tisotumab vedotin-tftv, but no dosage adjustment in the starting dose of tisotumab vedotin-tftv is recommended.

Common Adverse Effects

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash.

General

Tisotumab vedotin-tftv is available in the following dosage form(s) and strength(s):

For Injection: 40 mg as a lyophilized cake or powder in a single-dose vial for reconstitution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• For intravenous infusion only. Do not administer tisotumab vedotin-tftv as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products.

• The recommended dose of tisotumab vedotin-tftv is 2 mg/kg (up to a maximum of 200 mg for patients weighing ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Strong CYP3A4 Inhibitors: Closely monitor for tisotumab vedotin-tftv adverse reactions.