Telisotuzumab vedotin

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

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

There are no data on the presence of telisotuzumab vedotin or MMAE 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 telisotuzumab vedotin and for 1 month after the last dose.

Carcinogenesis

Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin or the small molecule MMAE.

Mutagenesis

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 L5178Y TK^+/- mouse lymphoma forward mutation assay.

Impairment of Fertility

Fertility studies with telisotuzumab vedotin or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats and monkeys indicate the potential for telisotuzumab vedotin to impair male and female reproductive function and fertility.

In a 2-week repeat-dose toxicology study in rats, telisotuzumab vedotin administered at doses ≥6 mg/kg (≥12 times the human exposure [AUC] at the recommended dose) resulted in decreased number/degeneration of germ cells in the testes largely due to loss of spermatogonia. The reversibility of these findings was not assessed.

In a 4-week repeat-dose toxicology study in sexually immature monkeys, telisotuzumab vedotin administered at doses ≥3 mg/kg (≥4 times the human exposure [AUC] at the recommended dose) resulted in degeneration of granulosa cells and decreased number of tertiary follicles in the ovaries and degeneration/necrosis of endometrial glands in the uterus. There was evidence of reversibility after an 8-week recovery period.

Clinical Trials Experience

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

LUMINOSITY

The safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to telisotuzumab vedotin in 168 patients with locally advanced or metastatic EGFR wild-type non-squamous NSCLC with c-Met protein overexpression who received telisotuzumab vedotin as a single agent administered at 1.9 mg/kg intravenously every 2 weeks in the LUMINOSITY study. Among patients who received telisotuzumab vedotin, 42% were exposed for 6 months or longer and 11% were exposed for greater than one year.

The median age of patients who received telisotuzumab vedotin was 64.5 years (range: 33 to 83 years); 70% were male; 65% were White; 1.8% were Black or African American, 33% were Asian; and 0.6% were of Hispanic or Latino ethnicity.

Serious adverse reactions occurred in 35% of patients. Serious adverse reactions occurring in ≥2% of patients included ILD/pneumonitis (5%), pneumonia (5%), peripheral neuropathy (3.6%), and pleural effusion (2.4%). Fatal adverse reactions occurred in 5% of patients who received telisotuzumab vedotin, including ILD/pneumonitis (1.8%), pneumonia (1.2%), sudden death (1.2%), noninfectious endocarditis (0.6%) and myocardial infarction (0.6%).

Permanent discontinuations of telisotuzumab vedotin due to adverse reactions occurred in 30% of patients. Adverse reactions which resulted in permanent discontinuation of telisotuzumab vedotin in ≥2% included peripheral neuropathy and ILD/pneumonitis.

Dosage interruptions due to adverse reactions occurred in 44% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included peripheral neuropathy, fatigue, pneumonia, increased ALT, blurred vision, COVID-19, ILD/pneumonitis, and keratitis.

Dose reductions due to adverse reactions occurred in 28% of patients. Adverse reactions which required dose reductions in ≥2% of patients included peripheral neuropathy, fatigue, and keratitis.

The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, decreased appetite, and peripheral edema.

The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, increased glucose, increased ALT, increased gamma glutamyl transferase, decreased phosphorus, decreased sodium, decreased hemoglobin and decreased calcium.

Table 1 summarizes the adverse reactions in LUMINOSITY.

Table 1. Adverse Reactions (≥10%) in Patients with EGFR Wild-Type Non-squamous NSCLC with c-Met Protein Overexpression in LUMINOSITY:

¹ Events were graded using NCI CTCAE version 4.03.
² Grouped term.
³ Includes vision blurred, visual acuity reduced, visual impairment.
⁴ Includes corneal cyst, corneal disorder, corneal erosion, corneal edema, corneal opacity, keratitis, keratitis interstitial, punctate keratitis.

Other clinically relevant adverse reactions in <10% of patients who received telisotuzumab vedotin included arthralgia, dizziness, dry eye, infusion-related reaction and photophobia.

Table 2 presents laboratory abnormalities in LUMINOSITY.

Table 2. Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with EGFR Wild-Type Non-squamous NSCLC with c-Met Protein Overexpression in LUMINOSITY:

Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.