Mirvetuximab Soravtansine (Elahere): FRα-Targeted ADC for Platinum-Resistant Ovarian Cancer

　　Drug Overview

　　Mirvetuximab soravtansine-gynx(brand name:Elahere)is an antibody-drug conjugate(ADC)developed by ImmunoGen,Inc.,USA,designed specifically for adult patients with folate receptor alpha(FRα)-positive,platinum-resistant epithelial ovarian,fallopian tube,or primary peritoneal cancer.The drug specifically binds to FRα,which is highly expressed on the surface of tumor cells,and precisely delivers the cytotoxic agent DM4,effectively inhibiting tumor growth and inducing apoptosis.

　　Indications

　　Elahere 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 1 to 3 prior systemic treatment regimens.Patients should be selected for therapy based on an FDA-approved test.

　　Dosage and Administration

　　Patient Selection

　　Before initiating treatment with Elahere for platinum-resistant epithelial ovarian,fallopian tube,or primary peritoneal cancer,confirm FRαexpression in tumor tissue using an FDA-approved test.

　　Recommended Dosage

　　The recommended dosage of Elahere is 6 mg/kg based on adjusted ideal body weight(AIBW),administered as an intravenous infusion every 3 weeks(21-day cycle)until disease progression or unacceptable toxicity.Dosage calculation using AIBW reduces exposure differences in underweight or overweight patients.

　　The total dose of Elahere is calculated based on the patient's AIBW using the following formulas:

　　AIBW=Ideal Body Weight(IBW,kg)+0.4×(Actual Body Weight–IBW)

　　Female IBW(kg)=0.9×Height(cm)–92

　　Premedication and Required Ocular Care

　　Before each infusion of Elahere,administer appropriate premedications to reduce the incidence and severity of infusion-related reactions,nausea,and vomiting.Patients who have experienced infusion-related reactions may consider additional corticosteroid premedication the day before administration.

　　Ophthalmic examinations and ocular premedication are essential components of treatment.Perform ophthalmic examinations,including visual acuity assessment and slit-lamp examination,before initiating Elahere,every cycle for the first 8 cycles,and as clinically indicated.Topical ocular corticosteroids are recommended.Prescribe or renew corticosteroid prescriptions only after each slit-lamp examination.The recommended regimen is 1 drop in each eye 6 times daily starting the day before each infusion and continuing through day 4;then 1 drop in each eye 4 times daily from days 5 to 8.

　　Lubricating eye drops are recommended at least 4 times daily as needed during treatment.Allow at least 10 minutes between administration of corticosteroid eye drops and lubricating eye drops.

　　Adverse Reactions

　　The most common adverse reactions(≥20%),including laboratory abnormalities,are:increased aspartate aminotransferase,fatigue,increased alanine aminotransferase,blurred vision,nausea,increased alkaline phosphatase,diarrhea,abdominal pain,corneal disorders,peripheral neuropathy,musculoskeletal pain,lymphopenia,thrombocytopenia,decreased magnesium,decreased hemoglobin,dry eye,constipation,leukopenia,vomiting,decreased albumin,decreased appetite,and neutropenia.

　　Contraindications

　　Absolute contraindications for Elahere are currently not established.

　　Precautions

　　Ocular Disorders

　　Elahere can cause severe ocular adverse reactions,including visual impairment,corneal disorders,dry eye,photophobia,eye pain,and uveitis.Advise premedication and the use of lubricating and topical corticosteroid eye drops during treatment with Elahere.Advise patients to avoid wearing contact lenses during treatment unless directed by a healthcare provider.

　　Refer patients to an ophthalmologist for ophthalmic examinations,including visual acuity and slit-lamp examinations,before starting treatment,every cycle for the first 8 cycles,and as clinically indicated.Instruct patients to immediately consult an ophthalmologist if they develop any new or worsening ocular symptoms.Monitor for ocular toxicity and interrupt,reduce the dose,or permanently discontinue Elahere based on the severity and duration of adverse reactions.

　　Pneumonitis

　　Patients treated with Elahere may develop severe,life-threatening,or fatal interstitial lung disease(ILD),including pneumonitis.Monitor patients for pulmonary symptoms suggestive of pneumonitis,including hypoxia,cough,dyspnea,or radiologic interstitial infiltrates.Rule out infection,tumor,and other causes through appropriate investigations.

　　Interrupt treatment in patients with persistent or recurrent Grade 2 pneumonitis until symptoms resolve to≤Grade 1 and consider dose reduction.Permanently discontinue Elahere in all patients with Grade 3 or 4 pneumonitis.Asymptomatic patients may continue treatment with close monitoring.

　　Peripheral Neuropathy

　　In clinical trials,peripheral neuropathy occurred in 36%of ovarian cancer patients treated with Elahere;3%experienced Grade 3 peripheral neuropathy.Adverse reactions of peripheral neuropathy include:peripheral neuropathy,peripheral sensory neuropathy,paresthesia,neurotoxicity,hypoesthesia,peripheral motor neuropathy,polyneuropathy,and peripheral sensorimotor neuropathy.

　　The median time to onset of peripheral neuropathy was 5.9 weeks(range:0.1 to 126.7 weeks).Among patients who developed peripheral neuropathy,23%had complete resolution and 12%had partial improvement at last follow-up.0.7%of patients discontinued Elahere due to peripheral neuropathy.

　　Monitor patients for symptoms of neuropathy,such as paresthesia,tingling,burning sensation,neuropathic pain,muscle weakness,or hypoesthesia.Interrupt,reduce the dose,or permanently discontinue Elahere in patients who develop new or worsening peripheral neuropathy based on severity.

　　Embryo-Fetal Toxicity

　　Based on its mechanism of action,Elahere contains the genotoxic compound DM4 and affects actively dividing cells,which can cause embryo-fetal harm when administered to pregnant women.Advise pregnant women of the potential risk to the fetus.Advise females of reproductive potential to use effective contraception during treatment with Elahere and for 7 months after the last dose.

　　Special Populations

　　Pregnancy

　　Based on its mechanism of action,Elahere contains the genotoxic component DM4 and affects actively dividing cells,which can cause embryo-fetal harm when administered to pregnant women.Human immunoglobulin G(IgG)crosses the placenta,therefore Elahere may be transmitted from mother to fetus.There are no available human data on the use of Elahere in pregnant women to evaluate drug-associated risk,and no reproductive and developmental toxicity studies with Elahere have been conducted.Inform patients of the potential risk to the fetus.

　　Lactation

　　There are no data on the presence of Elahere in human milk,or its effects on the breastfed infant or milk production.Because of the potential for serious adverse reactions in breastfed infants,advise women to discontinue breastfeeding during treatment with Elahere and for 1 month after the last dose.

　　Females and Males of Reproductive Potential

　　Elahere can cause embryo-fetal harm when administered to pregnant women.Verify the pregnancy status of females of reproductive potential before initiating treatment with Elahere.Advise females of reproductive potential to use effective contraception during treatment with Elahere and for 7 months after the last dose.

　　Pediatric Use

　　The safety and effectiveness of Elahere in pediatric patients have not been established.

　　Geriatric Use

　　Of the 682 patients with epithelial ovarian cancer who received Elahere in all studies,44%were 65 years of age or older.The incidence of Grade 3 or higher adverse reactions was 51%in patients 65 years of age or older and 45%in younger patients.No clinically meaningful differences in efficacy or safety were observed between patients 65 years of age or older and younger patients.Age has no clinically significant effect on the pharmacokinetics of Elahere.

　　Renal Impairment

　　No dosage adjustment is recommended for patients with mild to moderate renal impairment(creatinine clearance 30 to 89 mL/min).The effect of severe renal impairment(creatinine clearance 15 to<30 mL/min)or end-stage renal disease on Elahere is not known.

　　Hepatic Impairment

　　Avoid use of Elahere in patients with moderate or severe hepatic impairment(total bilirubin>1.5 times the upper limit of normal).No dosage adjustment is recommended for patients with mild hepatic impairment(total bilirubin≤upper limit of normal and AST>upper limit,or total bilirubin>1 to 1.5 times upper limit of normal regardless of AST level).

　　Drug Interactions

　　DM4 is a substrate of CYP3A4.Concomitant use of Elahere with strong CYP3A4 inhibitors may increase the exposure of unconjugated DM4,which may increase the risk of adverse reactions from Elahere.Monitor patients closely for adverse reactions when used concomitantly.

　　Overdosage

　　Clinical data on Elahere overdosage is currently limited.

　　Pharmacokinetics

　　Unless otherwise noted,the pharmacokinetic characteristics of Elahere are derived from patients who received mirvetuximab soravtansine at doses ranging from 0.16 to 8.7 mg/kg based on adjusted ideal body weight(AIBW)(0.03 to 1.4 times the approved recommended dose of 6 mg/kg AIBW).

　　Peak plasma concentrations of Elahere are reached near the end of the intravenous infusion;peak concentrations of unconjugated DM4 occur on day 2 after administration;peak concentrations of S-methyl-DM4 occur approximately on day 3 after administration.All three reach steady state after one 3-week cycle,with minimal accumulation following multiple cycles of administration.

　　The steady-state mean apparent volume of distribution of Elahere is 2.6 L.In vitro studies show that the plasma protein binding of DM4 and S-methyl-DM4 is>99%in human plasma.

　　The total plasma clearance of Elahere is 19 mL/h;the mean terminal elimination half-life of the first dose is 4.8 days,and steady state is reached in approximately 24 days.The total plasma clearance of unconjugated DM4 is 14 L/h;the mean terminal elimination half-life is 2.8 days.The total plasma clearance of S-methyl-DM4 is 4.3 L/h;the mean terminal elimination half-life is 5 days.

　　The monoclonal antibody portion of Elahere is expected to be degraded into small peptides via catabolic pathways.Unconjugated DM4 and S-methyl-DM4 are primarily metabolized by CYP3A4.The major circulating metabolites in human plasma are DM4 and S-methyl-DM4,accounting for approximately 0.4%and 1.4%of the AUC of Elahere,respectively.

　　Within 24 hours after infusion,the major metabolites detected in urine are S-methyl-DM4 and DM4-sulfo-SPDB-lysine.