Enfortumab vedotin

Based on physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increase unconjugated MMAE C_max 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 receiving concomitant 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.

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.

In rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may alter male fertility. Monomethyl auristatin E (MMAE) has been shown to have aneugenic properties. Therefore, men being treated with this medicinal product are advised to have sperm samples frozen and stored before treatment. There are no data on the effect of enfortumab vedotin on human fertility.

Enfortumab vedotin can cause foetal harm when administered to pregnant women based upon findings from animal studies. Embryo-foetal development studies in female rats have shown that intravenous administration of enfortumab vedotin resulted in reduced numbers of viable foetuses, reduced litter size, and increased early resorptions. Enfortumab vedotin is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

It is unknown whether enfortumab vedotin is excreted in human milk. A risk to breast-fed children cannot be excluded. Breastfeeding should be discontinued during enfortumab vedotin treatment and for at least 6 months after the last dose.

Women of childbearing potential / Contraception in males and females

Pregnancy testing is recommended for females of reproductive potential within 7 days prior to initiating treatment. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 12 months after stopping treatment. Men being treated with enfortumab vedotin are advised not to father a child during treatment and for up to 9 months following the last dose of enfortumab vedotin.

Fertility

In rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may alter male fertility. Monomethyl auristatin E (MMAE) has been shown to have aneugenic properties. Therefore, men being treated with this medicinal product are advised to have sperm samples frozen and stored before treatment. There are no data on the effect of enfortumab vedotin on human fertility.

Enfortumab vedotin has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions with enfortumab vedotin were alopecia (48.8%), fatigue (46.8%), decreased appetite (44.9%), peripheral sensory neuropathy (38.7%), diarrhoea (37.6%), nausea (36%), pruritus (33.4%), dysgeusia (29.9%), anaemia (26.5%), weight decreased (23.4%), rash maculo-papular (22.9%), dry skin (21.6%), vomiting (18.4%), aspartate aminotransferase increased (15.3%), hyperglycaemia, (13.1%), dry eye (12.8%), alanine aminotransferase increased (12.1%) and rash (10.4%).

The most common serious adverse reactions were diarrhoea (2%) and hyperglycaemia (2%). Nine percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reaction (≥2%) leading to dose discontinuation was peripheral sensory neuropathy (4%). Adverse reactions leading to dose interruption occurred in 44% of patients; the most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (15%), fatigue (7%), rash maculo-papular (4%), aspartate aminotransferase increased (4%), alanine aminotransferase increased (4%), anaemia (3%), diarrhoea (3%) and hyperglycaemia (3%). Thirty percent of patients required a dose reduction due to an adverse reaction; the most common adverse reactions (≥2%) leading to a dose reduction were peripheral sensory neuropathy (10%), fatigue (5%), rash maculo-papular (4%) and decreased appetite (2%).

Tabulated summary of adverse reactions

The safety of enfortumab vedotin as monotherapy has been evaluated in 680 patients with locally advanced or metastatic urothelial cancer receiving 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle in clinical studies (see table). Patients were exposed to enfortumab vedotin for a median duration of 4.7 months (range: 0.3 to 34.8 months).

Adverse reactions observed during clinical studies are listed 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions:

¹ Based on global post-marketing experience.

Description of selected adverse reactions

Immunogenicity

A total of 590 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg; 15 patients were confirmed to be positive at baseline for anti-drug antibody (ADA), and in patients that were negative at baseline (N=575), a total of 16 (2.8%) were positive postbaseline (13 transiently and 3 persistently). Due to the limited number of patients with antibodies against enfortumab vedotin, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy, safety or pharmacokinetics.

Skin reactions

In clinical studies, skin reactions occurred in 55% (375) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Severe (Grade 3 or 4) skin reactions occurred in 13% (85) of patients and a majority of these reactions included maculo-papular rash, rash erythematous, rash or drug eruption. The median time to onset of severe skin reactions was 0.62 months (range: 0.1 to 6.4 months). Serious skin reactions occurred in 3.8% (26) of patients.

In the EV-201 (N=214) clinical study, of the patients who experienced skin reactions, 75% had complete resolution and 14% had partial improvement.

Hyperglycaemia

In clinical studies, hyperglycaemia (blood glucose >13.9 mmol/L) occurred in 14% (98) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Serious events of hyperglycaemia occurred in 2.2% of patients, 7% of patients developed severe (Grade 3-4) hyperglycaemia and 0.3% of patients experienced fatal events, one event each of hyperglycaemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycaemia increased consistently in patients with higher body mass index and in patients with higher baseline haemoglobin A1C (HbA1c). The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3).

In the EV-201 (N=214) clinical study, at the time of their last evaluation, 61% of patients had complete resolution, and 19% of patients had partial improvement.

Peripheral neuropathy

In clinical studies peripheral neuropathy occurred in 52% (352) of the 680 patients treated with enfortumab vedotin 1.25 mg/kg. Four percent of patients experienced severe (Grade 3-4) peripheral neuropathy including sensory and motor events. The median time to onset of Grade ≥2 was 4.6 months (range: 0.1 to 15.8).

In the EV-201 (N=214) clinical study, at the time of their last evaluation, 19% of patients had complete resolution, and 39% of patients had partial improvement.

Ocular disorders

In clinical studies, 30% of patients experienced dry eye during treatment with enfortumab vedotin 1.25 mg/kg. Treatment was interrupted in 1.3% of patients and 0.1% of patients permanently discontinued treatment due to dry eye. Severe (Grade 3) dry eye only occurred in 3 patients (0.4%). The median time to onset of dry eye was 1.7 months (range: 0 to 19.1 months).