Mirvetuximab – Uses, Dosage, Side Effects, Interaction

Mirvetuximab soravtansine-gynx (IMGN853) is an antibody-drug conjugate (ADC) formed by a monoclonal antibody (M9346A) that targets folate receptor alpha (FRα), covalently joined by a cleavable disulfide linker to the genotoxic compound DM4 (also known as soravtansine or ravtansine).^[rx],[rx]DM4 is conjugated to the antibody with a drug-to-antibody ratio of 3.5:1.^[rx]

The antibody component of mirvetuximab soravtansine-gynx binds to FRα, a receptor overexpressed on the surface of epithelial tumor cells, characteristic of ovarian, endometrial, triple-negative breast, and non-small-cell lung cancers.^[rx] After an ADC/receptor complex is formed, mirvetuximab soravtansine-gynx is internalized, and DM4 is released inside the cell. DM4 leads to cell-cycle arrest and apoptosis and is also able to diffuse into neighboring cells and induce further cell death.^[rx]

On November 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for the treatment of adult patients with FRα–positive, platinum-resistant epithelial ovarian, fallopian tube?, or primary peritoneal cancer who have received 1-3 prior systemic? treatment regimens. This decision was supported by findings from the phase 3 SORAYA trial (NCT04296890).^[rx],[rx]

Mechanism of action

Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC) formed by three components: a chimeric IgG1 antibody against folate receptor alpha (FRα), the small molecule anti-tubulin agent DM4 (a maytansine derivative) and a sulfo-SPDB linker that joins DM4 to the mirvetuximab antibody.^[rx] FRα is expressed on the cell surface and has a restricted distribution in normal tissues. However, abnormally high levels of FRα have been detected in serous and endometrioid epithelial ovarian cancer, endometrial adenocarcinoma, and non–small cell lung cancer of the adenocarcinoma subtype. In ovarian cancer patients, its expression is maintained in metastatic foci and recurrent? carcinomas.^[rx] Mirvetuximab soravtansine-gynx binds with high affinity to FRα and is then internalized through antigen-mediated endocytosis. Inside FRα-expressing tumor cells, DM4 is released via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, leading to cell cycle arrest and apoptosis.^[rx,rx] Since DM4 is electrically neutral and lipophilic, it is able to diffuse across cell membranes and lead to the death of neighboring antigen-negative cells. This “bystander effect” is an important component of mirvetuximab soravtansine-gynx, allowing it to exert a cytotoxic effect even in cells that do not express FRα on their surface.^[rx],[rx]

There is an exposure-response relationship for mirvetuximab soravtansine-gynx. The increased exposure of mirvetuximab soravtansine-gynx was associated with a higher incidence of ocular adverse reactions and peripheral neuropathy? grade 2 or higher. Mirvetuximab soravtansine-gynx did not cause large QTc increases (>10 msec) at the approved recommended dose.^[rx] The use of mirvetuximab soravtansine-gynx has been associated with severe? ocular adverse reactions, such as visual impairment, keratopathy, dry eye, photophobia?, eye pain?, and uveitis. Severe, life-threatening, or fatal interstitial lung disease? (ILD?), including pneumonitis, as well as peripheral neuropathy?, may also occur in patients treated with mirvetuximab soravtansine-gynx. Since mirvetuximab soravtansine-gynx contains DM4, a genotoxic compound, the use of this drug may cause embryo-fetal harm in pregnant women.^[rx]

Indications

• Mirvetuximab soravtansine is indicated for the treatment of adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Patients are selected for therapy based on an FDA-approved test.^[rx]
• Mirvetuximab soravtansine is a folate receptor alpha-directed antibody and microtubule inhibitor conjugate used to treat folate receptor alpha-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
• 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.^[rx]
• Mirvetuximab soravtansine is indicated for the treatment of adults with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.^[rx][rx] Recipients are selected for therapy based on an FDA-approved test
• Platinum-Resistant Primary Peritoneal Cancer
• Platinum-resistant Epithelial Ovarian Cancer
• Platinum drug-resistant Fallopian tube cancer

Use in Cancer

Mirvetuximab soravtansine-gynx is approved to treat:

• The ovarian epithelial, fallopian tube, or primary peritoneal cancer that is folate receptor–alpha positive. It is used in adults whose cancer did not respond to or is no longer responding to platinum chemotherapy? and who have received one to three types of systemic therapy.

Mirvetuximab soravtansine-gynx is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that it provides a clinical benefit in these patients. Mirvetuximab soravtansine-gynx is also being studied in the treatment of other types of cancer.

Contraindications

• a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: gynx 100 mg/20 mL

Ovarian Cancer

• Usual dose: 6 mg/kg adjusted ideal body weight (AIBW) as an IV infusion once every 3 weeks
• Duration of therapy: Until disease progression? or unacceptable toxicity
• This indication is granted accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• Confirm the presence of folate receptor alpha tumor expression prior to initiation of treatment.
• Information regarding FDA-approved tests for folate receptor alpha tumors is available at http://www.fda.gov/CompanionDiagnostics.
• Refer to manufacturer product information for AIBW calculation.
• Administer premedications (corticosteroid, antihistamine, antipyretic, antiemetic) before each infusion of this drug to reduce the incidence of severity of infusion-related reactions (IRRs), nausea?, and vomiting?.
• Refer to the manufacturer’s product labeling for more information on the dosing of premedications.
• Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with folate receptor alpha-positive tumor expression who have previously received one to three lines of systemic treatments.

Fallopian Tube Cancer

• Usual dose: 6 mg/kg adjusted ideal body weight (AIBW) as an IV infusion once every 3 weeks
• Duration of therapy: Until disease progression? or unacceptable toxicity
• This indication is granted accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• Confirm the presence of folate receptor alpha tumor expression prior to initiation of treatment.
• Information regarding FDA-approved tests for folate receptor alpha tumors is available at http://www.fda.gov/CompanionDiagnostics.
• Refer to manufacturer product information for AIBW calculation.
• Administer premedications (corticosteroid, antihistamine, antipyretic, antiemetic) before each infusion of this drug to reduce the incidence of severity of infusion-related reactions (IRRs), nausea, and vomiting.
• Refer to the manufacturer’s product labeling for more information on the dosing of premedications.
• Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with folate receptor alpha-positive tumor expression who have previously received one to three lines of systemic treatments

Peritoneal Cancer

• Usual dose: 6 mg/kg adjusted ideal body weight (AIBW) as an IV infusion once every 3 weeks
• Duration of therapy: Until disease progression or unacceptable toxicity
• This indication is granted accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• Confirm the presence of folate receptor alpha tumor expression prior to initiation of treatment.
• Information regarding FDA-approved tests for folate receptor alpha tumors is available at http://www.fda.gov/CompanionDiagnostics.
• Refer to manufacturer product information for AIBW calculation.
• Administer premedications (corticosteroid, antihistamine, antipyretic, antiemetic) before each infusion of this drug to reduce the incidence of severity of infusion-related reactions (IRRs), nausea, and vomiting.
• Refer to the manufacturer’s product labeling for more information on the dosing of premedications.
• Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with folate receptor alpha-positive tumor expression who have previously received one to three lines of systemic treatments.

Dose Adjustments

DOSE REDUCTION FOR ADVERSE REACTIONS:

• Starting dose: 6 mg/kg AIBW
• First dose reduction: 5 mg/kg AIBW
• Second dose reduction: 4 mg/kg AIBW
• This drug should be discontinued permanently in patients who cannot tolerate 4 mg/kg AIBW dose.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
Keratitis/Keratopathy:

• Nonconfluent superficial keratitis: Monitor
• Confluent superficial keratitis, a cornea? epithelial defect, or 3-line or more loss in best corrected visual acuity?: Withhold dose until improved or resolved, then maintain at same dose level or consider dose reduction.
• Corneal ulcer? or stromal opacity or best-corrected distance visual acuity 20/200 or worse: Withhold the dose until improved or resolved, then resume at one lower dose level.
• Corneal perforation: Discontinue the drug permanently.

Uveitis:

• Grade 1/Rare cell in anterior chamber: Monitor
• Grade 2/1-2+ Cell or Flare? in anterior chamber: Withhold the dose until severity reduces to grade 1 or less, then maintain dose at same dose level.
• Grade 3/3+ Cell or Flare in anterior chamber: Withhold the dose until severity reduces to grade 1 or less, then resume at one lower dose level.
• Grade 4/Hypopyon: Discontinue the drug permanently.

Pneumonitis:

• Grade 1: Monitor
• Grade 2: Withhold the dose until severity reduces to grade 1 or less, then maintain the same dose or consider dose reduction by one dose level
• Grade 3 or 4: Discontinue the drug permanently.

Infusion-Related Reactions/Hypersensitivity:

• Grade 1: Maintain infusion rate
• Grade 2:
• Interrupt infusion and administer supportive treatment.
• Post recovery from symptoms, resume the infusion at 50% of the previous rate, and if no further symptoms develop, consider increasing the infusion rate as appropriate until the completion.
• Administer additional premedication for future cycles.
• Grade 3 or 4:
• Immediately stop infusion and administer supportive treatment.
• Advise patients to seek emergency? treatment and notify their healthcare provider, promptly, if the infusion-related symptoms reappear.
• Discontinue the drug permanently.

Other adverse reactions:

• Grade 3: Withhold the dose until severity reduces to grade 1 or less, then resume at one lower dose level.
• Grade 4: Discontinue the drug permanently.

Administration advice:

• The infusion bag should be visually inspected for particulate matter and discoloration prior to administration.
• Pre-medications should be administered before administering this drug.
• For IV administration only; 0.2 or 0.22-micron polyethersulfone (PES) in-line filter should be used and must not be substituted with any other filter.
• The initial dose should be administered as an IV infusion at the rate of 1 mg/min; If well tolerated after 30 minutes, the infusion rate can be increased to 3 mg/min; If well tolerated after 30 minutes, the infusion rate can be increased to 5 mg/min.
• If the patient does not experience any infusion-related reactions with the previous dose, the subsequent infusions can be administered at a maximum infusion rate of 5 mg/min, as tolerated.
• After infusion, the infusion line should be flushed with 5% dextrose injection, USP to ensure full delivery of dose; Other IV fluids are not compatible with this drug and must not be used for flushing.

Reconstitution/preparation techniques:

• This drug is hazardous. Follow appropriate handling and disposal procedures.
• Refer to manufacturer product information for reconstitution/preparation techniques.

IV compatibility:

• This drug is incompatible with 0.9% sodium chloride injection.
• This should not be mixed with any other drug or intravenous fluid.

Patient advice:

• Patients should read the FDA-approved drug product labeling.
• Patients should be informed about possible ocular toxicities and the need for an eye examination before initiating and during the treatment.
• If a patient experiences any ocular discomfort, immediately contact the health care provider.
• Patients should take prophylactic care of their eyes by using steroid? eye drops and artificial tear substitutes.
• Patients should immediately report any new or worsening respiratory symptoms to their healthcare provider.
• Females of childbearing potential or pregnant women should be apprised of the potential risk to a fetus.
• Inform health care provider in case of known or suspected pregnancy.
• Females of childbearing potential should use an effective method of contraception? during the treatment and for 7 months after the last dose.
• Women should not breastfeed during treatment and for 1 month after the last dose.

Side Effects

The Most Common

• feeling tired
• diarrhea?
• nausea
• abdominal pain?
• constipation
• muscle weakness or spasms
• trouble breathing, cough, shortness of breath, or chest pain
• new or worsening tingling or numbness in your hands or feet or muscle weakness

More Common

• dry eyes, sensitivity to light, blurred vision, eye pain, or new or worsening vision changes;
• cough, chest pain, trouble breathing, shortness of breath; or
• numbness, tingling, or burning pain in your hands or feet.
• abnormal lab results;
• nausea, stomach pain, diarrhea, constipation;
• fever, mouth sores, skin sores, sore throat, cough; or
• pale skin, tiredness, feeling light-headed or short of breath, cold hands and feet.

Rare

• 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,
• decreased hemoglobin.^[rx]

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells, Nonclinical Toxicology. Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, ELAHERE has the potential to be transmitted from the mother to the developing fetus. There are no available human data on ELAHERE 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.

Lactation

No information is available on the clinical use of mirvetuximab soravtansine during breastfeeding. Because mirvetuximab is a large protein molecule with a molecular weight of 150,000 Da, the amount in milk is likely to be very low. It is also likely to be partially destroyed in the infant’s gastrointestinal tract and absorption by the infant is probably minimal. However, mirvetuximab is conjugated with the small-molecule toxin, mafodotin, which might be excreted into milk. The manufacturer recommends that breastfeeding be discontinued during therapy and for 1 month after the last dose.