Tisotumab vedotin

MMAE is a CYP3A4 substrate. Concomitant use of tisotumab vedotin with strong CYP3A4 inhibitors may increase unconjugated MMAE exposure, which may increase the risk of tisotumab vedotin adverse reactions. Closely monitor patients for adverse reactions of tisotumab vedotin when used concomitantly with strong CYP3A4 inhibitors.

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, but no dosage adjustment in the starting dose of tisotumab vedotin is recommended.

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), tisotumab vedotin may impair female fertility. The effect on fertility is reversible.

Males

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

Risk Summary

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

Data

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, 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).

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 and for 3 weeks after the last dose.

Carcinogenicity studies in animals have not been performed with tisotumab vedotin-tftv or MMAE.

MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism. MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178 TK+/- mouse lymphoma forward mutation assay.

Fertility studies with tisotumab vedotin-tftv or MMAE have not been conducted. However, results of a repeatdose toxicity study in monkeys indicate the potential for tisotumab vedotin-tftv to impair male reproductive function and fertility.

In a repeat-dose toxicology study conducted in monkeys for 13 weeks, doses ≥1 mg/kg tisotumab vedotin-tftv (≥0.6 times the human exposure [AUC] at the recommended dose) resulted in decreased testicular size and seminiferous tubule atrophy, reduction or absence in sperm count, and decreased sperm motility. Findings of sperm absence and decreased motility did not reverse by the end of the recovery period at doses ≥3 mg/kg (≥1.7 times the human exposure [AUC] at the recommended dose).

MMAE-containing ADCs have been associated with adverse ovarian effects when administered to sexually immature animals. Adverse effects included decrease in, or absence of, secondary and tertiary ovarian follicles after weekly administration to cynomolgus monkeys in studies of 4-week duration. These effects showed a trend towards recovery 6 weeks after the end of dosing; no changes were observed in primordial follicles.

• Ocular adverse reactions
• Peripheral neuropathy
• Hemorrhage
• Pneumonitis
• Severe cutaneous adverse reactions

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS section reflect exposure to tisotumab vedotin in 425 patients with recurrent or metastatic cervical cancer who received at least one dose of tisotumab vedotin at 2 mg/kg intravenously every 3 weeks in innovaTV 301, innovaTV 204, innovaTV 201 (NCT02001623), innovaTV 202 (NCT02552121), innovaTV 203 (NCT03245736), and innovaTV 206 (NCT03913741). The median duration of treatment with tisotumab vedotin was 3.7 months (range: 0.4-40.2). In this pooled safety population, the most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (45%), peripheral neuropathy (39%), conjunctival adverse reactions (38%), nausea (37%), fatigue (36%), aspartate aminotransferase increased (33%), epistaxis (33%), alopecia (31%), alanine aminotransferase increased (30%), and hemorrhage (28%). The data described in this section reflect exposure to tisotumab vedotin from innovaTV 301 and innovaTV 204.

innovaTV 301

The safety of tisotumab vedotin was evaluated in an open-label, randomized study in patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy. A total of 250 patients received tisotumab vedotin 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment with tisotumab vedotin was 3.7 months (range: 0.4-19).

Serious adverse reactions occurred in 33% of patients receiving tisotumab vedotin. The most common (≥2%) serious adverse reactions were urinary tract infection (4.8%), small intestinal obstruction (2.4%), sepsis (2%), abdominal pain (2%), and hemorrhage (2%). Fatal adverse reactions occurred in 1.6% of patients who received tisotumab vedotin, including acute kidney injury (0.4%), pneumonia (0.4%), sepsis (0.4%) and Stevens-Johnson syndrome (0.4%).

Adverse reactions leading to permanent discontinuation occurred in 15% of patients receiving tisotumab vedotin; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (6%) and ocular adverse reactions (6%).

Adverse reactions leading to dose interruption occurred in 39% of patients receiving tisotumab vedotin; the most common (≥3%) adverse reactions leading to dose interruption were ocular adverse reactions (16%) and peripheral neuropathy (6%).

Adverse reactions leading to dose reduction occurred in 30% of patients receiving tisotumab vedotin; the most common (≥3%) adverse reactions leading to dose reduction were peripheral neuropathy (10%) and ocular adverse reactions (10%). The ocular adverse reactions included conjunctival disorders (4.8%), keratopathy (4%), and dry eye (0.8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, in patients receiving tisotumab vedotin were hemoglobin decreased, peripheral neuropathy, conjunctival adverse reactions, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, fatigue, sodium decreased, epistaxis, and constipation.

Table 1 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 301.

Table 1. Adverse Reactions (≥10%) in Patients Who Received Tisotumab vedotin in innovaTV 301:

¹ Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, muscular weakness, peripheral sensorimotor neuropathy, peripheral motor neuropathy, neurotoxicity, gait disturbance, neuralgia, hypoaesthesia, neuropathy peripheral, and skin burning sensation.
² Conjunctival adverse reactions includes conjunctivitis, conjunctivitis bacterial, conjunctivitis viral, episcleritis, ocular hyperemia, conjunctival hemorrhage, conjunctival hyperemia, conjunctival ulcer, conjunctivitis allergic, conjunctival disorder, symblepharon, conjunctival erosion, conjunctival oedema, conjunctivochalasis, and conjunctival scar.
³ Corneal adverse reactions includes keratitis, punctate keratitis, corneal erosion, ulcerative keratitis, corneal degeneration, corneal opacity, and keratopathy.
⁴ Dry eye includes dry eye, eye discharge, eye pruritus, eye pain, eye irritation, and lacrimation increased.
⁵ Nausea includes nausea and retching.
⁶ Diarrhea includes diarrhea and gastroenteritis.
⁷ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower.
⁸ Fatigue includes fatigue and asthenia.
⁹ Hemorrhage includes hematuria, vaginal hemorrhage, rectal hemorrhage, hemoptysis, anal hemorrhage, hemorrhage, gastrointestinal hemorrhage, hemorrhagic shock, lower gastrointestinal hemorrhage, gingival bleeding, tumor hemorrhage, intra-abdominal hemorrhage, gastric hemorrhage, genital hemorrhage, uterine hemorrhage, urinary tract hemorrhage, hemorrhoidal hemorrhage.
¹⁰ Rash includes rash maculo-papular, eczema, rash macular, rash pustular, dermatitis acneiform, erythema, rash, urticaria, dermatitis, and rash erythematous.
¹¹ Urinary tract infection includes urinary tract infection, pyelonephritis acute, cystitis, and urinary tract infection bacterial.

Clinically relevant adverse reactions in <10% of patients who received tisotumab vedotin in innovaTV 301 include periorbital adverse reactions (9%) and intestinal obstruction (4.4%, including small bowel, large bowel, and malignant gastrointestinal obstruction).

Table 2 summarizes the laboratory abnormalities in innovaTV 301.

Table 2. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline In Patients Who Received Tisotumab vedotin in innovaTV 301:

¹ The denominator used to calculate the rate varied from 206 to 244 based on the number of patients with a baseline value and at least one post-treatment value.

innovaTV 204

The safety of tisotumab vedotin was evaluated in a single arm study in patients (n=101) with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Patients received tisotumab vedotin 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7-16).

Serious adverse reactions occurred in 43% of patients. The most common (≥3%) serious adverse reactions were ileus (6%), hemorrhage (5%), pneumonia (4%), peripheral neuropathy, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received tisotumab vedotin, including septic shock (1%), pneumonitis (1%), sudden death (1%), and multisystem organ failure (1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving tisotumab vedotin; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (5%) and corneal adverse reactions (4%).

Adverse reactions leading to dose interruption occurred in 47% of patients; the most (≥3%) common adverse reactions leading to dose interruption were peripheral neuropathy (8%), conjunctival adverse reactions (4%), and hemorrhage (4%).

Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) adverse reactions leading to dose reduction were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

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. Table 3 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 204.

Table 3. Adverse Reactions (≥10%) in Patients Who Received Tisotumab vedotin in innovaTV 204:

¹ Fatigue includes fatigue and asthenia.
² Nausea includes nausea and retching.
³ Diarrhea includes diarrhea, gastroenteritis, and colitis.
⁴ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal distention and abdominal discomfort.
⁵ Peripheral neuropathy includes neuropathy peripheral, peripheral sensorimotor neuropathy, polyneuropathy, peripheral sensory neuropathy, paresthesia, hypoesthesia, burning sensation, neuralgia, sensory loss, peripheral motor neuropathy, muscular weakness, gait disturbance, and hyperesthesia.
⁶ Rash includes rash, rash maculo-papular, rash macular, dermatitis acneiform, dermatitis allergic, and erythema.
⁷ Hemorrhage includes vaginal hemorrhage, hematuria, rectal hemorrhage, cystitis hemorrhagic, lower gastrointestinal hemorrhage, urinary bladder hemorrhage, hematochezia, anal hemorrhage, gingival bleeding, post procedural hemorrhage, radiation associated with hemorrhage, metrorrhagia, large intestinal hemorrhage, paranasal sinus hemorrhage, and hemoptysis.
⁸ Conjunctival adverse reactions includes conjunctivitis, conjunctival abrasion, conjunctival erosion, conjunctival hyperemia, conjunctival scar, noninfective conjunctivitis, ocular hyperemia, and conjunctival hemorrhage.
⁹ Dry eye includes dry eye and lacrimation increased.
¹⁰ Corneal adverse reactions includes keratitis, punctate keratitis, ulcerative keratitis, corneal erosion, corneal scar, keratopathy, and corneal bleeding.
¹¹ Periorbital adverse reactions includes blepharitis, meibomianitis, eye pruritus, entropion, trichiasis, chalazion, and meibomian gland dysfunction.
¹² Myalgia includes myalgia, musculoskeletal discomfort, and musculoskeletal pain
¹³ Pain in extremity includes pain in extremity and limb discomfort.
¹⁴ Urinary tract infection includes urinary tract infection, urinary tract infection bacterial, and cystitis.

Clinically relevant adverse reactions in <10% of patients who received tisotumab vedotin in innovaTV 204 included venous thrombosis (3%), pulmonary embolism (3%), and pneumonitis (2%).

Table 4 summarizes the laboratory abnormalities in innovaTV 204.

Table 4. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline In Patients Who Received Tisotumab vedotin in innovaTV 204:

¹ The denominator used to calculate the rate varied from 96 to 101 based on the number of patients with a baseline value and at least one post-treatment value.