Padcev Adverse Reactions

Summary of the safety profile: Padcev as a single agent: The most common adverse reactions with Padcev were alopecia (48.3%), fatigue (47.5%), decreased appetite (46.1%), peripheral sensory neuropathy (40.1%), diarrhea (38.4%), nausea (37.1%), pruritus (33.3%), dysgeusia (30.7%), anemia (26.6%), weight decreased (25.0%), rash maculo-papular (24.0%), dry skin (22.4%), vomiting (18.1%), aspartate aminotransferase increased (14.3%), hyperglycemia (13.0%), dry eye (12.9%), alanine aminotransferase increased (11.0%) and rash (10.0%).
The most common serious adverse reactions were diarrhea (2%) and hyperglycemia (2%). Twenty percent of patients permanently discontinued Padcev for adverse events; the most common adverse reaction (≥2%) leading to dose discontinuation was peripheral sensory neuropathy (5%). Adverse events leading to dose interruption occurred in 62% 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 (3%), anemia (3%), diarrhea (3%), hyperglycemia (3%), neutrophil count decreased (3%) and rash (2%). Thirty-six percent of patients required a dose reduction due to an adverse event; the most common adverse reactions (≥2%) leading to a dose reduction were peripheral sensory neuropathy (11%), fatigue (5%), rash maculo-papular (4%) and decreased appetite (2%).
Tabulated summary of adverse reactions: The safety of Padcev as a single agent has been evaluated in 753 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 6). Patients were exposed to Padcev for a median duration of 4.7 months (range: 0.3 to 52.1 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. (See Table 6.)

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Padcev with pembrolizumab: Serious adverse reactions occurred in 50% of patients. The most common serious adverse reactions (≥2%) were anemia (2%) and diarrhea (2%).
Adverse reactions leading to discontinuation of either Padcev, pembrolizumab, or both occurred in 49% of patients; 22% Padcev only, 20% pembrolizumab only, and 12% both. The most common adverse reactions (≥2%) leading to discontinuation of Padcev, pembrolizumab or the combination were peripheral sensory neuropathy (14%), pneumonitis (5%), rash maculo-papular (5%), myasthenia gravis (3%) and peripheral motor neuropathy (3%).
Adverse reactions leading to dose interruption of Padcev, pembrolizumab, or both occurred in 80% of patients; 39% Padcev only, 37% pembrolizumab only, and 50% both. The most common adverse reactions (≥2%) leading to dose interruption of Padcev, pembrolizumab or the combination were peripheral sensory neuropathy (23%), rash maculo-papular (12%), fatigue (7%), lipase increased (7%), neutropenia (7%), diarrhea (6%), pneumonitis (6%), anemia (3%), alanine aminotransferase increased (3%), dermatitis bullous (3%), hyperglycemia (3%), peripheral motor neuropathy (3%) and peripheral sensorimotor neuropathy (3%).
Adverse reactions leading to dose reduction of Padcev occurred in 46% of patients. The most common adverse reactions (≥2%) leading to dose reduction of Padcev were peripheral sensory neuropathy (14%), rash maculo-papular (8%), neutropenia (5%), fatigue (5%) and diarrhea (4%).
Tabulated summary of adverse reactions: The safety of Padcev was evaluated in combination with pembrolizumab in 121 patients who received at least one dose of Padcev 1.25 mg/kg and pembrolizumab in one phase 2 study (EV-103) (see Table 7).
Adverse reactions observed during the clinical study 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. (See Table 7.)

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Selected Adverse Reactions: Immunogenicity: A total of 655 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg as a single agent; 15 patients were confirmed to be positive at baseline for anti-therapeutic antibody (ATA), and in patients that were negative at baseline (n=640), a total of 23 (3.6%) were positive post baseline. A total of 110 patients were tested for immunogenicity against enfortumab vedotin following enfortumab vedotin in combination with pembrolizumab; 5 patients were confirmed to be positive at baseline for ATA, and in patients that were negative at baseline (n=105), a total of 3 (2.9%) were positive post baseline. The incidence of treatment-emergent anti-enfortumab vedotin antibody formation was consistent when assessed following Padcev administration as a single agent and in combination with pembrolizumab.
Due to the limited number of patients with antibodies against enfortumab vedotin, no conclusions can be drawn concerning a potential effect of immunogenicity on pharmacokinetics, pharmacodynamics, efficacy, safety or pharmacokinetics.
Skin Reactions: In clinical studies of Padcev as a single agent, skin reactions occurred in 56% (418) of the 753 patients treated with Padcev 1.25 mg/kg. Severe (Grade 3 or 4) skin reactions occurred in 12% (92) of patients and a majority of these reactions included rash maculo-papular, rash erythematous, rash or drug eruption. The time to onset of severe skin reactions ranged from 0.1 to 6.4 months (median 0.7 months). Serious skin reactions occurred in 3.7% (28) 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.
When enfortumab vedotin 1.25 mg/kg was given in combination with pembrolizumab (n=121), skin reactions occurred in 72% (87) patients. The majority of the skin reactions that occurred with combination therapy included rash maculo-papular, rash macular and rash papular. Severe (Grade 3 or 4) skin reactions occurred in 21% (25) patients on combination therapy (Grade 3: 19%, Grade 4: 2%). The time to onset of severe skin reactions ranged from 0.3 to 16.1 months (median 2.6 months) (see Precautions).
Hyperglycemia: In clinical studies of Padcev as a single agent, hyperglycemia (blood glucose >13.9 mmol/L) occurred in 14% (108) of the 753 patients treated with Padcev 1.25 mg/kg. Serious events of hyperglycemia occurred in 2.3% of patients, 7% of patients developed severe (Grade 3-4) hyperglycemia and 0.3% of patients experienced fatal events, one event each of hyperglycemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline hemoglobin A1C. The time to onset of hyperglycemia ranged from 0 to 20.3 months (median 0.6 months).
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 (see Precautions).
Pneumonitis/interstitial lung disease: In clinical studies of Padcev as a single agent, pneumonitis occurred in 17 (2.3%) and interstitial lung disease occurred in 2 (0.3%) of the 753 patients treated with Padcev 1.25 mg/kg. Less than 1% of patients experienced severe (Grade 3-4) pneumonitis or interstitial lung disease.
When Padcev 1.25 mg/kg was given in combination with pembrolizumab (n=121), pneumonitis occurred in 11 (9%) of the 121 patients treated with combination therapy. Four patients (3%) experienced severe (Grade 3) and one patient experienced a fatal event of pneumonitis. The time to onset of pneumonitis ranged from 0.6 to 26.2 months (median 6 months) (see Precautions).
Peripheral Neuropathy: In clinical studies of Padcev as a single agent, peripheral neuropathy occurred in 53% (401) of the 753 patients treated with Padcev 1.25 mg/kg. Five percent of patients experienced severe (Grade 3-4) peripheral neuropathy including sensory and motor events. The time to onset of Grade ≥2 ranged from 0.1 to 20.2 months (median 4.9 months).
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 (see Precautions).
Ocular Disorders: In clinical studies of Padcev as a single agent, 30.8% 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 time to onset ranged from 0 to 19.1 months (median 1.6 months) (see Precautions).