Mirvetuximab Soravtansine

Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) that carries a cytotoxic payload to tumour cells that display folate receptor alpha (FRα). It has three parts: an engineered IgG1 antibody directed against FRα (made in Chinese hamster ovary cells by recombinant DNA technology), a cleavable sulfo-SPDB linker, and DM4, a maytansinoid anti-tubulin agent. On average 3.4 DM4 molecules are attached to each antibody.

Mechanism of Action

• Target: FRα sits on the surface of many epithelial ovarian cancer cells, including metastases and recurrences, while its distribution in normal tissue is restricted.
• Uptake: the antibody binds FRα with high affinity and the complex is taken into the cell by receptor-mediated endocytosis.
• Payload release: inside the cell, proteases cleave the linker and free DM4 is released.
• Cell death: DM4 disrupts the microtubule network, causing cell-cycle arrest and apoptosis.
• Bystander effect: DM4 is neutral and lipophilic, so it can cross cell membranes and also kill neighbouring tumour cells that do not carry FRα.
• Exposure and toxicity: higher exposure has been linked to more ocular adverse reactions and to peripheral neuropathy of grade 2 or higher.
• Cardiac electrophysiology: at the recommended dose there was no mean QTc increase above 10 ms.

Pharmacokinetics

• Exposure: given by intravenous infusion only. After the first 3-week cycle at 6 mg/kg AIBW, the intact conjugate had a mean Cmax of 137.3 µg/mL and a mean AUC over the dosing interval of 20.65 h·mg/mL. Unconjugated DM4 had a Cmax of 4.11 ng/mL (AUC 530 h·ng/mL) and its metabolite S-methyl-DM4 a Cmax of 6.98 ng/mL (AUC 1,848 h·ng/mL). The conjugate peaks near the end of the infusion, DM4 about 2 days later and S-methyl-DM4 about 3 days later. Steady state is reached within one cycle, with minimal accumulation.
• Distribution: mean steady-state volume of distribution of the conjugate 2.63 L. DM4 and S-methyl-DM4 are more than 99% bound to plasma proteins in vitro.
• Metabolism: the antibody part is expected to be broken down into small peptides by normal protein catabolism. Free DM4 is reduced and S-methylated to S-methyl-DM4; both are metabolised by CYP3A4. They are the main circulating metabolites, at about 0.4% and 1.4% of the conjugate AUC.
• Elimination: mean total plasma clearance of the conjugate 18.9 mL/h; terminal half-life about 4.9 days after the first dose (DM4 about 2.8 days, S-methyl-DM4 about 5.1 days). S-methyl-DM4 and DM4-sulfo-SPDB-lysine are the main metabolites found in urine within 24 hours of the infusion.
• Special populations: dose recommendations for older patients and for renal or hepatic impairment are given under Administration and Dosage.

• Ovarian, fallopian tube or primary peritoneal cancer: monotherapy for adults with folate receptor alpha (FRα)-positive, platinum-resistant high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who have received one to three prior systemic treatment regimens.
• FRα status: eligible patients have tumours in which at least 75% of viable tumour cells show moderate (2+) and/or strong (3+) membrane staining by immunohistochemistry, assessed with a CE-marked in vitro diagnostic for this purpose. If none is available, an alternative validated test is used.

• Hypersensitivity to mirvetuximab soravtansine or to any of the excipients (glacial acetic acid, sodium acetate, sucrose, polysorbate 20, water for injections).

The frequencies below are pooled from four clinical studies in 682 patients with epithelial ovarian, fallopian tube or primary peritoneal cancer, treated with 6 mg/kg AIBW every 3 weeks (median treatment 19.1 weeks). The most common reactions are blurred vision (43%), nausea (41%), diarrhoea (39%), fatigue (35%), abdominal pain (30%), keratopathy (29%), dry eye (27%), constipation (26%), vomiting (23%), decreased appetite (22%), peripheral neuropathy (20%), headache (19%), asthenia (18%), increased AST (16%) and arthralgia (16%).

Very common (≥1/10): urinary tract infection, anaemia, thrombocytopenia, decreased appetite, hypomagnesaemia, peripheral neuropathy, headache, keratopathy, cataract, blurred vision, photophobia, eye pain, dry eye, pneumonitis, dyspnoea, cough, diarrhoea, abdominal pain, constipation, abdominal distension, vomiting, nausea, arthralgia, fatigue, increased AST and ALT.

Common (≥1/100 to <1/10): neutropenia, hypokalaemia, dehydration, insomnia, dysgeusia, dizziness, ocular discomfort, hypertension, ascites, gastro-oesophageal reflux disease, stomatitis, dyspepsia, hyperbilirubinaemia, pruritus, myalgia, back pain, pain in extremity, muscle spasms, pyrexia, increased blood alkaline phosphatase, increased gamma-glutamyl transferase, weight decreased, infusion-related reaction or hypersensitivity.

The SmPC groups related terms: for example, “keratopathy” covers corneal erosion, opacity and deposits, keratitis and punctate keratitis, and “blurred vision” also covers reduced visual acuity, visual impairment, diplopia and vitreous floaters.

Important and serious reactions:

• Eye disorders: ocular reactions (grouped terms) occurred in 59% of patients; 11% had grade 3 and fewer than 1% grade 4. The most common grade 3 or higher were blurred vision and keratopathy (5% each) and cataract (4%). The median time to the first ocular reaction was 5.1 weeks. Of the patients affected, 53% recovered completely and 38% improved in part; at last follow-up 0.3% (2 of 682) still had a grade 3 or higher ocular event. Ocular reactions led to dose delays in 24%, dose reductions in 15% and permanent discontinuation in 1%.
• Pneumonitis: pneumonitis (grouped terms, including interstitial lung disease) occurred in 10%, with grade 3 in 0.9% and grade 4 in 0.2%. Two patients (0.3%) died of respiratory failure, one in the setting of grade 1 pneumonitis with lung metastases and one of unknown cause without pneumonitis. The median time to onset was 18.1 weeks. It led to delays in 3%, dose reductions in 1% and permanent discontinuation in 3%.
• Peripheral neuropathy: occurred in 36% (grouped terms), grade 3 in 3%, at a median of 5.9 weeks. It led to delays in 2%, dose reductions in 4% and permanent discontinuation in 0.7%.
• Other serious reactions: the most commonly reported were pneumonitis (4%), small intestinal obstruction (3%), intestinal obstruction (3%), pleural effusion (2%), abdominal pain (2%), dehydration (1%), constipation (1%), nausea (1%), ascites (1%) and thrombocytopenia (below 1%).
• Dose changes and discontinuation: reactions most often leading to dose reduction or delay were blurred vision (17%), keratopathy (10%), dry eye (5%), neutropenia (5%), keratitis (4%), cataract (3%), reduced visual acuity (3%), thrombocytopenia (3%), peripheral neuropathy (3%) and pneumonitis (3%). Overall, 12% of patients stopped treatment permanently because of an adverse reaction, most often for gastrointestinal disorders (4%) and respiratory disorders (3%).

No clinical drug interaction studies have been conducted with mirvetuximab soravtansine. The free payload DM4 is a CYP3A4 substrate.

• Strong CYP3A4 inhibitors (for example ceritinib, clarithromycin, cobicistat, idelalisib, itraconazole, ketoconazole, nefazodone, posaconazole, ritonavir, telithromycin, voriconazole): they may raise exposure to unconjugated DM4 and so increase the risk of adverse reactions. If they cannot be avoided, patients should be monitored closely for adverse reactions.
• Strong CYP3A4 inducers (for example phenytoin, rifampicin, carbamazepine): they may lower exposure to unconjugated DM4.
• Eye drops: topical steroid and lubricating eye drops are part of the treatment plan; allow at least 15 minutes between them (see Administration and Dosage).

Treatment must be started and supervised by a physician experienced in anticancer medicines. FRα status must first be confirmed (see Indications). Mirvetuximab soravtansine is given only as an intravenous infusion, after dilution with 5% glucose, through a 0.2 or 0.22 µm polyethersulfone (PES) in-line filter. It contains a cytotoxic component attached to the antibody, so special handling and disposal rules apply (SmPC section 6.6).

Recommended Dose

• 6 mg/kg adjusted ideal body weight (AIBW) once every 3 weeks (21-day cycle), until disease progression or unacceptable toxicity.
• Calculating AIBW: ideal body weight (IBW) for a woman in kg = 0.9 × height in cm − 92; AIBW = IBW + 0.4 × (actual weight − IBW). Example: a woman 165 cm tall weighing 80 kg has an IBW of 56.5 kg and an AIBW of 65.9 kg. Dosing by AIBW reduces the variability in exposure in underweight and overweight patients.
• Infusion rate: start at 1 mg/min. If well tolerated after 30 minutes, increase to 3 mg/min; if well tolerated after a further 30 minutes, increase to 5 mg/min.

Pre-medication

Given before every infusion to reduce infusion-related reactions, nausea and vomiting:

• Corticosteroid: intravenous dexamethasone 10 mg (or equivalent), at least 30 minutes before the infusion.
• Antihistamine: oral or intravenous diphenhydramine 25–50 mg (or equivalent), at least 30 minutes before.
• Antipyretic: oral or intravenous paracetamol 325–650 mg (or equivalent), at least 30 minutes before.
• Antiemetic: an oral or intravenous 5-HT3 receptor antagonist or an appropriate alternative, before each dose and after the other pre-medication. Further antiemetics may be added as needed.
• After a grade 2 or higher infusion-related reaction, extra dexamethasone 8 mg twice daily (or equivalent) the day before the next infusion should be considered.

Eye Examination and Eye Drops

• Ophthalmic examination: including visual acuity and slit lamp examination, before the first dose and whenever a patient develops new or worsening eye symptoms before the next dose. In patients with ocular reactions of grade 2 or higher, further examinations are done at least every other cycle and as clinically indicated until resolution or return to baseline.
• Lubricating eye drops: recommended throughout treatment.
• Topical steroid eye drops: when slit lamp examination shows a grade 2 corneal reaction (keratopathy), steroid eye drops are recommended for the following cycles, unless the eye care professional judges the risks to outweigh the benefits. They are used on the day of the infusion and for the next 7 days of each later cycle, and lubricating drops are instilled at least 15 minutes afterwards. Intraocular pressure and slit lamp findings are checked regularly during steroid treatment.

Dose Adjustments for Side Effects

The dosing interval stays at 3 weeks. Severity grades follow NCI CTCAE version 5.0.

• Dose levels: starting dose 6 mg/kg AIBW; first reduction 5 mg/kg AIBW; second reduction 4 mg/kg AIBW. Patients who cannot tolerate 4 mg/kg AIBW stop treatment permanently.
• Keratitis or keratopathy: non-confluent superficial changes, monitor. Confluent superficial keratitis or keratopathy, a corneal epithelial defect, or a loss of 3 or more lines of best corrected visual acuity, withhold until improved to non-confluent superficial changes or better, then keep the same dose; consider a reduction if confluent changes recur despite best supportive care or ocular toxicity lasts longer than 14 days. Corneal ulcer, stromal opacity or best corrected distance visual acuity of 6/60 or worse, withhold until improved, then reduce by one dose level. Corneal perforation, stop permanently.
• Pneumonitis: grade 1, monitor; grade 2, withhold until grade 1 or lower, then keep the same dose, or consider a reduction if it recurs, lasts longer than 28 days or at the physician’s discretion; grade 3 or 4, stop permanently.
• Peripheral neuropathy: grade 2, withhold until grade 1 or lower, then reduce by one dose level; grade 3 or 4, stop permanently.
• Infusion-related reactions or hypersensitivity: grade 1, keep the infusion rate. Grade 2, interrupt the infusion and give supportive treatment; after recovery resume at 50% of the previous rate and increase as appropriate if no further symptoms appear, with extra dexamethasone 8 mg orally twice daily the day before future infusions. Grade 3 or 4, stop the infusion at once, give supportive treatment, tell the patient to seek emergency care and inform their healthcare professional if symptoms return after leaving the infusion area, and stop permanently.
• Haematological reactions: grade 3 or 4, withhold until grade 1 or lower, then resume one dose level lower.
• Other adverse reactions: grade 3, withhold until grade 1 or lower, then resume one dose level lower; grade 4, stop permanently.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years and over.
• Renal impairment: no adjustment in mild to moderate impairment (creatinine clearance 30 to below 90 mL/min). Not evaluated in severe impairment (15 to below 30 mL/min) or end-stage renal disease, so the need for adjustment cannot be determined.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin at or below ULN with AST above ULN, or total bilirubin above 1 and up to 1.5 × ULN with any AST). Avoid in moderate to severe impairment (total bilirubin above 1.5 × ULN with any AST).
• Children and adolescents: there is no relevant use in children for ovarian, fallopian tube or primary peritoneal cancer.

Eye Examination and Eye Care

Mirvetuximab soravtansine can cause severe ocular adverse reactions, including visual impairment (mostly blurred vision), keratopathy (corneal disorders), dry eye, photophobia and eye pain. The SmPC sets out these precautions:

• Before treatment: refer the patient to an eye care professional for an ophthalmic examination before the first dose.
• Before each cycle: tell the patient to report any new or worsening eye symptoms to the treating physician or another qualified person.
• When symptoms appear: an ophthalmic examination is done and its report reviewed before the next dose, and the dose may be changed according to the severity of the findings.
• Eye drops: lubricating eye drops are recommended during treatment; ophthalmic topical steroids are recommended for later cycles in patients with grade 2 corneal reactions.
• Contact lenses: patients should avoid them during treatment unless a healthcare professional directs otherwise.
• Management: the physician monitors for ocular toxicity and withholds, reduces or permanently stops treatment according to the severity and persistence of the reaction.

Pneumonitis

Severe, life-threatening or fatal interstitial lung disease, including pneumonitis, can occur. Patients are monitored for respiratory signs and symptoms such as hypoxia, cough, dyspnoea or interstitial infiltrates on imaging, and infectious, neoplastic and other causes are excluded. Treatment is withheld for persistent or recurrent grade 2 pneumonitis until it falls to grade 1 or lower, and a dose reduction is considered; it is stopped permanently for grade 3 or 4. Patients without symptoms may continue with close monitoring.

Peripheral Neuropathy

Peripheral neuropathy, including grade 3 or higher, has occurred. Patients are monitored for paraesthesia, tingling or burning sensations, neuropathic pain, muscle weakness or dysaesthesia, and the dose is withheld, reduced or stopped according to severity.

Traceability

As a biological medicinal product, the name and batch number of each administered product must be clearly recorded.

Embryo-foetal Toxicity, Pregnancy, Breastfeeding and Fertility

• Pregnancy status: verify it before treatment starts.
• Contraception: patients of childbearing potential should use effective contraception during treatment and for 7 months after the last dose.
• Pregnancy: the medicine could cause embryo-foetal harm because it contains a genotoxic compound (DM4) and acts on actively dividing cells. Human IgG crosses the placenta. There are no human data, and no reproductive or developmental animal studies were done. Use in pregnancy is not recommended. A patient who becomes pregnant must contact her doctor immediately, and close monitoring is recommended if pregnancy occurs during treatment or within 7 months after the last dose.
• Breastfeeding: not to be used during breastfeeding and for 1 month after the last dose. It is unknown whether the medicine passes into breast milk, and IgG is known to do so.
• Fertility: fertility studies have not been conducted with mirvetuximab soravtansine or DM4.

Polysorbate 20

Each vial contains 2.11 mg of polysorbate 20.

Effect on Driving

Mirvetuximab soravtansine has a moderate influence on the ability to drive and use machines. Patients with visual disturbances, peripheral neuropathy, fatigue or dizziness should not drive or use machines until the symptoms have completely resolved.

Store the vial upright in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Keep the cold chain unbroken during transport and delivery to the hospital pharmacy. After dilution, the solution must be used within the in-use periods given under Shelf Life.

• Unopened vial: 5 years. Do not use after the expiry date.
• Diluted solution (1–2 mg/mL): chemical and physical stability has been shown for 8 hours at 15–25 °C, or for 24 hours at 2–8 °C followed by 8 hours at 15–25 °C. From a microbiological point of view the product should be used immediately, unless the dilution method excludes the risk of microbial contamination; otherwise in-use times and conditions are the user’s responsibility.

Prescription only (Rx), as a medicinal product subject to restricted medical prescription, on the prescription of a physician experienced in anticancer medicines. Mirvetuximab soravtansine is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, with refrigerated (2–8 °C) cold-chain delivery. FRα-positive tumour status and a baseline ophthalmic examination are required before treatment starts.