4.1. Therapeutic indications

ELAHERE as monotherapy is indicated for the treatment of adult patients 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 (see section 4.2).

4.2. Posology and method of administration

ELAHERE must be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patient selection

Eligible patients should have FRα tumour status defined as ≥75% viable tumour cells demonstrating moderate (2+) and/or strong (3+) membrane staining by immunohistochemistry (IHC), assessed by a CE-marked in vitro diagnostic (IVD) with the corresponding intended purpose. If a CE-marked IVD is not available, an alternative validated test should be used.

Posology

The recommended dose of ELAHERE is 6 mg/kg adjusted ideal body weight (AIBW) administered once every 3 weeks (21-day cycle) as an intravenous infusion until disease progression or unacceptable toxicity. Dosing based on AIBW reduces exposure variability for patients who are either underweight or overweight.

The total dose of ELAHERE is calculated based on each patient's AIBW using the following formula:

Female IBW (Ideal Body Weight [kg]) = 0.9*height [cm] – 92

AIBW = IBW [kg] + 0.4*(Actual weight [kg] – IBW)

For example, for a female patient who is 165 cm in height and 80 kg in weight

First, calculate IBW:

IBW = 0.9 * 165 – 92 = 56.5 kg

Then calculate AIBW:

AIBW = 56.5 + 0.4 * (80 – 56.5) = 65.9 kg

Pre-medication

Pre-medication for infusion related reactions (IRRs), nausea, and vomiting

Administer the pre-medications in Table 1 prior to each infusion of ELAHERE to reduce the incidence and severity of IRRs, nausea, and vomiting.

Table 1: Pre-medication prior to each ELAHERE infusion

Pre-medication

Route of administration

Examples (or equivalent)

Administration time prior to ELAHERE infusion

Corticosteroid

intravenous

dexamethasone 10 mg

at least 30 minutes prior

Antihistamine

oral or intravenous

chlorphenamine 10 mg

Antipyretic

oral or intravenous

paracetamol 500 mg to 1000 mg

Antiemetic

oral or intravenous

5-HT3 serotonin receptor antagonist or appropriate alternatives

before each dose and following the administration of other premedication

For patients experiencing nausea and/or vomiting, additional antiemetics may be considered thereafter as needed.

For patients who experience an IRR Grade ≥2, additional pre-medication with dexamethasone 8 mg two times a day (BID) (or equivalent) the day before ELAHERE administration should be considered.

Ophthalmic exam and pre-medication

Ophthalmic exam: An ophthalmic exam including visual acuity and slit lamp exam should be conducted before the initiation of ELAHERE and if a patient develops any new or worsening ocular symptoms prior to the next dose. In patients with ≥ Grade 2 ocular adverse reactions, additional ophthalmic exams should be conducted at a minimum of every other cycle and as clinically indicated until resolution or return to baseline.

Ophthalmic topical steroids: For patients found to have signs of ≥ Grade 2 corneal adverse reactions (keratopathy) on slit lamp examination, secondary prophylaxis with ophthalmic topical steroids is recommended for subsequent cycles of ELAHERE, unless the patient's eye care professional determines that the risks outweigh the benefits of such therapy.

• Patients should be instructed to use steroid eye drops on the day of infusion and through the next 7 days of each subsequent cycle of ELAHERE (see Table 3).

• Patients should be advised to wait at least 15 minutes after ophthalmic topical steroid administration before instilling lubricating eye drops.

During treatment with ophthalmic topical steroids the measurement of intraocular pressure and an examination with slit lamp should be carried out regularly.

Lubricating eye drops: It is recommended to instruct patients to use lubricating eye drops throughout treatment with ELAHERE.

Dose modifications

Before the start of each cycle, the patient should be advised to report any new or worsening symptoms to the treating physician or qualified individual.

In patients who develop new or worsening ocular symptoms, an ophthalmic exam should be conducted before dosing. The treating physician should review the patient's ophthalmic examination report before dosing and determine the dose of ELAHERE based on the severity of findings in the most severely affected eye.

Table 2 and Table 3 provide dose reductions and modifications for adverse reactions. The schedule of administration should be maintained at a 3-week interval between the doses.

Table 2: Dose reduction schedule

ELAHERE dose levels

Starting dose

6 mg/kg AIBW

First dose reduction

5 mg/kg AIBW

Second dose reduction

4 mg/kg AIBW*

* Permanently discontinue in patients who cannot tolerate 4 mg/kg AIBW.

Table 3: Dose modifications for adverse reactions

Adverse reaction

Severity of adverse reaction*

Dose modification

Keratitis/keratopathy

(see sections 4.4 and 4.8)

Non-confluent superficial keratitis/keratopathy

Monitor

Confluent superficial keratitis/keratopathy, a cornea epithelial defect, or 3-line or more loss in best corrected visual acuity

Withhold dose until improved to nonconfluent superficial keratitis/keratopathy or better or resolved, then maintain at same dose level. Consider dose reduction for patients with recurrent confluent keratitis/keratopathy despite best supportive care or in patients with ocular toxicity lasting longer than 14 days.

Corneal ulcer or stromal opacity or best corrected distance visual acuity 6/60 or worse

Withhold dose until improved to nonconfluent superficial keratitis/keratopathy or better or resolved, then reduce by one dose level.

Corneal perforation

Permanently discontinue

Pneumonitis

(see sections 4.4 and 4.8)

Grade 1

Monitor

Grade 2

Withhold dose until Grade 1 or less, then maintain at same dose level or consider dose reduction if recurrent, lasts longer than 28 days, or at physician discretion.

Adverse reaction

Severity of adverse reaction*

Dose modification

Grade 3 or 4

Permanently discontinue

Peripheral neuropathy

(see sections 4.4 and 4.8)

Grade 2

Withhold dose until Grade 1 or less, then reduce by one dose level.

Grade 3 or 4

Permanently discontinue

Infusion-related reactions/ hypersensitivity

(see sections 4.4 and 4.8)

Grade 1

Maintain infusion rate

Grade 2

• Interrupt infusion and administer supportive treatment.

• After recovery from symptoms, resume the infusion at 50% of the previous rate, and if no further symptoms appear, increase rate as appropriate until infusion is completed.

• Administer additional pre-medication with dexamethasone 8 mg oral BID the day before infusion (or local equivalent) for future cycles.

Grade 3 or 4

• Immediately stop infusion and administer supportive treatment.

• Advise patient to seek emergency treatment and immediately notify their healthcare professional if the infusion- related symptoms recur after discharge from the infusion area.

• Permanently discontinue

Haematological

(see section 4.8)

Grade 3 or 4

Withhold dose until Grade 1 or less, then resume at one lower dose level.

Other adverse reactions

(see section 4.8)

Grade 3

Withhold dose until Grade 1 or less, then resume at one lower dose level.

Grade 4

Permanently discontinue

*: Unless otherwise specified, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Special populations

Paediatric population

There is no relevant use of ELAHERE for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer in the paediatric population (see section 5.1).

Elderly

No dose adjustment of ELAHERE is recommended in patients ≥65 years of age (see section 5.2).

Renal impairment

No dose adjustment of ELAHERE is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to <90 mL/min). ELAHERE has not been evaluated in patients with severe renal impairment (CLcr 15 to <30 mL/min) or end-stage renal disease and the potential need for dose adjustment in these patients cannot be determined (see section 5.2).

Hepatic impairment

No dose adjustment of ELAHERE is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin >1 to 1.5 times ULN and any AST) (see section 5.2).

ELAHERE should be avoided in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST).

Method of administration

ELAHERE is for intravenous infusion at a 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 at 3 mg/min, the infusion rate can be increased to 5 mg/min.

For incompatibilities, see section 6.2.

ELAHERE requires dilution with 5% glucose for intravenous infusion. For instructions on dilution of the medicinal product before administration, see section 6.6.

ELAHERE must be administered as an intravenous infusion only, using a 0.2 or 0.22 µm polyethersulfone (PES) in-line filter (see Special handling and disposal procedures in section 6.6).

Precautions to be taken before handling or administering the medicinal product

This medicinal product contains a cytotoxic component, which is covalently attached to the monoclonal antibody (see special handling and disposal procedures in section 6.6).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Ocular disorders

Mirvetuximab soravtansine can cause severe ocular adverse reactions, including visual impairment (predominantly blurred vision), keratopathy (corneal disorders), dry eye, photophobia, and eye pain (see sections 4.7 and 4.8).

Patients should be referred to an eye care professional for an ophthalmic exam before initiation of mirvetuximab soravtansine.

Before the start of each cycle, the patient should be advised to report any new or worsening ocular symptoms to the treating physician or qualified individual.

If ocular symptoms develop, an ophthalmic exam should be conducted, the patient's ophthalmic report should be reviewed and the dose of mirvetuximab soravtansine may be modified based on the severity of the findings (see section 4.2).

Use of lubricating eye drops during treatment with mirvetuximab soravtansine is recommended. In patients who develop ≥Grade 2 corneal adverse reactions, ophthalmic topical steroids are recommended for subsequent cycles of mirvetuximab soravtansine (see section 4.2).

The physician should monitor patients for ocular toxicity and withhold, reduce, or permanently discontinue mirvetuximab soravtansine based on the severity and persistence of ocular adverse reactions (see section 4.2).

Patients should be advised to avoid use of contact lenses during treatment with mirvetuximab soravtansine unless directed by a healthcare professional.

Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with mirvetuximab soravtansine (see section 4.8).

Patients should be monitored for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnoea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations.

Mirvetuximab soravtansine treatment should be withheld for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤Grade 1 and dose reduction should be considered. Mirvetuximab soravtansine should be permanently discontinued in all patients with Grade 3 or 4 pneumonitis (see section 4.2). Patients who are asymptomatic may continue dosing of mirvetuximab soravtansine with close monitoring.

Peripheral neuropathy

Peripheral neuropathy has occurred with mirveutximab soravtansine, including Grade ≥3 reactions (see section 4.8).

Patients should be monitored for signs and symptoms of neuropathy, such as paraesthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, mirvetuximab soravtansine dose should be withheld, reduced, or permanently discontinued based on the severity of peripheral neuropathy (see section 4.2).

Embryo-foetal toxicity

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

Patients of childbearing potential should use effective contraception during treatment with mirvetuximab soravtansine and for 7 months after the last dose (see section 4.6).

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

This medicinal product contains 2.11 mg of polysorbate 20 in each vial.

4.5. Interaction with other medicinal products and other forms of interaction

Clinical drug-drug interaction studies with ELAHERE have not been conducted.

DM4 is a CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure (see section 5.2), which may increase the risk of ELAHERE adverse reactions (see section 4.8). If concomitant use with strong CYP3A4 inhibitors (e.g. ceritinib, clarithromycin, cobicistat, idelalisib, itraconazole, ketoconazole, nefazodone, posaconazole, ritonavir, telithromycin, voriconazole) cannot be avoided, patients should be closely monitored for adverse reactions. Strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine) may decrease the exposure of unconjugated DM4.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

The pregnancy status in patients of childbearing potential should be verified prior to initiating mirvetuximab soravtansine treatment.

Patients of childbearing potential should use effective contraception during treatment with mirvetuximab soravtansine and for 7 months after the last dose.

Pregnancy

Based on its mechanism of action, mirvetuximab soravtansine can cause embryo-foetal harm when administered to a pregnant patient because it contains a genotoxic compound (DM4) and affects actively dividing cells (see sections 5.1 and 5.3). Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, mirvetuximab soravtansine has the potential to be transmitted from the pregnant patient to the developing foetus. There are no available human data on mirvetuximab soravtansine use in pregnant patients to inform a drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.

Administration of ELAHERE to pregnant patients is not recommended, and patients should be informed of the potential risks to the foetus if they become or wish to become pregnant. Patients who become pregnant must immediately contact their doctor. If a patient becomes pregnant during treatment with ELAHERE or within 7 months following the last dose, close monitoring is recommended.

Breast-feeding

It is unknown whether mirvetuximab soravtansine/metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded as human immunoglobulin G (IgG) is known to pass on in breast milk. ELAHERE should not be used during breast-feeding and for 1 month after the last dose.

Fertility

Fertility studies have not been conducted with mirvetuximab soravtansine or DM4. There are no data on the effect of ELAHERE on human fertility. However, given the mechanism of action of ELAHERE leads to microtubule disruption and death of rapidly dividing cells, there is the potential for drug- related fertility effects.

4.7. Effects on ability to drive and use machines

ELAHERE has moderate influence on the ability to drive and use machines. If patients experience visual disturbances, peripheral neuropathy, fatigue, or dizziness during treatment with mirvetuximab soravtansine, they should be instructed not to drive or use machines until complete resolution of symptoms is confirmed.

4.8. Undesirable effects

Summary of safety profile

The most common adverse reactions with mirvetuximab soravtansine were 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%), AST increased (16%), and arthralgia (16%).

The most commonly reported serious adverse reactions 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 (<1%).

Adverse reactions that most commonly led to dose reduction or dose delay were blurred vision (17%), keratopathy (10%), dry eye (5%), neutropenia (5%), keratitis (4%), cataract (3%), visual acuity reduced (3%), thrombocytopenia (3%), peripheral neuropathy (3%), and pneumonitis (3%).

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received mirvetuximab soravtansine, including most commonly, gastrointestinal disorders (4%), respiratory, thoracic, and mediastinal disorders (3%), blood and lymphatic system disorders (1%), nervous system disorders (1%), and eye disorders (1%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from 4 clinical studies which included 682 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer (collectively referenced as Epithelial Ovarian Cancer (EOC) treated with mirvetuximab soravtansine 6 mg/kg AIBW administered once every 3 weeks. The median duration of treatment with mirvetuximab soravtansine was 19.1 weeks (range: 3, 132 weeks).

The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, for which, after thorough assessment, a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

Table 4: Tabulated list of all grade adverse reactions in patients treated with mirvetuximab soravtansine in clinical studies

System Organ Class

Frequency category

Adverse reactions

Infections and infestations

Very common

Urinary tract infection

Blood and lymphatic system disorders

Very common

Anaemia, thrombocytopenia

Common

Neutropenia

Metabolism and nutrition disorders

Very common

Decreased appetite, hypomagnesaemia

Common

Hypokalaemia, dehydration

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Very common

Peripheral neuropathy1, headache,

Common

Dysgeusia, dizziness

Eye disorders

Very common

Keratopathy2, cataract3, blurred vision event4, photophobia, eye pain, dry eye5

Common

Ocular discomfort6

Vascular disorders

Common

Hypertension

Respiratory, thoracic and mediastinal disorders

Very common

Pneumonitis7, dyspnoea, cough

Gastrointestinal disorders

Very common

Diarrhoea, abdominal pain8, constipation, abdominal distension, vomiting, nausea

Common

Ascites, gastro-oesophageal reflux disease, stomatitis, dyspepsia

Hepatobiliary disorders

Common

Hyperbilirubinaemia

System Organ Class

Frequency category

Adverse reactions

Skin and subcutaneous tissue disorders

Common

Pruritus

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Common

Myalgia, back pain, pain in extremity, muscle spasms

General disorders and administration site conditions

Very common

Fatigue

Common

Pyrexia

Investigations

Very common

Aspartate aminotransferase increased, alanine aminotransferase increased

Common

Blood alkaline phosphatase increased, gamma-glutamyl transferase increased, weight decreased

Injury, poisoning and procedural complication

Common

Infusion related reaction/hypersensitivity9

1 Peripheral neuropathy grouped term includes hypoaesthesia, neuropathy peripheral, neurotoxicity, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and polyneuropathy (see section Description of selected adverse reactions).

2 Keratopathy group term includes corneal cyst, corneal deposits, corneal disorder, corneal epithelial microcysts, corneal epithelium defect, corneal erosion, corneal opacity, corneal pigmentation, keratitis, keratitis interstitial, keratopathy, limbal stem cell deficiency, and punctate keratitis (see section Description of selected adverse reactions).

3 Cataract grouped term includes cataract, cataract cortical, and cataract nuclear (see section Description of selected adverse reactions).

4 Blurred vision event grouped term includes accommodation disorder, diplopia, hypermetropia, presbyopia, refraction disorder, vision blurred, visual impairment, visual acuity reduced, and vitreous floaters (see section Description of selected adverse reactions).

5 Dry eye grouped term includes dry eye and lacrimation decreased (see section Description of selected adverse reactions).

6 Ocular discomfort grouped term includes eye irritation, eye pruritus, foreign body sensation in eye, and ocular discomfort (see section Description of selected adverse reactions).

7 Pneumonitis group term includes interstitial lung disease, organising pneumonia, pneumonitis, pulmonary fibrosis, and respiratory failure (see section Description of selected adverse reactions).

8 Abdominal pain grouped term includes abdominal discomfort, abdominal pain, abdominal pain lower, and abdominal pain upper.

9 Infusion related reaction/hypersensitivity grouped term includes SMQ Hypersensitivity narrow and flushing, erythema, erythema of eyelid.

Description of selected adverse reactions

Ocular disorders

Ocular adverse reactions (grouped terms) occurred in 59% of patients with EOC treated with mirvetuximab soravtansine. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions and <1% experienced Grade 4 events. The most common ≥ Grade 3 ocular adverse reactions were blurred vision and keratopathy (both 5%, grouped terms) and cataract (4%).

The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution (Grade 0) and 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade). At the last follow-up, 0.3% (2/682) patients had ≥ Grade 3 ocular adverse events (1 patient with Grade 3 decreased visual acuity and 1 patient with Grade 4 cataract).

Ocular adverse reactions led to dose delays in 24% of patients, and dose reductions in 15% of patients. Ocular adverse reactions led to permanent discontinuation of mirvetuximab soravtansine in 1% of patients.

Pneumonitis

Pneumonitis (grouped terms) occurred in 10% of patients with EOC treated with mirvetuximab soravtansine, including 0.9% (6/682) patients with Grade 3 events, and 0.2% (1/682) patient with a Grade 4 event. Two patients (0.3%) died due to respiratory failure. One patient (0.2%) died due to respiratory failure in the setting of Grade 1 pneumonitis and lung metastases confirmed at autopsy. One patient (0.2%) died due to respiratory failure of unknown aetiology without concurrent pneumonitis.

The median time to onset of pneumonitis was 18.1 weeks (range 1.6 to 97.0). Pneumonitis resulted in mirvetuximab soravtansine dose delays in 3%, dose reductions in 1%, and permanent discontinuation in 3% of patients.

Peripheral neuropathy

Peripheral neuropathy (grouped terms) occurred in 36% of patients with EOC treated with mirvetuximab soravtansine across clinical studies; 3% of patients experienced Grade 3 peripheral neuropathy.

The median time to onset of peripheral neuropathy was 5.9 weeks (range 0.1 to 126.7). Peripheral neuropathy resulted in mirvetuximab soravtansine dose delays in 2%, dose reductions in 4%, and led to permanent discontinuation in 0.7% of patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known treatment/antidote available for overdose of mirvetuximab soravtansine. In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment initiated.