Mirvetuximab Soravtansine (Monograph)

Brand name: Elahere
Drug class: Antineoplastic Agents
CAS number: 1453084-36-0

Introduction

Mirvetuximab soravtansine-gynx, a folate receptor alpha (FRα)-directed antibody and microtubule inhibitor conjugate, is an antineoplastic agent.

Uses for Mirvetuximab Soravtansine

Mirvetuximab soravtansine-gynx has the following uses:

Mirvetuximab soravtansine-gynx is indicated for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test.

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 a confirmatory trial.

Mirvetuximab Soravtansine Dosage and Administration

General

Mirvetuximab soravtansine-gynx is available in the following dosage form(s) and strength(s):

• Injection concentrate: 100 mg/20 mL (5 mg/mL) in a single-dose vial.

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

• Administer mirvetuximab soravtansine-gynx as an intravenous infusion only after dilution in 5% dextrose injection. Mirvetuximab soravtansine-gynx is incompatible with normal saline.

• The recommended dose of mirvetuximab soravtansine-gynx is 6 mg/kg based on adjusted ideal body weight (AIBW) administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.

• Premedicate with a corticosteroid, antihistamine, and antipyretic prior to each infusion.

• Premedicate with an antiemetic, ophthalmic topical steroids, and lubricating eye drops.

• See full Prescribing Information for preparation and administration instructions and dose modifications for adverse reactions.

Cautions for Mirvetuximab Soravtansine

Contraindications

• None.

Warnings/Precautions

Ocular Disorders

Mirvetuximab soravtansine-gynx can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.

Ocular adverse reactions occurred in 61% of patients with ovarian cancer treated with mirvetuximab soravtansine-gynx. Nine percent (9%) of patients experienced Grade 3 ocular adverse reactions, including visual impairment, keratopathy/keratitis (corneal disorders), dry eye, photophobia, and eye pain; and one patient (0.2%) experienced Grade 4 keratopathy. The most common (≥5%) ocular adverse reactions were visual impairment (49%), keratopathy (36%), dry eye (26%), cataract (15%), photophobia (13%), and eye pain (12%).

The median time to onset for first ocular adverse reaction was 1.2 months (range: 0.03 to 12.9). Of the patients who experienced ocular events, 49% had complete resolution and 39% 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 permanent discontinuation of mirvetuximab soravtansine-gynx in 0.6% of patients.

Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with mirvetuximab soravtansine-gynx are recommended. Advise patients to avoid use of contact lenses during treatment with mirvetuximab soravtansine-gynx unless directed by a healthcare provider.

Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.

Monitor for ocular toxicity and withhold, reduce, or permanently discontinue mirvetuximab soravtansine-gynx based on severity and persistence of ocular adverse reactions.

Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with mirvetuximab soravtansine-gynx.

Pneumonitis occurred in 10% of patients treated with mirvetuximab soravtansine-gynx, including 0.8% with Grade 3 events, and 1 patient (0.2%) with a Grade 4 event. One patient (0.2%) died due to respiratory failure in the setting of pneumonitis and lung metastases. Pneumonitis resulted in mirvetuximab soravtansine-gynx dose reduction in 1%, dose interruptions in 3%, and permanent discontinuation in 3% of patients.

Monitor patients for pulmonary signs and symptoms of pneumonitis, which 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 mirvetuximab soravtansine-gynx for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue mirvetuximab soravtansine-gynx in all patients with Grade 3 or 4 pneumonitis. Patients who are asymptomatic may continue dosing of mirvetuximab soravtansine-gynx with close monitoring.

Peripheral Neuropathy

Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with mirvetuximab soravtansine-gynx across clinical trials; 2% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (19%), peripheral sensory neuropathy (9%), paresthesia (6%), neurotoxicity (3%), hypoesthesia (2%), peripheral motor neuropathy (1%), neuralgia (0.4%), polyneuropathy (0.2%), and oral hypoesthesia (0.2%).

The median time to onset of peripheral neuropathy was 1.3 months (range 0.03 to 29.1). Of the patients who experienced peripheral neuropathy, 28% had complete resolution and 13% 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 mirvetuximab soravtansine-gynx in 0.4% of patients.

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 dosage, dose reduce, or permanently discontinue mirvetuximab soravtansine-gynx based on the severity of peripheral neuropathy.

Embryo-fetal Toxicity

Based on its mechanism of action, mirvetuximab soravtansine-gynx can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with mirvetuximab soravtansine-gynx and for 7 months after the last dose.

Specific Populations

Pregnancy

Based on its mechanism of action, mirvetuximab soravtansine-gynx can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells. Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, mirvetuximab soravtansine-gynx has the potential to be transmitted from the mother to the developing fetus. There are no available human data on mirvetuximab soravtansine-gynx use in pregnant women to inform a drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine-gynx. Advise patients of the potential risk to a fetus.

The estimated 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.

No reproductive or developmental animal toxicity studies have been conducted with mirvetuximab soravtansine-gynx. The cytotoxic component of mirvetuximab soravtansine-gynx, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

Lactation

There are no data on the presence of mirvetuximab soravtansine-gynx in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with mirvetuximab soravtansine-gynx and for 1 month after the last dose.

Females and Males of Reproductive Potential

Mirvetuximab soravtansine-gynx can cause embryo-fetal harm when administered to a pregnant woman.

Verify pregnancy status in females of reproductive potential prior to initiating mirvetuximab soravtansine-gynx.

Advise females of reproductive potential to use effective contraception during treatment with mirvetuximab soravtansine-gynx and for 7 months after the last dose.

Pediatric Use

Safety and effectiveness of mirvetuximab soravtansine-gynx have not been established in pediatric patients.

Geriatric Use

Of the 106 patients who were treated in the principal efficacy study, 44% of patients were ≥65 years old. Grade ≥3 adverse reactions occurred in 49% of patients ≥65 years and in 51% <65 years. No clinically meaningful differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of mirvetuximab soravtansine-gynx.

Renal Impairment

No dosage adjustment of mirvetuximab soravtansine-gynx is recommended for patients with mild to moderate renal impairment (Cl_cr 30 to 90 mL/minute). The effect of severe renal impairment (Cl_cr 15 to < 30 mL/minute) or end-stage renal disease on mirvetuximab soravtansine-gynx is unknown.

Hepatic Impairment

Avoid use of mirvetuximab soravtansine-gynx in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).

No dosage adjustment of mirvetuximab soravtansine-gynx is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST).

Common Adverse Effects

The most common (≥20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.

Drug Interactions

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: Concomitant use of mirvetuximab soravtansine-gynx with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of adverse reactions. Closely monitor for mirvetuximab soravtansine-gynx adverse reactions.

Actions

Mechanism of Action

Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC). The antibody is a chimeric IgG1 directed against folate receptor alpha (FRα). The small molecule, DM4, is a microtubule inhibitor attached to the antibody via a cleavable linker. Upon binding to FRα, mirvetuximab soravtansine-gynx is internalized followed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Inform patients about the need for eye exams before and during treatment with mirvetuximab soravtansine-gynx.

• Advise patients to contact their healthcare provider promptly if they experience any visual changes. Advise patients to use steroid eye drops and artificial tear substitutes.

• Risk of pneumonitis; advise patients to immediately report new or worsening respiratory symptoms.

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients to inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with mirvetuximab soravtansine-gynx and for 7 months after the last dose.

• Advise women not to breastfeed during treatment with mirvetuximab soravtansine-gynx and for 1 month after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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