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Leaflet PADCEV 20mg powder for concentrate for solution for infusion
- Product code:
- W70382001
- Quantity:
- 1
- Indicated for:
- urothelial cancer
- Route of administration:
- infusion
- Substance:
- enfortumab vedotin (antibody-drug conjugate)
- ATC
- L01FX13 — Antineoplastic and immunomodulating agents | Monoclonal antibodies and antibody drug conjugates | Other monoclonal antibodies and antibody drug conjugates
Enfortumab vedotin is a medication used to treat certain advanced forms of bladder cancer. It is an antibody-drug conjugate that targets cancer cells specifically, delivering a cytotoxic agent to destroy them and limit the spread of the disease. Enfortumab vedotin is recommended for patients who have not responded to other therapies or immunotherapy.
The medication is administered by intravenous infusion in a hospital setting, under the supervision of a specialized medical team. The treatment schedule and dose are determined by the doctor based on the patient's general condition and response to therapy.
Side effects may include fatigue, nausea, hair loss, skin rashes, peripheral neuropathy, or infections. Rarely, severe reactions such as liver damage or serious allergic responses may occur. Careful monitoring is essential throughout the treatment.
Enfortumab vedotin provides a modern therapeutic option for patients with advanced bladder cancer, but its use requires strict medical supervision to effectively manage possible side effects.
The medication is administered by intravenous infusion in a hospital setting, under the supervision of a specialized medical team. The treatment schedule and dose are determined by the doctor based on the patient's general condition and response to therapy.
Side effects may include fatigue, nausea, hair loss, skin rashes, peripheral neuropathy, or infections. Rarely, severe reactions such as liver damage or serious allergic responses may occur. Careful monitoring is essential throughout the treatment.
Enfortumab vedotin provides a modern therapeutic option for patients with advanced bladder cancer, but its use requires strict medical supervision to effectively manage possible side effects.
General data about PADCEV 20mg
- Substance:
- enfortumab vedotin
- Date of latest medicines list:
- 01-09-2026
- Product code:
- W70382001
- Concentration:
- 20mg
- Pharmaceutical form:
- powder for concentrate for solution for infusion
- Quantity:
- 1
- Product type:
- Generic medicine
- Price:
- 3126.04 RON
- Prescription status:
- P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Concentrations available for enfortumab vedotin
- 20mg
- 30mg
Official documents
- Added to database:
- 05/05/2022
- Source record updated:
- 24/09/2026
Precautions:
Additional monitoring
This medicine is subject to additional monitoring.
Contents of the package leaflet for the medicine PADCEV 20mg powder for concentrate for solution for infusion
Find in leaflet
Leaflet PADCEV 20mg
1. NAME OF THE MEDICINAL PRODUCT
Padcev 20 mg powder for concentrate for solution for infusion
Padcev 30 mg powder for concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Padcev 20 mg powder for concentrate for solution for infusion
One vial of powder for concentrate for solution for infusion contains 20 mg enfortumab vedotin.
Padcev 30 mg powder for concentrate for solution for infusion
One vial of powder for concentrate for solution for infusion contains 30 mg enfortumab vedotin.
After reconstitution, each mL of solution contains 10 mg of enfortumab vedotin.
Enfortumab vedotin is comprised of a fully human IgG1 kappa antibody, conjugated to themicrotubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavablemaleimidocaproyl valine-citrulline linker.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to off-white lyophilized powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Muscle invasive bladder cancer (MIBC)
Padcev, in combination with pembrolizumab, as neoadjuvant treatment and then continued afterradical cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with resectablemuscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.
Unresectable or metastatic urothelial cancer
Padcev, in combination with pembrolizumab, is indicated for the first-line treatment of adult patientswith unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy.
Locally advanced or metastatic urothelial cancer
Padcev as monotherapy is indicated for the treatment of adult patients with locally advanced ormetastatic urothelial cancer who have previously received a platinum-containing chemotherapy and aprogrammed death receptor-1 or programmed death-ligand 1 inhibitor (see section 5.1).
4.2 Posology and method of administration
Treatment with Padcev should be initiated and supervised by a physician experienced in the use ofanti-cancer therapies. Ensure good venous access prior to starting treatment (see section 4.4).
PosologyTable 1. Recommended dose for enfortumab vedotin in combination with pembrolizumab*
Recommended enfortumab
Indication vedotin dose Duration of therapy
Neoadjuvant and Enfortumab vedotin Cisplatin-ineligible patientsadjuvant muscle invasive 1.25 mg/kg (up to a Neoadjuvant: 3 cycles or until diseasebladder cancer (MIBC) maximum of 125 mg for progression that precludes curative intentpatients ≥100 kg) on Days 1 radical cystectomy or unacceptableand 8 of a 21-day cycle. toxicity.
Adjuvant: 6 cycles or until diseaserecurrence or unacceptable toxicity.
Unresectable or Enfortumab vedotin Until disease progression ormetastatic urothelial 1.25 mg/kg (up to a unacceptable toxicity.cancer maximum of 125 mg forpatients ≥100 kg) on Days 1and 8 of a 21-day cycle.
*Patients should be administered pembrolizumab after enfortumab vedotin when given on the same day. Referto the pembrolizumab SmPC for additional dosing information of pembrolizumab.
Table 2. Recommended dose for enfortumab vedotin as monotherapy
Recommended enfortumab
Indication Duration of therapyvedotin dose
Locally advanced or Enfortumab vedotin Until disease progression ormetastatic urothelial 1.25 mg/kg (up to a unacceptable toxicity.cancer maximum of 125 mg forpatients ≥100 kg) on Days 1,8 and 15 of a 28-day cycle.
Table 3. Recommended dose reductions of enfortumab vedotin foradverse reactions
Dose reduction schedule Dose level
Starting dose 1.25 mg/kg up to 125 mg
First dose reduction 1.0 mg/kg up to 100 mg
Second dose reduction 0.75 mg/kg up to 75 mg
Third dose reduction 0.5 mg/kg up to 50 mg
Dose modificationsTable 4. Dose interruption, reduction and discontinuation of enfortumab vedotin
Adverse reaction Severity* Dose modification*
Suspected Stevens-Johnsonsyndrome (SJS) or toxic Immediately withhold and refer toepidermal necrolysis (TEN)or specialised care.
bullous lesions
Confirmed SJS or TEN;
Skin reactions Grade 4 or recurrent Grade 3 Permanently discontinue.
* Withhold until Grade ≤1.
Grade 2 worsening * Referral to specialised care
Grade 2 with fever should be considered.
Grade 3 * Resume at the same dose level orconsider dose reduction by onedose level (see Table 3).
* Withhold until elevated bloodglucose has improved to
Hyperglycaemia Blood glucose≤13.9 mmol/L (≤250 mg/dL).
>13.9 mmol/L (>250 mg/dL)
* Resume treatment at the samedose level.
* Withhold until Grade ≤1, then
Pneumonitis/ Grade 2 resume at the same dose orinterstitial lung consider dose reduction by onedisease (ILD) dose level (see Table 3).
Grade ≥3 Permanently discontinue.
* Withhold until Grade ≤1.
* For first occurrence, resumetreatment at the same dose level.
Peripheral Grade 2 * For a recurrence, withhold untilneuropathy Grade ≤1, then resume treatmentreduced by one dose level (see
Table 3).
Grade ≥3 Permanently discontinue.
*Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events
Version 5.0 (NCI-CTCAE v5.0) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe and Grade 4 islife-threatening.
Special populationsElderly
No dose adjustment is necessary in patients ≥65 years of age (see section 5.2).
Renal impairmentNo dose adjustment is necessary in patients with mild [creatinine clearance (CrCL) >60-90 mL/min],moderate (CrCL 30-60 mL/min) or severe (CrCL 15-<30 mL/min) renal impairment. Enfortumabvedotin has not been evaluated in patients with end-stage renal disease (CrCL <15 mL/min) (seesection 5.2).
Hepatic impairmentNo dose adjustment is necessary in patients with mild hepatic impairment [total bilirubin of 1 to1.5 × upper limit of normal (ULN) and AST any, or total bilirubin ≤ ULN and AST > ULN].
Enfortumab vedotin has only been evaluated in a limited number of patients with moderate and severehepatic impairment. Hepatic impairment is expected to increase the systemic exposure to MMAE (thecytotoxic drug); therefore, patients should be closely monitored for potential adverse events. Due tothe sparsity of the data in patients with moderate and severe hepatic impairment, no specific doserecommendation can be given (see section 5.2).
Paediatric populationThere is no relevant use of enfortumab vedotin in the paediatric population for the indication of locallyadvanced or metastatic urothelial cancer and MIBC.
Method of administrationPadcev is for intravenous use. The recommended dose must be administered by intravenous infusionover 30 minutes. Enfortumab vedotin must not be administered as an intravenous push or bolusinjection.
For instructions on reconstitution and dilution of the medicinal product before administration, seesection 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 numberof the administered product should be clearly recorded.
Skin reactionsSkin reactions are associated with enfortumab vedotin as a result of enfortumab vedotin binding to
Nectin-4 expressed in the skin. Fever or flu-like symptoms may be the first sign of a severe skinreaction, and patients should be observed, if this occurs.
Mild to moderate skin reactions, predominantly rash maculo-papular, have been reported withenfortumab vedotin. The incidence of skin reactions occurred at a higher rate when enfortumabvedotin was given in combination with pembrolizumab compared to enfortumab vedotin asmonotherapy (see section 4.8). Severe cutaneous adverse reactions, including SJS and TEN, with fataloutcome have also occurred in patients treated with enfortumab vedotin, predominantly during the firstcycle of treatment.
Patients should be monitored starting with the first cycle and throughout treatment for skin reactions.
Appropriate treatment such as topical corticosteroids and antihistamines can be considered for mild tomoderate skin reactions. For suspected SJS or TEN, or in case of bullous lesions onset, withholdtreatment immediately and refer to specialised care; histologic confirmation, including considerationof multiple biopsies, is critical to early recognition, as diagnosis and intervention can improveprognosis. Permanently discontinue Padcev for confirmed SJS or TEN, Grade 4 or recurrent Grade 3skin reactions. For Grade 2 worsening, Grade 2 with fever or Grade 3 skin reactions, treatment shouldbe withheld until Grade ≤1 and referral for specialised care should be considered. Treatment should beresumed at the same dose level or consider dose reduction by one dose level (see section 4.2).
Pneumonitis/ILD
Severe, life-threatening or fatal pneumonitis/ILD have occurred in patients treated with enfortumabvedotin. The incidence of pneumonitis/ILD, including severe events occurred at a higher rate whenenfortumab vedotin was given in combination with pembrolizumab compared to enfortumab vedotinas monotherapy (see section 4.8).
Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough,dyspnoea or interstitial infiltrates on radiologic exams. Corticosteroids should be administered for
Grade ≥2 events (e.g., initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper).
Withhold Padcev for Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue
Padcev for Grade ≥3 pneumonitis/ILD (see section 4.2).
HyperglycaemiaHyperglycaemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with andwithout pre-existing diabetes mellitus, treated with enfortumab vedotin (see section 4.8).
Hyperglycaemia occurred more frequently in patients with pre-existing hyperglycaemia or a high bodymass index (≥30 kg/m2). Patients with baseline HbA1c ≥8% were excluded from clinical studies.
Blood glucose levels should be monitored prior to dosing and periodically throughout the course oftreatment as clinically indicated in patients with or at risk for diabetes mellitus or hyperglycaemia. Ifblood glucose is elevated >13.9 mmol/L (>250 mg/dL), Padcev should be withheld until blood glucoseis ≤13.9 mmol/L (≤250 mg/dL) and treat as appropriate (see section 4.2).
Serious infections and opportunistic infectionsSerious infections such as sepsis or pneumonia (including fatal outcomes) and opportunistic infectionssuch as fungal infections have been reported in patients treated with Padcev. Patients should becarefully monitored during treatment for the emergence of possible serious and opportunisticinfections.
Peripheral neuropathyPeripheral neuropathy, predominantly peripheral sensory neuropathy, has occurred with enfortumabvedotin, including Grade ≥3 reactions (see section 4.8). Patients with preexisting peripheralneuropathy Grade ≥2 were excluded from clinical studies. Patients should be monitored for symptomsof new or worsening peripheral neuropathy as these patients may require a delay, dose reduction ordiscontinuation of enfortumab vedotin (see Table 3). Padcev should be permanently discontinued for
Grade ≥3 peripheral neuropathy (see section 4.2).
Ocular disorders
Ocular disorders, predominantly dry eye, have occurred in patients treated with enfortumab vedotin(see section 4.8). Patients should be monitored for ocular disorders. Consider artificial tears forprophylaxis of dry eye and referral for ophthalmologic evaluation if ocular symptoms do not resolve orworsen.
Infusion site extravasationSkin and soft tissue injury following enfortumab vedotin administration has been observed whenextravasation occurred (see section 4.8). Ensure good venous access prior to starting Padcev andmonitor for possible infusion site extravasation during administration. If extravasation occurs, stop theinfusion and monitor for adverse reactions.
Embryo-foetal toxicity and contraception
Pregnant women should be informed of the potential risk to a foetus (see sections 4.6 and 5.3).
Females of reproductive potential should be advised to have a pregnancy test within 7 days prior tostarting treatment with enfortumab vedotin, to use effective contraception during treatment and for atleast 6 months after stopping treatment. Men being treated with enfortumab vedotin are advised not tofather a child during treatment and for at least 4 months following the last dose of Padcev.
Patient information pack
The prescriber must discuss the risks of Padcev therapy, including combination therapy withpembrolizumab, with the patient. The patient should be provided with the patient information leafletand patient card with each prescription.
4.5 Interaction with other medicinal products and other forms of interaction
Formal drug-drug interaction studies with enfortumab vedotin have not been conducted. Concomitantadministration of enfortumab vedotin and CYP3A4 (substrates) metabolised medicinal products, hasno clinically relevant risk of inducing pharmacokinetic interactions (see section 5.2).
Effects of other medicinal products on enfortumab vedotin
CYP3A4 inhibitors, substrates or inducers
Based on physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumabvedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increaseunconjugated MMAE Cmax and AUC exposure to a minor extent, with no change in ADC exposure.
Caution is advised in case of concomitant treatment with CYP3A4 inhibitors. Patients receivingconcomitant strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir,itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin,voriconazole) should be monitored more closely for signs of toxicities.
Unconjugated MMAE is not predicted to alter the AUC of concomitant medicines that are CYP3A4substrates (e.g. midazolam).
Strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort[Hypericum perforatum]) may decrease the exposure of unconjugated MMAE with moderate effect(see section 5.2).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Pregnancy testing is recommended for females of reproductive potential within 7 days prior toinitiating treatment. Females of reproductive potential should be advised to use effective contraceptionduring treatment and for at least 6 months after stopping treatment. Men being treated with enfortumabvedotin are advised not to father a child during treatment and for at least 4 months following the lastdose of Padcev.
PregnancyPadcev can cause foetal harm when administered to pregnant women based upon findings from animalstudies. Embryo-foetal development studies in female rats have shown that intravenous administrationof enfortumab vedotin resulted in reduced numbers of viable foetuses, reduced litter size and increasedearly resorptions (see section 5.3). Padcev is not recommended during pregnancy and in women ofchildbearing potential not using effective contraception.
Breast-feedingIt is unknown whether enfortumab vedotin is excreted in human milk. A risk to breast-fed childrencannot be excluded. Breastfeeding should be discontinued during Padcev treatment and for at least6 months after the last dose.
FertilityIn rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may altermale fertility. MMAE has been shown to have aneugenic properties (see section 5.3). Therefore, menbeing treated with this medicinal product are advised to have sperm samples frozen and stored beforetreatment. There are no data on the effect of Padcev on human fertility.
4.7 Effects on ability to drive and use machines
Padcev has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
Immunogenicity
Elderly
Enfortumab vedotin in combination with pembrolizumab
When enfortumab vedotin is administered in combination with pembrolizumab, refer to the SmPC forpembrolizumab prior to initiation of treatment.
Muscle invasive bladder cancer
The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 167 patientswho received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumabin a phase 3 study (EV-303) (see Table 5). Patients were exposed to the combination of enfortumabvedotin and pembrolizumab for a median duration of 6.3 months (range: 0.03 to 19.7 months). Themedian duration of exposure to enfortumab vedotin alone was 5.5 months (range: 0.03 to14.1 months).
The most common adverse reactions with enfortumab vedotin in combination with pembrolizumabwere pruritus (47.3%), alopecia (34.7%), diarrhoea (34.1%), fatigue (32.3%), anaemia (30.5%),decreased appetite (28.1%), dysgeusia (28.1%), nausea (25.7%), rash (25.1%), aspartateaminotransferase increased (24%), weight decreased (19.8%), alanine aminotransferase increased(19.2%), rash maculo-papular (16.2%), dry skin (15%), hypothyroidism (14.4%), peripheral sensoryneuropathy (13.8%), hyperglycaemia (12.6%) and neuropathy peripheral (10.2%).
The most common serious adverse reaction (≥2%) was diarrhoea (2.4%). Forty-one percent of patientspermanently discontinued enfortumab vedotin for adverse reactions; the most common adversereaction (≥2%) leading to discontinuation was peripheral sensory neuropathy (2.4%).
Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 44% of patients. Themost common adverse reactions (≥2%) leading to dose interruption were diarrhoea (4.2%), rash(4.2%), neutropenia (3.6%), fatigue (3%), hyperglycaemia (3%) and pruritus (2.4%).
Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 17% of patients. Themost common adverse reactions (≥2%) leading to dose reduction were rash (2.4%) and weightdecreased (2.4%).
Unresectable or metastatic urothelial cancer
The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 564 patientswho received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumabin one phase 2 study (EV-103) and one phase 3 study (EV-302) (see Table 5). Patients were exposed toenfortumab vedotin in combination with pembrolizumab for a median duration of 9.4 months (range:0.3 to 34.4 months).
The most common adverse reactions with enfortumab vedotin in combination with pembrolizumabwere peripheral sensory neuropathy (53.4%), pruritus (41.1%), fatigue (40.4%), diarrhoea (39.2%),alopecia (38.5%), rash maculo-papular (36%), weight decreased (36%), decreased appetite (33.9%),nausea (28.4%), anaemia (25.7%), dysgeusia (24.3%), dry skin (18.1%), alanine aminotransferaseincreased (16.8%), hyperglycaemia (16.7%), aspartate aminotransferase increased (15.4%), dry eye(14.4%), vomiting (13.3%), rash macular (11.3%), hypothyroidism (10.5%) and neutropenia (10.1%).
The most common serious adverse reactions (≥2%) were diarrhoea (3%) and pneumonitis (2.3%).
Thirty-six percent of patients permanently discontinued enfortumab vedotin for adverse reactions; themost common adverse reactions (≥2%) leading to discontinuation were peripheral sensory neuropathy(12.2%) and rash maculo-papular (2%).
Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 72% of patients. Themost common adverse reactions (≥2%) leading to dose interruption were peripheral sensoryneuropathy (17%), rash maculo-papular (6.9%), diarrhoea (4.8%), fatigue (3.7%), pneumonitis (3.7%),hyperglycaemia (3.4%), neutropenia (3.2%), alanine aminotransferase increased (3%), pruritus (2.3%)and anaemia (2%).
Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 42.4% of patients. Themost common adverse reactions (≥2%) leading to dose reduction were peripheral sensory neuropathy(9.9%), rash maculo-papular (6.4%), fatigue (3.2%), diarrhoea (2.3%) and neutropenia (2.1%).
Enfortumab vedotin as monotherapy
The safety of enfortumab vedotin was evaluated as monotherapy in 793 patients who received at leastone dose of enfortumab vedotin 1.25 mg/kg in two phase 1 studies (EV-101 and EV-102), threephase 2 studies (EV-103, EV-201 and EV-203) and one phase 3 study (EV-301) (see Table 5). Patientswere exposed to enfortumab vedotin for a median duration of 4.7 months (range: 0.3 to 55.7 months).
The most common adverse reactions with enfortumab vedotin were alopecia (47.7%), decreasedappetite (47.2%), fatigue (46.8%), diarrhoea (39.1%), peripheral sensory neuropathy (38.5%), nausea(37.8%), pruritus (33.4%), dysgeusia (30.4%), anaemia (29.1%), weight decreased (25.2%), rashmaculo-papular (23.6%), dry skin (21.8%), vomiting (18.7%), aspartate aminotransferase increased(17%), hyperglycaemia (14.9%), dry eye (12.7%), alanine aminotransferase increased (12.7%) andrash (11.6%).
The most common serious adverse reactions (≥2%) were diarrhoea (2.1%) and hyperglycaemia(2.1%). Twenty-one percent of patients permanently discontinued enfortumab vedotin for adversereactions; the most common adverse reaction (≥2%) leading to dose discontinuation was peripheralsensory neuropathy (4.8%). Adverse reactions leading to dose interruption occurred in 62% ofpatients; the most common adverse reactions (≥2%) leading to dose interruption were peripheralsensory neuropathy (14.8%), fatigue (7.4%), rash maculo-papular (4%), aspartate aminotransferaseincreased (3.4%), alanine aminotransferase increased (3.2%), anaemia (3.2%), hyperglycaemia (3.2%),neutrophil count decreased (3%), diarrhoea (2.8%), rash (2.4%) and peripheral motor neuropathy(2.1%). Thirty-eight percent of patients required a dose reduction due to an adverse reaction; the mostcommon adverse reactions (≥2%) leading to a dose reduction were peripheral sensory neuropathy(10.3%), fatigue (5.3%), rash maculo-papular (4.2%) and decreased appetite (2.1%).
Tabulated summary of adverse reactionsAdverse reactions observed during clinical studies of enfortumab vedotin as monotherapy or incombination with pembrolizumab, or reported from post-marketing use of enfortumab vedotin arelisted in this section by frequency category. Frequency categories are defined as follows: 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); not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.
Table 5. Adverse reactions in patients treated with enfortumab vedotin
Frequency Monotherapy In combination withpembrolizumab
Infections and infestationsVery common Urinary tract infection Urinary tract infection
Common Sepsis, pneumonia Sepsis, pneumonia
Not known1 Fungal infection Fungal infection
Blood and lymphatic system disordersVery common Anaemia Anaemia
Common Thrombocytopenia, leukopenia Thrombocytopenia, leukopenia
Not known1 Neutropenia, febrile neutropenia, Neutropenia, febrile neutropenia,neutrophil count decreased neutrophil count decreased
Endocrine disordersVery common Hypothyroidism
Metabolism and nutrition disordersVery common Hyperglycaemia, decreased appetite Hyperglycaemia, decreased appetite
Not known1 Diabetic ketoacidosis Diabetic ketoacidosis
Nervous system disordersVery common Peripheral sensory neuropathy, Peripheral sensory neuropathy,dysgeusia dysgeusia
Neuropathy peripheral, peripheral Neuropathy peripheral, peripheralmotor neuropathy, peripheral motor neuropathy, peripheral
Common sensorimotor neuropathy, sensorimotor neuropathy,paraesthesia, hypoaesthesia, gait paraesthesia, hypoaesthesia, gaitdisturbance, muscular weakness disturbance, muscular weakness,neurotoxicity
Demyelinating polyneuropathy, Dysaesthesia, polyneuropathy,polyneuropathy, neurotoxicity, motor myasthenia gravis, neuralgia,dysfunction, dysaesthesia, muscle peroneal nerve palsy, skin burning
Uncommonatrophy, neuralgia, peroneal nerve sensationpalsy, sensory loss, skin burningsensation, burning sensation
Eye disordersVery common Dry eye Dry eye
Respiratory, thoracic and mediastinal disordersCommon Pneumonitis/ILD2 Pneumonitis/ILD2
Gastrointestinal disordersVery common Diarrhoea, vomiting, nausea Diarrhoea, vomiting, nausea
In combination with
Frequency Monotherapypembrolizumab
Skin and subcutaneous tissue disordersAlopecia, pruritus, rash, rash Alopecia, pruritus, rash
Very commonmaculo-papular, dry skin maculo-papular, dry skin
Drug eruption, skin exfoliation, Rash, skin exfoliation,conjunctivitis, dermatitis bullous, conjunctivitis, dermatitis bullous,blister, stomatitis, palmar-plantar blister, stomatitis, palmar-plantar
Common erythrodysesthesia syndrome, erythrodysesthesia syndrome,eczema, erythaema, rash eczema, erythaema, rasherythaematous, rash macular, rash erythaematous, rash macular, rashpapular, rash pruritic, rash vesicular papular, rash pruritic, rash vesicular,dermatitis
Dermatitis exfoliative generalised, Drug eruption, dermatitis exfoliativeerythaema multiforme, exfoliative generalised, erythaema multiforme,rash, pemphigoid, rash exfoliative rash, pemphigoid,
Uncommon maculovesicular, dermatitis, dermatitis allergic, dermatitisdermatitis allergic, dermatitis contact, contact, intertrigo, skin irritation,intertrigo, skin irritation, stasis stasis dermatitisdermatitis, blood blister
Toxic epidermal necrolysis, skin Toxic epidermal necrolysis, skinhyperpigmentation, skin hyperpigmentation, skindiscolouration, pigmentation disorder, discolouration, pigmentation1 Stevens-Johnson syndrome, disorder, Stevens-Johnson
Not known epidermal necrosis, symmetrical syndrome, epidermal necrosis,drug-related intertriginous and symmetrical drug-relatedflexural exanthaema intertriginous and flexuralexanthaema
Musculoskeletal and connective tissue disordersUncommon Myositis
General disorders and administration site conditionsVery common Fatigue Fatigue
Common Infusion site extravasation Infusion site extravasation
InvestigationsAlanine aminotransferase increased, Alanine aminotransferase increased,
Very common aspartate aminotransferase increased, aspartate aminotransferase increased,weight decreased weight decreased
Common Lipase increased
Injury, poisoning and procedural complicationsCommon Infusion related reaction Infusion related reaction1Based on global post-marketing experience.2Includes: acute respiratory distress syndrome, autoimmune lung disease, immune-mediated lung disease,interstitial lung disease, lung opacity, organising pneumonia, pneumonitis, pulmonary fibrosis, pulmonarytoxicity, pulmonary sarcoidosis and sarcoidosis.
Description of selected adverse reactionsImmunogenicity
A total of 159 patients were tested for immunogenicity against enfortumab vedotin followingenfortumab vedotin in combination with pembrolizumab for the treatment of MIBC; 3 patients wereconfirmed to be positive at baseline for ADA, and in patients that were negative at baseline (n=156), atotal of 2 (1.3%) were positive post baseline.
A total of 490 patients were tested for immunogenicity against enfortumab vedotin followingenfortumab vedotin in combination with pembrolizumab for the treatment of unresectable ormetastatic urothelial cancer; 24 patients were confirmed to be positive at baseline for ADA, and inpatients that were negative at baseline (n=466), a total of 14 (3%) were positive post baseline.
A total of 697 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg asmonotherapy; 16 patients were confirmed to be positive at baseline for anti-drug antibody (ADA), andin patients that were negative at baseline (n=681), a total of 24 (3.5%) were positive post baseline.
The incidence of treatment-emergent anti-enfortumab vedotin antibody formation was consistent whenassessed following enfortumab vedotin administration as monotherapy and in combination withpembrolizumab.
Due to the limited number of patients with antibodies against Padcev, no conclusions can be drawnconcerning a potential effect of immunogenicity on efficacy, safety or pharmacokinetics.
Skin reactionsIn clinical studies of enfortumab vedotin in combination with pembrolizumab, skin reactions occurredin 89% (648) of the 731 patients and a majority of these skin reactions included rash maculo-papular,rash macular, rash and rash papular. Severe (Grade 3 or 4) skin reactions occurred in 19% (135) ofpatients (Grade 3: 17%, Grade 4: 2%). A fatal event of toxic epidermal necrolysis occurred inone patient. The median time to onset of severe skin reactions was 1.6 months (range: 0.1 to17.2 months). Of the patients who experienced skin reactions and had data regarding resolution(n=496), 76% had complete resolution, 16% had partial improvement and 8% had no improvement atthe time of their last evaluation. Of the 24% of patients with residual skin reactions at last evaluation,25% had Grade ≥2 events.
In clinical studies of enfortumab vedotin as monotherapy, skin reactions occurred in 57% (452) of the793 patients treated with enfortumab vedotin 1.25 mg/kg. Severe (Grade 3 or 4) skin reactionsoccurred in 14% (108) of patients and a majority of these reactions included rash maculo-papular,stomatitis, rash erythematous, rash or drug eruption. The median time to onset of severe skin reactionswas 0.7 months (range: 0.1 to 8.2 months). Serious skin reactions occurred in 4.3% (34) of patients. Ofthe patients who experienced skin reactions and had data regarding resolution (n=366), 61% hadcomplete resolution, 24% had partial improvement and 15% had no improvement at the time of theirlast evaluation. Of the 39% of patients with residual skin reactions at last evaluation, 38% had
Grade ≥2 events.
Pneumonitis/ILD
In clinical studies of enfortumab vedotin in combination with pembrolizumab, pneumonitis/ILDoccurred in 9.4% (69) of the 731 patients. Severe (Grade 3 or 4) pneumonitis/ILD occurred in20 patients (Grade 3: 2.3%, Grade 4: 0.4%). Pneumonitis/ILD led to discontinuation of enfortumabvedotin in 2.1% of patients. Three patients experienced a fatal event of pneumonitis/ILD. The mediantime to onset of any grade pneumonitis/ILD was 4.1 months (range: 0.3 to 26.2 months).
In clinical studies of enfortumab vedotin as monotherapy, pneumonitis/ILD occurred in 3.3% (26) ofthe 793 patients treated with enfortumab vedotin 1.25 mg/kg. Less than 1% of patients experiencedsevere (Grade 3 or 4) pneumonitis/ILD (Grade 3: 0.5%, Grade 4: 0.3%). Pneumonitis/ILD led todiscontinuation of enfortumab vedotin in 0.5% of patients. There were no deaths frompneumonitis/ILD. The median time to onset of any grade pneumonitis/ILD was 2.7 months (range: 0.6to 6.0 months) and the median duration for pneumonitis/ILD was 1.6 months (range: 0.1 to43.0 months). Of the 26 patients who experienced pneumonitis/ILD, 8 (30.8%) had resolution ofsymptoms.
HyperglycaemiaIn clinical studies of enfortumab vedotin as monotherapy, hyperglycaemia (blood glucose>13.9 mmol/L) occurred in 17% (133) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg.
Serious events of hyperglycaemia occurred in 2.5% of patients, 7% of patients developed severe(Grade 3 or 4) hyperglycaemia and 0.3% of patients experienced fatal events, one event each ofhyperglycaemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycaemia increasedconsistently in patients with higher body mass index and in patients with higher baseline haemoglobin
A1C (HbA1c). The median time to onset of hyperglycaemia was 0.5 months (range: 0 to 20.3 months).
Of the patients who experienced hyperglycaemia and had data regarding resolution (n=106), 66% hadcomplete resolution, 19% had partial improvement and 15% had no improvement at the time of theirlast evaluation. Of the 34% of patients with residual hyperglycaemia at last evaluation, 64% had
Grade ≥2 events.
Peripheral neuropathyIn clinical studies of enfortumab vedotin as monotherapy, peripheral neuropathy occurred in 53%(422) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Five percent of patientsexperienced severe (Grade 3 or 4) peripheral neuropathy including sensory and motor events. Themedian time to onset of Grade ≥2 peripheral neuropathy was 5 months (range: 0.1 to 20.2 months). Ofthe patients who experienced neuropathy and had data regarding resolution (n=340), 14% hadcomplete resolution, 46% had partial improvement and 41% had no improvement at the time of theirlast evaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade ≥2events.
Ocular disorders
In clinical studies of enfortumab vedotin as monotherapy, 30% of patients experienced dry eye duringtreatment with enfortumab vedotin 1.25 mg/kg. Treatment was interrupted in 1.5% of patients and0.1% of patients permanently discontinued treatment due to dry eye. Severe (Grade 3) dry eye onlyoccurred in 3 patients (0.4%). The median time to onset of dry eye was 1.7 months (range: 0 to30.6 months).
Special populationsElderly
Enfortumab vedotin in combination with pembrolizumab has been studied in 202 patients <65 yearsand 529 patients ≥65 years. Generally, adverse event frequencies were higher in patients ≥65 years ofage compared to <65 years of age, particularly for serious adverse events (58.8% and 40.1%,respectively) and Grade ≥3 events (79.8% and 65.3%, respectively).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no known antidote for overdosage with enfortumab vedotin. In case of overdosage, the patientshould be closely monitored for adverse reactions, and supportive treatment should be administered asappropriate taking into consideration the half-life of 3.6 days (ADC) and 2.6 days (MMAE).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, monoclonal antibodies,
ATC code: L01FX13
Mechanism of actionEnfortumab vedotin is an antibody drug conjugate (ADC) targeting Nectin-4, an adhesion proteinlocated on the surface of the urothelial cancer cells. It is comprised of a fully human IgG1-kappaantibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavablemaleimidocaproyl valine-citrulline linker. Nonclinical data suggest that the anticancer activity ofenfortumab vedotin is due to the binding of the ADC to Nectin-4-expressing cells, followed byinternalisation of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage.
Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cyclearrest, apoptosis and immunogenic cell death. MMAE released from enfortumab vedotin targeted cellscan diffuse into nearby Nectin-4 low-expressing cells resulting in cytotoxic cell death. Combination ofenfortumab vedotin with PD-1 inhibitors results in enhanced anti-tumour activity, consistent with thecomplementary mechanisms of MMAE induced cell cytotoxicity and induction of immunogenic celldeath, plus the up-regulation of immune function by PD-1 inhibition.
Cardiac electrophysiologyAt the recommended dose of 1.25 mg/kg, enfortumab vedotin did not prolong the mean QTc intervalto any clinically relevant extent based on ECG data from a study in patients with advanced urothelialcancer.
Clinical efficacy and safetyEnfortumab vedotin in combination with pembrolizumab
Neoadjuvant and adjuvant treatment of cisplatin-ineligible patientswith muscle invasive bladder cancer
EV-303 (KEYNOTE-905)
The efficacy of Padcev in combination with pembrolizumab as neoadjuvant treatment and thencontinued after radical cystectomy (RC) as adjuvant treatment was evaluated in study EV-303(KEYNOTE-905), an open-label, randomised, phase 3, multicentre study that enrolled patients whoreceived neoadjuvant and adjuvant enfortumab vedotin and pembrolizumab versus RC and pelviclymph node dissection (PLND). Key eligibility criteria were previously untreated cT2-T4aN0M0 orcT1-T4aN1M0 MIBC in patients who were ineligible for or declined cisplatin-based chemotherapyand were eligible for RC and PLND, regardless of PD-L1 status. Patients with active autoimmunedisease that required systemic therapy within 2 years of treatment or a medical condition that requiredimmunosuppression were ineligible.
Patients were randomised 1:1:1 to receive neoadjuvant and adjuvant enfortumab vedotin incombination with pembrolizumab, neoadjuvant and adjuvant pembrolizumab monotherapy or RC and
PLND alone. The hypothesis testing was updated to prioritize the comparison of the enfortumabvedotin in combination with pembrolizumab arm versus the RC and PLND alone arm for EFS;therefore, randomisation to the pembrolizumab monotherapy arm was stopped early. The evaluation ofefficacy was based on the comparison between the following treatment arms:
* Enfortumab vedotin in combination with pembrolizumab (n=170): Neoadjuvant enfortumabvedotin 1.25 mg/kg as an intravenous infusion over 30 minutes on Days 1 and 8 andneoadjuvant pembrolizumab 200 mg over 30 minutes on Day 1 of each 3-week (21-day) cyclefor 3 cycles. Following RC and PLND, adjuvant enfortumab vedotin 1.25 mg/kg over30 minutes on Days 1 and 8 of each 3-week (21-day) cycle for 6 cycles and adjuvantpembrolizumab 200 mg over 30 minutes on Day 1 of each 3-week (21-day) cycle for 14 cycles.
* RC and PLND alone (n=174).
Treatment continued until completion of the treatment, disease progression that precluded RC and
PLND, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase orunacceptable toxicity. Assessment of tumour status was performed at baseline, within 5 weeks prior to
RC and PLND and at 6 weeks post-surgery. Following RC and PLND, assessment of tumour statuswas performed every 12 weeks up to 2 years, and every 24 weeks thereafter. Randomisation wasstratified by tumor stage (T2N0 versus T3/T4aN0 versus T1-T4aN1), cisplatin-eligibility(cisplatin-ineligible versus cisplatin-eligible but declined) and geographic region (United States versus
European Union versus Rest of World).
The median age was 73 years (range: 46 to 87 years); 78% were male; and 78% White. Patients had abaseline Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (86%) or 2 (14%).
Forty-seven percent were CPS ≥10 and 52% CPS <10. Eighteen percent were T2N0, 77% T3/T4aN0and 5% T1-T4aN1. Forty-one percent of patients had baseline creatinine clearance of ≥60 mL/min,59% had <60 mL/min but ≥30 mL/min and 0.3% had <30 mL/min, respectively. Ninety-one percent ofpatients had urothelial carcinoma histology; 4% had urothelial carcinoma with squamousdifferentiation, 3% had urothelial carcinoma with glandular differentiation and 2% had urothelialcarcinoma with other variant histology.
In the overall population, 149 (88%) patients in the enfortumab vedotin in combination withpembrolizumab arm and 156 (90%) patients in the RC and PLND alone arm underwent RC and
PLND. Of the patients treated with enfortumab vedotin in combination with pembrolizumab,100 patients initiated adjuvant treatment and 43 patients completed all planned cycles.
The primary efficacy outcome measure was event-free survival (EFS) as assessed by blindedindependent central review (BICR). Secondary efficacy outcome measures were overall survival (OS)and pathological complete response (pCR) rate as assessed by blinded independent pathology review(BIPR).
The study showed statistically significant improvements in EFS, OS and pCR in patients treated withneoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab compared with RCand PLND alone. The median follow-up time for this study was 18.5 months (range: 0.6 to53.7 months).
Table 6, Figures 1 and 2 summarise the efficacy results for EV-303.
Table 6. Efficacy Results in EV-303
Padcev + RC + PLND alone
Endpoint pembrolizumabn=170 n=174
Event-free survivala
Number (%) of patients with events 48 (28.2) 95 (54.6)
Median in months (95% CI)b NR (37.3, NR) 15.7 (10.3, 20.5)
Hazard ratioc (95% CI) 0.40 (0.28, 0.57)1-sided p-valued <0.0001
Overall survival
Number (%) of patients with events 38 (22.4) 68 (39.1)
Median in months (95% CI)b NR (NR, NR) 41.7 (31.8, NR)
Hazard ratioc (95% CI) 0.50 (0.33, 0.74)1-sided p-valued 0.0002
Pathological complete response
Number of patients with pCR 97 15pCR rate (%) (95% CI) 57.1 (49.3, 64.6) 8.6 (4.9, 13.8)
Treatment difference estimate (%) (95% CI)e 48.3 (39.5, 56.5)1-sided p-valuee <0.000001
NR = Not reached.
a. EFS is defined as time from randomisation to any of the following events: Radiographic diseaseprogression precluding a curative intent surgery as assessed by BICR prior to RC + PLND; Failure toundergo surgery for participants with residual muscle invasive disease and any radiographic diseasepresent; Gross residual disease left behind at time of surgery (surgeon unable to complete curative intentsurgery due to unresectable tumor or newly discovered metastatic disease); Local or distant recurrencepost-RC + PLND as assessed by CT or MRI by BICR and/or biopsy - if biopsy is not feasible due toparticipant safety, CT/MRI alone will be sufficient; Death from any cause.
b. Based on Kaplan-Meier estimates.
c. Based on stratified Cox regression model with Efron’s method of tie handling with treatment as acovariate.
d. Based on stratified log-rank test.
e. Based on stratified Miettinen and Nurminen method.
Figure 1. Kaplan Meier plot of event-free survival, EV-30310 Treatment arm
Padcev + pembro
RC + PLND0 6 12 18 24 30 36 42 48 54
Time in months
Number at risk
Padcev + pembro 170 140 116 73 56 42 35 16 3 0
RC + PLND 174 116 84 48 33 22 14 9 1 0
Figure 2. Kaplan Meier plot of overall survival, EV-30310 Treatment arm
Padcev + pembro
RC + PLND0 6 12 18 24 30 36 42 48 54
Time in months
Number at risk
Padcev + pembro 170 159 144 94 68 56 45 28 10 0
RC + PLND 174 150 130 75 54 45 30 18 6 0
Overall survival (%) Event-free survival (%)
Previously untreated locally advanced or metastatic urothelial cancer
EV-302 (KEYNOTE-A39)
The efficacy of Padcev in combination with pembrolizumab was evaluated in study EV-302(KEYNOTE-A39), an open-label, randomised, phase 3, multicentre study that enrolled 886 patientswith unresectable or metastatic urothelial cancer who had not received prior systemic therapy forlocally advanced or metastatic disease. Patients that received neoadjuvant chemotherapy or patientsthat received adjuvant chemotherapy following cystectomy were included in the study if recurrencewas >12 months from completion of therapy. Patients were considered cisplatin-ineligible if they hadat least one of the following criteria: glomerular filtration rate (GFR) between 30-59 mL/min, ECOGperformance status ≥2, Grade ≥2 hearing loss or New York Heart Association (NYHA) Class III heartfailure.
Patients were randomised 1:1 to receive either enfortumab vedotin in combination withpembrolizumab (arm A) or gemcitabine and platinum-based chemotherapy (cisplatin or carboplatin)(arm B). Patients in arm A received enfortumab vedotin 1.25 mg/kg as an intravenous infusion over30 minutes on Days 1 and 8 of a 21-day cycle, followed by pembrolizumab 200 mg on Day 1 of a21-day cycle approximately 30 minutes after enfortumab vedotin. Patients in arm B receivedgemcitabine 1000 mg/m2 administered on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m2 orcarboplatin (AUC = 4.5 or 5 mg/mL/min according to local guidelines) administered on Day 1 of a21-day cycle. Treatment was continued until disease progression, unacceptable toxicity or completionof the maximum number of treatment cycles (chemotherapy, 6 cycles; pembrolizumab, 35 cycles;enfortumab vedotin, no set maximum).
Patients randomised to the gemcitabine and platinum-based chemotherapy arm were permitted toreceive maintenance immunotherapy (e.g., avelumab). Randomisation was stratified by cisplatineligibility (eligible versus ineligible), PD-L1 expression (CPS ≥10 versus CPS <10) and presence ofliver metastases (present versus absent). PD-L1 expression was based on the PD-L1 IHC 22C3pharmDx kit.
Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motorneuropathy Grade ≥2, uncontrolled diabetes defined as haemoglobin A1C (HbA1c) ≥8% or
HbA1c ≥7% with associated diabetes symptoms, autoimmune disease or a medical condition thatrequired immunosuppression, pneumonitis or other forms of interstitial lung disease.
The median age was 69 years (range: 22 to 91 years); 77% were male; and most were White (67%) or
Asian (22%). Patients had a baseline ECOG performance status of 0 (49%), 1 (47%) or 2 (3%).
Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% ofpatients had metastatic urothelial cancer and 5% of patients had unresectable urothelial cancer.
Seventy-two percent of patients had visceral metastasis at baseline including 22% with livermetastases. Eighty-five percent of patients had urothelial carcinoma (UC) histology, 6% had UCmixed squamous differentiation and 2% had UC mixed other histologic variants. Forty-six percent ofpatients were cisplatin-ineligible and 54% were cisplatin-eligible at time of randomisation. Of the877 patients tested who had tissue evaluable for PD-L1 expression, 58% of patients had tumours thatexpressed PD-L1 with a CPS ≥10 and 42% had tumours that expressed PD-L1 with a CPS <10. Themedian follow-up time was 17.3 months (range: 0.3 to 37.2 months).
The primary efficacy outcome measures were Overall Survival (OS) and Progression Free Survival(PFS) as assessed by BICR according to RECIST v1.1. Secondary efficacy outcome measuresincluded Objective Response Rate (ORR) as assessed by BICR according to RECIST v1.1.
The study showed statistically significant improvements in OS, PFS and ORR for patients randomisedto enfortumab vedotin in combination with pembrolizumab as compared to gemcitabine andplatinum-based chemotherapy.
Table 7, Figures 3 and 4 summarise the efficacy results for EV-302.
Table 7. Efficacy Results in EV-302
Padcev + Gemcitabine
Endpoint pembrolizumab +platinumn=442 n=444
Overall Survival
Number (%) of patients with events 133 (30.1) 226 (50.9)
Median in months (95% CI)a 31.5 (25.4, -) 16.1 (13.9, 18.3)
Hazard ratiob (95% CI) 0.468 (0.376, 0.582)2-sided p-valuec <0.00001
Progression Free Survivald
Number (%) of patients with events 223 (50.5) 307 (69.1)
Median in months (95% CI)a 12.5 (10.4, 16.6) 6.3 (6.2, 6.5)
Hazard ratiob (95% CI) 0.450 (0.377, 0.538)2-sided p-valuec <0.00001
Objective Response Rate (CR + PR)d,f
Confirmed ORR (%) (95% CI)e 67.7 (63.1, 72.1) 44.4 (39.7, 49.2)2-sided p-valueg <0.00001
Duration of Responsed,f
Median in months (95% CI)a NR (20.2, -) 7.0 (6.2, 10.2)
NR = Not reached.
a. Based on the complementary log-log transformation method (Collett, 1994).
b. Based on stratified Cox proportional hazards model. A hazard ratio <1 favors the enfortumab vedotin incombination with pembrolizumab arm.
c. Based on stratified log-rank test.
d. Evaluated by BICR using RECIST v1.1.
e. Based on the Clopper-Pearson method (Clopper 1934).
f. Includes only patients with measurable disease at baseline (n=437 for enfortumab vedotin in combinationwith pembrolizumab, n=441 for gemcitabine plus platinum). The duration of response was estimated forresponders.
g. Based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility and livermetastases.
Figure 3. Kaplan Meier plot of overall survival, EV-302100 Padcev + pembro Plat + gem
Padcev + pembro censored Plat + gem censored0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Time in months
Number at risk
Padcev + pembro 442 426 409 394 376 331 270 222 182 141 108 67 36 22 12 8 1 1 1
Plat + gem 444 423 393 356 317 263 209 164 125 90 60 37 25 18 12 7 6 2 1
Figure 4. Kaplan Meier plot of progression-free survival, EV-302100 Padcev + pembro Plat + gem
Padcev + pembro censored Plat + gem censored0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time in months
Number at risk
Padcev + pembro 442 409 361 303 253 204 167 132 102 73 45 33 17 6 3 1
Plat + gem 444 380 297 213 124 78 56 41 30 19 8 6 5 3 2 1 1
Progression-free survival (%) Overall survival (%)
Enfortumab vedotin as monotherapy
Previously treated locally advanced or metastatic urothelial cancer
EV-301
The efficacy of Padcev as monotherapy was evaluated in study EV-301, an open-label, randomised,phase 3, multicentre study that enrolled 608 patients with locally advanced or metastatic urothelialcancer who have previously received a platinum-containing chemotherapy and a programmed deathreceptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor. The primary endpoint of the studywas Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS) and
Objective Response Rate (ORR) [PFS and ORR were evaluated by investigator assessment using
RECIST v1.1]. Patients were randomised 1:1 to receive either enfortumab vedotin 1.25 mg/kg on
Days 1, 8 and 15 of a 28-day cycle, or one of the following chemotherapies as decided by theinvestigator: docetaxel 75 mg/m2 (38%), paclitaxel 175 mg/m2 (36%) or vinflunine 320 mg/m2 (25%)on Day 1 of a 21-day cycle.
Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motorneuropathy ≥ Grade 2, known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2),active Hepatitis B or C, or uncontrolled diabetes defined as HbA1c ≥8% or HbA1c ≥7% withassociated diabetes symptoms.
The median age was 68 years (range: 30 to 88 years), 77% were male, and most patients were White(52%) or Asian (33%). All patients had a baseline ECOG performance status of 0 (40%) or 1 (60%).
Ninety-five percent (95%) of patients had metastatic disease and 5% had locally advanced disease.
Eighty percent of patients had visceral metastases including 31% with liver metastases. Seventy-sixpercent of patients had urothelial carcinoma/transitional cell carcinoma (TCC) histology, 14% hadurothelial carcinoma mixed and approximately 10% had other histologic variants. A total of 76 (13%)patients had received ≥3 lines of prior systemic therapy. Fifty-two percent (314) of patients hadreceived prior PD-1 inhibitor, 47% (284) had received prior PD-L1 inhibitor, and an additional 1% (9)patients had received both PD-1 and PD-L1 inhibitors. Only 18% (111) of patients had a response toprior therapy with a PD-1 or PD-L1 inhibitor. Sixty-three percent (383) of patients had received priorcisplatin-based regimens, 26% (159) had received prior carboplatin-based regimens, and an additional11% (65) had received both cisplatin and carboplatin-based regimens.
Table 8 summarises the efficacy results for the EV-301 study, after a median follow-up time of11.1 months (95% CI: 10.6 to 11.6).
Table 8. Efficacy results in EV-301
Endpoint Padcev Chemotherapyn=301 n=307
Overall Survival
Number (%) of patients with events 134 (44.5) 167 (54.4)
Median in months (95% CI) 12.9 (10.6, 15.2) 9.0 (8.1, 10.7)
Hazard ratio (95% CI) 0.702 (0.556, 0.886)1-sided p-value 0.00142a
Progression Free Survivalb
Number (%) of patients with events 201 (66.8) 231 (75.2)
Median in months (95% CI) 5.6 (5.3, 5.8) 3.7 (3.5, 3.9)
Hazard ratio (95% CI) 0.615 (0.505, 0.748)1-sided p-value <0.00001c
Objective Response Rate (CR + PR)b
ORR (%) (95% CI) 40.6 (35.0, 46.5) 17.9 (13.7, 22.8)1-sided p-value <0.001d
Complete response rate (%) 4.9 2.7
Partial response rate (%) 35.8 15.2
Duration of Response for responders
Median in months (95% CI) 7.4 (5.6, 9.5) 8.1 (5.7, 9.6)
a. Pre-determined efficacy boundary = 0.00679, 1-sided (adjusted by observed deaths of 301).
b. Evaluated by investigator assessment using RECIST v1.1.
c. Pre-determined efficacy boundary = 0.02189, 1-sided (adjusted by observed PFS1 events of 432).
d. Pre-determined efficacy boundary = 0.025, 1-sided (adjusted by 100% information fraction).
Figure 5. Kaplan Meier plot of overall survival, EV-3011.0 Padcev Chemotherapy
Padcev censored Chemotherapy censored0.80.60.40.20.00 1 2 3 4 5 6 7 8 9 10 16 17 22 23 24
Duration of overall survival (months)
Number at risk
Padcev 301 286 272 257 246 234 222 190 158 130 105 85 63 52 42 33 23 15 7 4 3 2 1 1 0
Chemotherapy 307 288 274 250 238 219 198 163 131 101 84 66 51 44 32 29 16 11 6 4 2 2 1 0 0
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies withenfortumab vedotin in all subsets of the paediatric population in urothelial cancer (see section 4.2 forinformation on paediatric use).
5.2 Pharmacokinetic properties
Distribution
Elderly
The mean estimate of steady-state volume of distribution of ADC was 12.8 L following 1.25 mg/kg ofenfortumab vedotin. In vitro, the binding of unconjugated MMAE to human plasma proteins rangedfrom 68% to 82%. Unconjugated MMAE is not likely to displace or to be displaced by highlyprotein-bound medicinal products. In vitro studies indicate that unconjugated MMAE is a substrate of
P-glycoprotein.
BiotransformationA small fraction of unconjugated MMAE released from enfortumab vedotin is metabolised. In vitrodata indicate that the metabolism of unconjugated MMAE occurs primarily via oxidation by CYP3A4.
EliminationThe mean clearance of ADC and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h,respectively. ADC elimination exhibited a multi-exponential decline with a half-life of 3.6 days.
Elimination of unconjugated MMAE appeared to be limited by its rate of release from enfortumabvedotin. Unconjugated MMAE elimination exhibited a multi-exponential decline with a half-life of2.6 days.
Probability of overall survival
Excretion
The excretion of unconjugated MMAE occurs mainly in faeces with a smaller proportion in urine.
After a single dose of another ADC that contained unconjugated MMAE, approximately 24% of thetotal unconjugated MMAE administered was recovered in faeces and urine as unchanged unconjugated
MMAE over a 1-week period. The majority of recovered unconjugated MMAE was excreted in faeces(72%). A similar excretion profile is expected for unconjugated MMAE after enfortumab vedotinadministration.
Special populationsElderly
Population pharmacokinetic analysis indicates that age [range: 24 to 90 years; 60% (450/748)>65 years, 19% (143/748) >75 years] does not have a clinically meaningful effect on thepharmacokinetics of enfortumab vedotin.
Race and genderBased on population pharmacokinetic analysis, race [69% (519/748) White, 21% (158/748) Asian,1% (10/748) Black and 8% (61/748) others or unknown] and gender [73% (544/748) male] do nothave a clinically meaningful effect on the pharmacokinetics of enfortumab vedotin.
Renal impairmentThe pharmacokinetics of ADC and unconjugated MMAE were evaluated after the administration of1.25 mg/kg of enfortumab vedotin to patients with mild (CrCL >60-90 mL/min), moderate(CrCL 30-60 mL/min) and severe (CrCL 15-<30 mL/min) renal impairment. No significantdifferences in AUC exposure of ADC or unconjugated MMAE were observed in patients with mild,moderate or severe renal impairment compared to patients with normal renal function. Enfortumabvedotin has not been evaluated in patients with end-stage renal disease (CrCL <15 mL/min).
Hepatic impairmentBased on population pharmacokinetics analysis using data from clinical studies in patients withmetastatic UC, there was no significant differences in ADC exposure and a 37% and 16% increase inunconjugated MMAE average concentrations in patients with previously treated and previouslyuntreated locally advanced or metastatic urothelial cancer, respectively, with mild hepatic impairment(total bilirubin of 1 to 1.5 × ULN and AST any, or total bilirubin ≤ ULN and AST > ULN) comparedto patients with normal hepatic function. Enfortumab vedotin has only been studied in a limitednumber of patients with moderate hepatic impairment (n=5) or severe hepatic impairment (n=1). Theeffect of moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and AST any) or livertransplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.
Physiologically based pharmacokinetic modeling predictions
Concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3Ainhibitor) is predicted to increase unconjugated MMAE Cmax and AUC exposure to a minor extent,with no change in ADC exposure.
Concomitant use of enfortumab vedotin with rifampin (a combined P-gp and strong CYP3A inducer)is predicted to decrease unconjugated MMAE Cmax and AUC exposure with moderate effect, with nochange in ADC exposure. The full impact of rifampin on the Cmax of unconjugated MMAE may beunderestimated in the PBPK model.
Concomitant use of enfortumab vedotin is predicted not to affect exposure to midazolam (a sensitive
CYP3A substrate). In vitro studies using human liver microsomes indicate that unconjugated MMAEinhibits CYP3A4/5 but not other CYP450 isoforms. Unconjugated MMAE did not induce major
CYP450 enzymes in human hepatocytes.
In vitro studiesIn vitro studies indicate that unconjugated MMAE is a substrate and not an inhibitor of the effluxtransporter P-glycoprotein (P-gp). In vitro studies determined that unconjugated MMAE was not asubstrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2(MRP2), organic anion transporting polypeptide 1B1 or 1B3 (OATP1B1 or OATP1B3), organic cationtransporter 2 (OCT2) or organic anion transporter 1 or 3 (OAT1 or OAT3). Unconjugated MMAE wasnot an inhibitor of the bile salt export pump (BSEP), P-gp, BCRP, MRP2, OCT1, OCT2, OAT1,
OAT3, OATP1B1 or OATP1B3 at clinically relevant concentrations.
5.3 Preclinical safety data
Genotoxicity studies showed that MMAE had no discernible genotoxic potential in a reverse mutationtest in bacteria (Ames test) or in a L5178Y TK+/- mouse lymphoma mutation assay. MMAE didinduce chromosomal aberrations in the micronucleus test in rats which is consistent with thepharmacological action of microtubule-disrupting agents.
Skin lesions were noted in repeat dose studies in rats (4- and 13-weeks) and in monkeys (4-weeks).
The skin changes were fully reversible by the end of a 6-week recovery period.
Hyperglycaemia reported in the clinical studies was absent in both the rat and monkey toxicity studiesand there were no histopathological findings in the pancreas of either species.
Foetal toxicity (reduced litter size or complete litter loss) was observed and decrease in the litter sizewas reflected in an increase in early resorptions. Mean foetal body weight in the surviving foetuses atthe 2 mg/kg dose level were reduced compared with control.
Enfortumab vedotin associated foetal skeletal variations were considered developmental delays. Adose of 2 mg/kg (approximately similar to the exposure at the recommended human dose) resulted inmaternal toxicity, embryo-foetal lethality and structural malformations that included gastroschisis,malrotated hindlimb, absent forepaw, malpositioned internal organs and fused cervical arch.
Additionally, skeletal anomalies (asymmetric, fused, incompletely ossified, and misshapen sternebrae,misshapen cervical arch, and unilateral ossification of the thoracic centra) and decreased foetal weightwere observed.
Testicular toxicity observed, only in rats, was partially reversed by the end of a 24-week recoveryperiod.
No dedicated preclinical safety studies were conducted with enfortumab vedotin in combination withpembrolizumab.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Histidine
Histidine hydrochloride monohydrate
Trehalose dihydrate
Polysorbate 20
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
6.3 Shelf life
Unopened vial4 years.
Reconstituted solution in the vial
From a microbiological point of view, after reconstitution, the solution from the vial(s) should beadded to the infusion bag immediately. If not used immediately, storage times and conditions prior touse of the reconstituted vials are the responsibility of the user and would normally not be longer than24 hours in refrigeration at 2°C to 8°C. Do not freeze.
Diluted dosing solution in the infusion bag
From a microbiological point of view, after dilution into the infusion bag, the diluted solution in thebag should be administered to the patient immediately. If not used immediately, storage times andconditions prior to use of the diluted dosing solution is the responsibility of the user and wouldnormally not be longer than 16 hours in refrigeration at 2°C to 8°C including infusion time. Do notfreeze.
6.4 Special precautions for storage
Unopened vials
Store in a refrigerator (2ºC to 8ºC).
Do not freeze.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Padcev 20 mg powder for concentrate for solution for infusion vial10 mL Type I glass vial with gray bromobutyl rubber stopper, 20 mm aluminum seal with a green ringand green cap. Each carton contains 1 vial.
Padcev 30 mg powder for concentrate for solution for infusion vial10 mL Type I glass vial with gray bromobutyl rubber stopper, 20 mm aluminum seal with a silver ringand yellow cap. Each carton contains 1 vial.
6.6 Special precautions for disposal and other handling
Instructions for preparation and administration
Reconstitution in single-dose vial1. Follow procedures for proper handling and disposal of anticancer medicinal products.2. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.3. Calculate the recommended dose based on the patient’s weight to determine the number andstrength (20 mg or 30 mg) of vials needed.4. Reconstitute each vial as follows and, if possible, direct the stream of sterile water for injectionalong the walls of the vial and not directly onto the lyophilized powder:
a. 20 mg vial: Add 2.3 mL of sterile water for injection, resulting in 10 mg/mL enfortumabvedotin.
b. 30 mg vial: Add 3.3 mL of sterile water for injection, resulting in 10 mg/mL enfortumabvedotin.5. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstitutedvial(s) to settle for at least 1 minute until the bubbles are gone. Do not shake the vial. Do notexpose to direct sunlight.
6. Visually inspect the solution for particulate matter and discolouration. The reconstituted solutionshould be clear to slightly opalescent, colourless to light yellow and free of visible particles.
Discard any vial with visible particles or discolouration.
Dilution in infusion bag7. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer intoan infusion bag.8. Dilute enfortumab vedotin with either dextrose 50 mg/mL (5%), sodium chloride 9 mg/mL(0.9%) or Lactated Ringer’s solution for injection. The infusion bag size should allow enoughsolvent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL enfortumab vedotin.
Diluted dosing solution of enfortumab vedotin is compatible with intravenous infusion bags composedof polyvinyl chloride (PVC), ethylvinyl acetate, polyolefin such as polypropylene (PP), or IV bottlescomprised of polyethylene (PE), polyethylene terephthalate glycol-modified, and infusion setscomposed of PVC with either plasticizer (bis(2-ethylhexyl) phthalate (DEHP) or tris(2-ethylhexyl)trimellitate (TOTM)), PE and with filter membranes (pore size: 0.2-1.2 μm) composed ofpolyethersulfone, polyvinylidene difluoride or mixed cellulose esters.
9. Mix diluted solution by gentle inversion. Do not shake the bag. Do not expose to direct sunlight.10. Visually inspect the infusion bag for any particulate matter or discolouration prior to use. Thereconstituted solution should be clear to slightly opalescent, colourless to light yellow and freeof visible particles. Do not use the infusion bag if particulate matter or discolouration isobserved.
11. Discard any unused portion left in the single-dose vials.
Administration12. Administer the infusion over 30 minutes through an intravenous line. Do not administer as anintravenous push or bolus.
No incompatibilities have been observed with closed system transfer device composed of acrylonitrilebutadiene styrene (ABS), acrylic, activated charcoal, ethylene propylene diene monomer, methacrylate
ABS, polycarbonate, polyisoprene, polyoxymethylene, PP, silicone, stainless steel, thermoplasticelastomer for reconstituted solution.
13. Do not co-administer other medicinal products through the same infusion line.14. In-line filters or syringe filters (the pore size: 0.2-1.2 μm, recommended materials:
polyethersulfone, polyvinylidene difluoride, mixed cellulose esters) are recommended to beused during administration.
DisposalAny unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.