Padcev Drug Information
Generic name: ENFORTUMAB VEDOTIN
Uses of Padcev
- PADCEV ®, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC). PADCEV ®, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC). PADCEV, as a single agent, is indicated for the treatment of adult patients with la/mUC who:
- Have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
- Are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. PADCEV is a Nectin-4-directed antibody and microtubule inhibitor conjugate indicated:
- In combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, for the treatment of adult patients with muscle invasive bladder cancer (MIBC).
- In combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC).
- As a single agent for the treatment of adult patients with la/mUC who: ○ have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or ○ are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
Dosage & Administration of Padcev
Recommended Dosage
The recommended dosages for PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, and PADCEV as a single agent are presented in Table 1 and Table 2. Administer PADCEV as an intravenous infusion over 30 minutes as recommended. Administer PADCEV prior to pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph if administering on the same day.
Table 1. For the recommended dosage of pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, refer to the respective Prescribing Information. Table 2.
Recommended Dosages for PADCEV as a single agent Pneumonitis/Interstitial Lung Disease (ILD)
Instructions for Preparation and Administration • Administer
PADCEV as an intravenous infusion only. • PADCEV is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Prior to administration, the PADCEV vial is reconstituted with Sterile Water for Injection (SWFI). The reconstituted solution is subsequently diluted in an intravenous infusion bag containing either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.
Reconstitution in Single-Dose Vial 1. Follow procedures for proper handling and disposal of anticancer drugs. 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 and strength (20 mg or 30 mg) of vials needed. 4. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least 1 minute until the bubbles are gone.
DO NOT SHAKE THE VIAL. Do not expose to direct sunlight. 6. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
The reconstituted solution should be clear to slightly opalescent, colorless to light yellow, and free of visible particles. Discard any vial with visible particles or discoloration. 7. Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately.
This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.
Discard unused vials with reconstituted solution beyond the recommended storage time. Dilution in Infusion Bag 1. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag. 2.
Dilute PADCEV with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection. The infusion bag size should allow enough diluent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL PADCEV. 3. Mix diluted solution by gentle inversion.
DO NOT SHAKE THE BAG. Do not expose to direct sunlight. 4. Visually inspect the infusion bag for any particulate matter or discoloration prior to use.
DO NOT USE the infusion bag if particulate matter or discoloration is observed. 5. Discard any unused portion left in the single-dose vials. Administration 1.
Immediately administer the infusion over 30 minutes through an intravenous line. 2. If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than 8 hours at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.
DO NOT administer PADCEV as an intravenous push or bolus. DO NOT mix PADCEV with, or administer as an infusion with, other medicinal products.
| Indication | Recommended PADCEV Dosage | Duration of Therapy |
|---|---|---|
| Neoadjuvant and Adjuvant Muscle Invasive Bladder Cancer (MIBC) | PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21-day cycle. | Patients who are cisplatin-eligible Cisplatin ineligibility is defined as meeting at least one of the following criteria: Creatinine clearance of less than 60 mL/min, ECOG PS 2 or higher, Grade 2 or higher hearing loss, NYHA Class III or higher heart failure, or Grade 2 or higher peripheral neuropathy.: • Neoadjuvant: 4 cycles or until disease progression that precludes curative intent cystectomy or unacceptable toxicity. • Adjuvant: 5 cycles or until disease recurrence or unacceptable toxicity. |
| Patients who are cisplatin-ineligible: • Neoadjuvant: 3 cycles or until disease progression that precludes curative intent cystectomy or unacceptable toxicity. • Adjuvant: 6 cycles or until disease recurrence or unacceptable toxicity. | ||
| Locally advanced or metastatic Urothelial Cancer (la/mUC) | PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21-day cycle. | Until disease progression or unacceptable toxicity. |
| Indication | Recommended PADCEV Dosage | Duration of Therapy |
|---|---|---|
| Locally advanced or metastatic Urothelial Cancer (la/mUC) | PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1, 8, and 15 of a 28-day cycle. | Until disease progression or unacceptable toxicity. |
| Adverse Reaction | Severity Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. | Dose Modification |
|---|---|---|
| Skin Reactions [see Boxed Warning, Warnings and Precautions ( 5.1 )] | For persistent or recurrent Grade 2 skin reactions | Consider withholding until Grade ≤1, then resume treatment at the same dose level or dose reduce by one dose level. |
| Grade 3 skin reactions | Withhold until Grade ≤1, then resume treatment at the same dose level or dose reduce by one dose level. | |
| Suspected SJS or TEN | Immediately withhold, consult a specialist to confirm the diagnosis. If not SJS/TEN, see Grade 2-4 skin reactions. | |
| Confirmed SJS or TEN; Grade 4 or recurrent Grade 3 skin reactions | Permanently discontinue. | |
| Hyperglycemia [see Warnings and Precautions ( 5.2 )] | Blood glucose >250 mg/dL | Withhold until elevated blood glucose has improved to ≤250 mg/dL, then resume treatment at the same dose level. |
| Pneumonitis/Interstitial Lung Disease (ILD) [see Warnings and Precautions ( 5.3 )] | Grade 2 | Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. |
| Grade ≥3 | Permanently discontinue. | |
| Peripheral Neuropathy [see Warnings and Precautions ( 5.4 )] | Grade 2 | Withhold until Grade ≤1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until Grade ≤1, then resume treatment reduced by one dose level. |
| Grade ≥3 | Permanently discontinue. | |
| Other Nonhematologic Toxicity [see Adverse Reactions ( 6 )] | Grade 3 | Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. |
| Grade 4 | Permanently discontinue. | |
| Hematologic Toxicity [see Adverse Reactions ( 6 )] | Grade 3, or Grade 2 thrombocytopenia | Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. |
| Grade 4 | Withhold until Grade ≤1, then reduce dose by one dose level or discontinue treatment. |
| Dose Reduction Schedule | Dose Level |
|---|---|
| Starting dose | 1.25 mg/kg up to 125 mg |
| First dose reduction | 1 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 |
Side Effects of Padcev
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab for the treatment of MIBC in for the treatment of MIBC, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, rash, increased creatinine, decreased lymphocytes, fatigue, pruritus, decreased sodium, peripheral neuropathy, increased potassium, diarrhea, alopecia, dysgeusia, decreased appetite, nausea, constipation, urinary tract infection, dry eye, increased glucose, decreased weight, decreased potassium, hyperglycemia, decreased phosphate, and decreased neutrophils. Among months.
In this pooled population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets. Among months. The data described in the following section reflects exposure to PADCEV in combination with intravenous pembrolizumab from EV‑302, the dose escalation cohort, Cohort A and Cohort K of EV-103, EV-303, and EV-304.
Patients from EV-302 and EV-103 received PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab until disease progression or unacceptable toxicity. The data described in the following section also reflects exposure to PADCEV as a single agent from an open-label, randomized, trial (EV‑301) and Cohort 1 and Cohort 2 of an open-label, single arm, two cohort trial (EV-201). Neoadjuvant and Adjuvant Treatment of Patients with MIBC Who Are Cisplatin-Eligible EV-304 The safety of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment and continued after radical cystectomy (RC) as adjuvant treatment was evaluated in an open-label, randomized, active-controlled, multicenter trial (EV-304) in patients with previously untreated MIBC who were eligible for cisplatin-based chemotherapy.
Patients received either PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab (n=403) before and after RC with pelvic lymph node dissection (PLND) or chemotherapy (gemcitabine with cisplatin) before RC with PLND (n=396). Table 5 summarizes the most common (≥20%) adverse reactions in EV-304. Table 5.
Table 6. Selected Laboratory Abnormalities Reported in ≥20% (All Grades) of Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV- 3 patients received at least one dose of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment before receiving RC. In the neoadjuvant phase, serious adverse reactions occurred in 27% of patients receiving PADCEV in combination with intravenous pembrolizumab.
Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%) and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock, and urosepsis (0.2% each). Additional fatal adverse reactions were reported in 2 patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (1 patient each). Adverse reactions leading to discontinuation of PADCEV in the neoadjuvant phase occurred in 21% of patients.
The most common adverse reactions (≥1%) leading to discontinuation of PADCEV were peripheral neuropathy (5%) and rash (3.5%). Adverse reactions leading to dose interruption of PADCEV in the neoadjuvant phase occurred in 35% of patients. Adverse reactions leading to dose reduction of PADCEV in the neoadjuvant phase occurred in 15% of patients.
The most common adverse reactions (≥1%) leading to dose reduction of PADCEV were rash (9%) and pruritus (2%). Of the 403 patients in the PADCEV in combination with intravenous pembrolizumab arm who received neoadjuvant treatment, 13 (3.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were multiple organ dysfunction syndrome (0.5%) and adenocarcinoma of colon, COVID-19 pneumonia, cardiac arrest, chronic obstructive pulmonary disease, coronary artery disease, glomerulonephritis, immune-mediated lung disease, myocarditis, pneumonia, pneumonitis, and urosepsis (0.2% each).
Of the 351 patients who received neoadjuvant treatment with PADCEV in combination with intravenous pembrolizumab and underwent RC, 26 (7%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions. Adjuvant Phase of EV-304 Patients who did not proceed to surgery were ineligible for adjuvant treatment. Of the 351 patients who underwent surgery, 225 patients received adjuvant treatment with PADCEV with or without intravenous pembrolizumab.
Of the 126 patients who did not receive adjuvant PADCEV, discontinuation of PADCEV prior to the adjuvant phase was due to an adverse event in 65 patients. In the adjuvant phase, serious adverse reactions occurred in 36% of patients receiving PADCEV. Fatal adverse reactions in the adjuvant phase in patients who received adjuvant PADCEV occurred in 3.1% of patients and included cardiac arrest, death, duodenal ulcer perforation, acute pancreatitis, renal failure, small cell lung cancer, and toxic shock syndrome (0.4% each).
Adverse reactions leading to discontinuation of PADCEV in the adjuvant phase occurred in 16% of patients who received PADCEV in the adjuvant phase. Adverse reactions leading to dose interruption of PADCEV in the adjuvant phase occurred in 34% of patients who received PADCEV in the adjuvant phase. Adverse reactions leading to dose reduction of PADCEV in the adjuvant phase occurred in 5% of patients who received PADCEV in the adjuvant phase.
The most common adverse reaction (>1%) resulting in dose reduction of PADCEV in the adjuvant phase included rash (1.3%). Out of 100 patients who received adjuvant treatment in the PADCEV in combination arm, 92 patients received PADCEV. Table 7 summarizes the most common (≥20%) adverse reactions in EV-303.
Table 7. Table 8. The most frequent (≥2%) serious adverse reactions were urinary tract infection (3.6%) and hematuria (2.4%).
Fatal adverse reactions occurred in 1.2% of patients including myasthenia gravis and TEN (0.6% each). Of the 167 patients in the PADCEV in combination with intravenous pembrolizumab arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions. The most common adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection and the deaths due to myasthenia gravis and TEN (0.6% each).
Of the 146 patients who underwent surgery, 92 patients received adjuvant treatment with PADCEV with or without intravenous pembrolizumab. Fatal adverse reactions occurred in 8% of patients who received PADCEV in the adjuvant phase, including urosepsis, hemorrhage intracranial, death, myocardial infarction, multiple organ dysfunction syndrome, and pneumonia pseudomonal (1.1% each). The most common adverse reaction (≥2%) leading to dose reduction of PADCEV was weight decreased (2.2%).
Previously Untreated LA/mUC EV-302 The safety of PADCEV in combination with intravenous pembrolizumab was evaluated in an open-label, randomized, multicenter trial (EV-302) in patients with la/mUC. Patients received either PADCEV 1.25 mg/kg and pembrolizumab (n=440) or gemcitabine and platinum chemotherapy (either cisplatin or carboplatin) (n=433). Among patients who received PADCEV and pembrolizumab, the median duration of exposure for PADCEV was 7 months (range: 0.3 to 31.9 months).
Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with intravenous pembrolizumab. The most common adverse reactions (≥2%) leading to dose interruption of %, increased alanine aminotransferase (3%), and pruritus (2.5%). Table 9 summarizes the most common (≥15%) adverse reactions in EV-302.
Table 9. Table 10. Selected Laboratory Abnormalities Reported in ≥15% (All Grades) of Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV- Previously Untreated Patients with LA/mUC Who Are Cisplatin-Ineligible EV-103 The safety of PADCEV was evaluated in combination with intravenous pembrolizumab in a multi cohort trial (EV-103) in 121 patients with la/mUC who were not eligible for cisplatin-containing chemotherapy and received at least one dose of PADCEV 1.25 mg/kg and pembrolizumab.
The median duration of exposure to PADCEV was 7 months (range: 0.6 to 33 months). Fatal adverse reactions occurred in 5% of patients treated with %. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (20%) and rash (6%).
Table in Combination with Intravenous Pembrolizumab in EV- Clinically relevant adverse reactions (<20%) include vomiting (20%), pyrexia (18%), hypothyroidism (11%), pneumonitis/ILD (10%), skin hyperpigmentation (8%), myasthenia gravis in Combination with Intravenous Pembrolizumab in EV- mg/kg and who were previously treated with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. Routine ophthalmologic exams were not conducted in EV-301. The median duration of exposure to PADCEV was 5 months (range: 0.5 to 19 months).
The most common serious adverse reactions (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each). Table 14.
Selected Laboratory Abnormalities Reported in ≥15% (Grades 2-4) or ≥5% (Grade 3-4) of Patients Treated with with la/mUC who had received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, sepsis, and pneumonitis/ILD (each 0.8%). Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%).
Table 15 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 1. Table 15. Table 16.
Selected Laboratory Abnormalities Reported in ≥15% (Grades 2-4) or ≥5% (Grade 3-4) of Patients Treated with mg/kg and had prior treatment with a PD-1 or PD-L1 inhibitor and were not eligible for cisplatin-based chemotherapy. The median duration of exposure was 5.98 months (range: 0.3 to 24.6 months). The most common serious adverse reactions (≥3%) were pneumonia, sepsis, and diarrhea (5% each).
Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common adverse reaction (≥2%) leading to discontinuation was peripheral neuropathy (7%). Table 17 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2.
Table 17. Table 18. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and subcutaneous tissue disorders: Epidermal necrosis, SJS, and TEN.
| Adverse Reaction | Perioperative PADCEV in combination with intravenous pembrolizumab n=403 | Neoadjuvant Gemcitabine with Cisplatin n=396 | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v5.0. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Skin and subcutaneous tissue disorders | ||||
| Rash Includes multiple terms. | 63 | 12 | 9 | 0.3 |
| Pruritus | 46 | 3.2 | 4.5 | 0 |
| Alopecia | 32 | 0.5 | 11 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 48 | 2.7 | 49 | 2.3 |
| Nervous system disorders | ||||
| Peripheral neuropathy | 43 | 3 | 11 | 0.8 |
| Dysgeusia | 28 | 0.2 | 10 | 0 |
| Gastrointestinal disorders | ||||
| Diarrhea | 36 | 3.2 | 16 | 1.3 |
| Nausea | 28 | 1 | 47 | 0.5 |
| Constipation | 27 | 0.7 | 37 | 0.5 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 29 | 1 | 18 | 0.5 |
| Hyperglycemia | 20 | 7 | 7 | 0.8 |
| Infections and Infestations | ||||
| Urinary tract infection | 25 | 10 | 21 | 10 |
| Eye disorders | ||||
| Dry eye | 25 | 0 | 1.3 | 0 |
| Investigations | ||||
| Decreased weight | 22 | 2.5 | 6 | 0.3 |
| Laboratory Abnormality The denominator used to calculate the rate of PADCEV in combination with intravenous pembrolizumab varied from 399 to 403 and the denominator used to calculate the rate for chemotherapy varied from 388 to 393 based on the number of patients with a baseline value and at least one post-treatment value. | Perioperative PADCEV in combination with intravenous pembrolizumab | Neoadjuvant Gemcitabine with Cisplatin | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v5.0. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Hematology | ||||
| Decreased hemoglobin | 70 | 8 | 92 | 20 |
| Decreased lymphocytes | 52 | 17 | 46 | 11 |
| Decreased neutrophils | 32 | 13 | 75 | 40 |
| Chemistry | ||||
| Increased aspartate aminotransferase | 69 | 7 | 23 | 0.5 |
| Increased alanine aminotransferase | 67 | 8 | 30 | 0 |
| Increased creatinine | 49 | 8 | 53 | 6 |
| Decreased sodium | 43 | 4.2 | 39 | 1.3 |
| Decreased albumin | 42 | 3.3 | 36 | 1.8 |
| Increased potassium | 35 | 4.7 | 31 | 5 |
| Decreased potassium | 22 | 3 | 20 | 2.8 |
| Adverse Reaction | Perioperative PADCEV in combination with intravenous pembrolizumab n=167 | RC with PLND alone n=159 | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Skin and subcutaneous tissue disorders | ||||
| Rash Includes multiple terms. | 54 | 7 | 1.3 | 0 |
| Pruritus | 47 | 3 | 0 | 0 |
| Alopecia | 35 | 0.6 | 0 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 47 | 4.2 | 6 | 0.6 |
| Nervous system disorders | ||||
| Peripheral neuropathy | 39 | 3 | 1.9 | 0 |
| Dysgeusia | 35 | 0 | 0 | 0 |
| Gastrointestinal disorders | ||||
| Diarrhea | 34 | 5 | 3.1 | 1.3 |
| Constipation | 28 | 1.8 | 8 | 0 |
| Nausea | 26 | 1.2 | 8 | 0.6 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 28 | 0.6 | 1.9 | 0 |
| Infections and infestations | ||||
| Urinary tract infection | 24 | 12 | 13 | 11 |
| Eye disorders | ||||
| Dry eye | 21 | 0 | 0 | 0 |
| Investigations | ||||
| Decreased weight | 20 | 0 | 3.1 | 0 |
| Laboratory Abnormality The denominator used to calculate the rate of PADCEV in combination with intravenous pembrolizumab was 167 and the denominator used to calculate the rate for RC and PLND alone varied from 110 to 121 based on the number of patients with a baseline value and at least one post-treatment value. | Perioperative PADCEV in combination with intravenous pembrolizumab | RC with PLND alone | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Chemistry | ||||
| Increased glucose | 72 | 12 | 24 | 1.7 |
| Increased aspartate aminotransferase | 55 | 6 | 11 | 1.8 |
| Increased alanine aminotransferase | 53 | 4.8 | 13 | 0.9 |
| Increased creatinine | 47 | 8 | 31 | 2.5 |
| Decreased sodium | 44 | 13 | 18 | 7 |
| Increased potassium | 39 | 7 | 20 | 6 |
| Decreased phosphate | 26 | 6 | 1.8 | 0 |
| Hematology | ||||
| Decreased hemoglobin | 60 | 13 | 48 | 8 |
| Decreased lymphocytes | 40 | 8 | 17 | 1.7 |
| Adverse Reaction | PADCEV in combination with intravenous pembrolizumab n=440 | Chemotherapy n=433 | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Skin and subcutaneous tissue disorders | ||||
| Rash Includes multiple terms. | 68 | 15 | 15 | 0 |
| Pruritus | 41 | 1.1 | 7 | 0 |
| Alopecia | 35 | 0.5 | 8 | 0.2 |
| Dry skin | 17 | 0.2 | 1 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 51 | 6 | 57 | 7 |
| Pyrexia | 18 | 0.7 | 16 | 1.2 |
| Nervous system disorders | ||||
| Peripheral neuropathy | 67 | 8 | 14 | 0 |
| Dysgeusia | 21 | 0 | 9 | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 33 | 1.8 | 26 | 1.8 |
| Gastrointestinal disorders | ||||
| Diarrhea | 38 | 4.5 | 16 | 1.4 |
| Nausea | 26 | 1.6 | 41 | 2.8 |
| Constipation | 26 | 0 | 34 | 0.7 |
| Investigations | ||||
| Decreased weight | 33 | 3.6 | 9 | 0.2 |
| Eye disorders | ||||
| Dry eye | 24 | 0 | 2.1 | 0 |
| Infections and infestations | ||||
| Urinary tract infection | 21 | 5 | 19 | 8 |
| Laboratory Abnormality The denominator used to calculate the rate varied from 407 to 439 based on the number of patients with a baseline value and at least one post-treatment value. | PADCEV in combination with intravenous pembrolizumab | Chemotherapy | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Chemistry | ||||
| Increased aspartate aminotransferase | 75 | 5 | 39 | 3 |
| Increased creatinine | 71 | 3 | 68 | 3 |
| Increased glucose | 66 | 14 | 54 | 5 |
| Increased alanine aminotransferase | 59 | 5 | 49 | 3 |
| Decreased sodium | 46 | 13 | 47 | 13 |
| Decreased phosphate | 44 | 9 | 36 | 9 |
| Decreased albumin | 39 | 2 | 35 | 0.5 |
| Decreased potassium | 26 | 5 | 16 | 3 |
| Increased potassium | 24 | 1 | 36 | 4 |
| Increased calcium | 21 | 1 | 14 | 0.2 |
| Hematology | ||||
| Decreased lymphocytes | 58 | 15 | 59 | 17 |
| Decreased hemoglobin | 53 | 7 | 89 | 33 |
| Decreased neutrophils | 30 | 9 | 80 | 50 |
| Adverse Reaction | PADCEV in combination with intravenous pembrolizumab n=121 | |
|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | |
| Skin and subcutaneous tissue disorders | ||
| Rash Includes multiple terms. | 71 | 21 |
| Alopecia | 52 | 0 |
| Pruritus | 40 | 3.3 |
| Dry skin | 21 | 0.8 |
| Nervous system disorders | ||
| Peripheral neuropathy | 65 | 3.3 |
| Dysgeusia | 35 | 0 |
| Dizziness | 23 | 0 |
| General disorders and administration site conditions | ||
| Fatigue | 60 | 11 |
| Peripheral edema | 26 | 0 |
| Investigations | ||
| Decreased weight | 48 | 5 |
| Gastrointestinal disorders | ||
| Diarrhea | 45 | 7 |
| Nausea | 36 | 0.8 |
| Constipation | 27 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 38 | 0.8 |
| Infections and infestations | ||
| Urinary tract infection | 30 | 12 |
| Eye disorders | ||
| Dry eye | 25 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 23 | 1.7 |
| Laboratory Abnormality The denominator used to calculate the rate varied from 114 to 121 based on the number of patients with a baseline value and at least one post-treatment value. | PADCEV in combination with intravenous pembrolizumab | |
|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | |
| Chemistry | ||
| Increased glucose | 74 | 13 |
| Increased aspartate aminotransferase | 73 | 9 |
| Increased creatinine | 69 | 3.3 |
| Decreased sodium | 60 | 19 |
| Increased alanine aminotransferase | 60 | 7 |
| Increased lipase | 59 | 32 |
| Decreased albumin | 59 | 4.2 |
| Decreased phosphate | 51 | 15 |
| Decreased potassium | 35 | 8 |
| Increased potassium | 27 | 1.7 |
| Increased calcium | 27 | 4.2 |
| Hematology | ||
| Decreased hemoglobin | 69 | 15 |
| Decreased lymphocytes | 64 | 17 |
| Decreased neutrophils | 32 | 12 |
| Adverse Reaction | PADCEV n=296 | Chemotherapy n=291 | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Skin and subcutaneous tissue disorders | ||||
| Rash Includes multiple terms. | 54 | 14 | 20 | 0.3 |
| Alopecia | 47 | 0 | 38 | 0 |
| Pruritus | 34 | 2 | 7 | 0 |
| Dry skin | 17 | 0 | 4 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 50 | 9 | 40 | 7 |
| Pyrexia | 22 | 2 | 14 | 0 |
| Nervous system disorders | ||||
| Peripheral neuropathy | 50 | 5 | 34 | 3 |
| Dysgeusia | 26 | 0 | 8 | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 41 | 5 | 27 | 2 |
| Gastrointestinal disorders | ||||
| Diarrhea | 35 | 4 | 23 | 2 |
| Nausea | 30 | 1 | 25 | 2 |
| Constipation | 28 | 1 | 25 | 2 |
| Abdominal Pain | 20 | 1 | 14 | 3 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal Pain | 25 | 2 | 35 | 5 |
| Eye Disorders | ||||
| Dry eye | 24 | 0.7 | 6 | 0.3 |
| Infections and infestations | ||||
| Urinary Tract Infection | 17 | 6 | 13 | 3 |
| Vascular disorders | ||||
| Hemorrhage | 17 | 3 | 13 | 2 |
| Investigations | ||||
| Decreased weight | 16 | 0.3 | 7 | 0 |
| Laboratory Abnormality The denominator used to calculate the rate varied from 262 to 287 based on the number of patients with a baseline value and at least one post-treatment value. | PADCEV | Chemotherapy | ||
|---|---|---|---|---|
| Grades 2-4 Graded per NCI CTCAE v4.03. % | Grade 3-4 % | Grades 2-4 % | Grade 3-4 % | |
| Hematology | ||||
| Decreased lymphocytes | 41 | 14 | 34 | 18 |
| Decreased hemoglobin | 28 | 4 | 42 | 14 |
| Decreased neutrophils | 27 | 12 | 25 | 17 |
| Chemistry | ||||
| Decreased phosphate | 39 | 8 | 24 | 6 |
| Increased glucose (non‑fasting) | 33 | 9 | 27 | 6 |
| Increased creatinine | 18 | 2 | 13 | 0 |
| Decreased potassium | 16 | 2 | 7 | 3 |
| Increased lipase | 13 | 8 | 7 | 4 |
| Decreased sodium | 8 | 8 | 5 | 5 |
| Adverse Reaction | PADCEV n=125 | |
|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. % | Grade 3-4 % | |
| General disorders and administration site conditions | ||
| Fatigue Includes multiple terms. | 56 | 6 |
| Nervous system disorders | ||
| Peripheral neuropathy | 56 | 4 |
| Dysgeusia | 42 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 52 | 2 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 52 | 13 |
| Alopecia | 50 | 0 |
| Dry skin | 26 | 0 |
| Pruritus | 26 | 2 |
| Gastrointestinal disorders | ||
| Nausea | 45 | 3 |
| Diarrhea | 42 | 6 |
| Vomiting | 18 | 2 |
| Eye disorders | ||
| Dry eye | 40 | 0 |
| Laboratory Abnormality Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available for 121 or 122 patients. | PADCEV | |
|---|---|---|
| Grades 2-4 Graded per NCI CTCAE v4.03. % | Grade 3-4 % | |
| Hematology | ||
| Decreased hemoglobin | 34 | 10 |
| Decreased lymphocytes | 32 | 10 |
| Decreased neutrophils | 14 | 5 |
| Chemistry | ||
| Decreased phosphate | 34 | 10 |
| Increased glucose (non-fasting) | 27 | 8 |
| Increased creatinine | 20 | 2 |
| Decreased potassium | 19 Includes Grade 1 (potassium 3.0-3.5 mmol/L) – Grade 4. | 1 |
| Increased lipase | 14 | 9 |
| Decreased sodium | 8 | 8 |
| Increased urate | 7 | 7 |
| Adverse Reaction | PADCEV n=89 | |
|---|---|---|
| All Grades Graded per NCI CTCAE v4.03. (%) | Grades 3-4 (%) | |
| Skin and subcutaneous tissue disorders | ||
| Rash Includes multiple terms. | 66 | 17 |
| Alopecia | 53 | 0 |
| Pruritus | 35 | 3 |
| Dry skin | 19 | 1 |
| Nervous system disorders | ||
| Peripheral neuropathy | 58 | 8 |
| Dysgeusia | 29 | 0 |
| General disorders and administration site conditions | ||
| Fatigue | 48 | 11 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 40 | 6 |
| Hyperglycemia | 16 | 9 |
| Gastrointestinal disorders | ||
| Diarrhea | 36 | 8 |
| Nausea | 30 | 1 |
| Investigations | ||
| Decreased weight | 35 | 1 |
| Eye disorders | ||
| Dry eye | 30 | 0 |
| Laboratory Abnormality Based on the number of patients with a baseline value and at least one post-treatment value. | PADCEV n=88 | |
|---|---|---|
| Grades 2-4 Graded per NCI CTCAE v4.03. % | Grade 3-4 % | |
| Hematology | ||
| Decreased lymphocytes | 43 | 15 |
| Decreased hemoglobin | 34 | 5 |
| Decreased neutrophils | 20 | 9 |
| Chemistry | ||
| Increased glucose (non-fasting) | 36 | 13 |
| Decreased phosphate | 25 | 7 |
| Increased creatinine | 23 | 3 |
| Increased lipase | 18 | 11 |
| Increased urate | 9 | 9 |
| Increased potassium | 8 | 6 |
| Decreased sodium | 7 | 7 |
Warnings & Cautions for Padcev
Skin Reactions
Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 65% (all grades) of the 570 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC in clinical trials.
The majority of the skin reactions that occurred with combination therapy included rash and maculo-papular rash. A fatal reaction of TEN occurred in one patient (0.2%). The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 24 months).
Skin reactions led to discontinuation of PADCEV in 8% of patients. Of the patients who experienced a skin reaction and had data regarding resolution (n=367), 87% had complete resolution and 13% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 31% (15/49) had Grade ≥2 skin reactions.
Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of la/mUC in clinical trials. When PADCEV was given in combination with intravenous pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months).
Of the patients who experienced a skin reaction and had data regarding resolution (n=391), 59% had complete resolution and 41% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 27% (43/159) had Grade ≥2 skin reactions. Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials.
Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions.
Of the patients who experienced a skin reaction and had data regarding resolution (n=328), 58% had complete resolution and 42% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 39% (53/137) had Grade ≥2 skin reactions. Monitor patients closely throughout treatment for skin reactions.
Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions.
Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
Hyperglycemia Hyperglycemia and diabetic ketoacidosis
(DKA), including fatal events, occurred in patients with and without pre‑existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. Fatal events of hyperglycemia and diabetic ketoacidosis occurred in one patient each (0.1%).
The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients.
Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin by the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia.
If blood glucose is elevated (>250 mg/dL), withhold PADCEV.
Pneumonitis/Interstitial Lung Disease (ILD)
Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. The median time to onset of any grade pneumonitis/ILD was 3.2 months (range: 0.7 to 13 months). A fatal event of pneumonitis/ILD occurred in two patients (0.4%).
The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months). The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months). Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams.
Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Of the patients with residual neuropathy at last evaluation, 30% (42/142) had Grade ≥2 neuropathy.
Of the patients with residual neuropathy at last evaluation, 45% (146/326) had Grade ≥2 neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. Peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy.
Neuropathy led to treatment discontinuation in 6% of patients. Of the patients who experienced neuropathy who had data regarding resolution (n=296), 11% had complete resolution, and 89% had residual neuropathy at the time of their last evaluation. Of the patients with residual neuropathy at last evaluation, 50% (132/262) had Grade ≥2 neuropathy.
Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 peripheral neuropathy.
Ocular Disorders
Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV.
The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve.
Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.
Infusion Site Extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak.
Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of enfortumab vedotin-ejfv to pregnant rats during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures similar to the clinical exposures at the recommended human dose of 1.25 mg/kg. Advise patients of the potential risk to the fetus.
Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose.
Drug Interactions with Padcev
Effects of Other Drugs on PADCEV Dual P-gp and Strong CYP3A4 Inhibitors Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated MMAE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.
Pregnancy Safety for Padcev
Pregnancy Risk Summary Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman. There are no available human data on PADCEV use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of enfortumab vedotin-ejfv to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations, and skeletal anomalies at maternal exposures similar to the exposures at the recommended human dose of 1.25 mg/kg (see Data ).
Advise patients of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data Animal Data In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg (approximately 3 times the exposure at the recommended human dose). A dose of 2 mg/kg (similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-fetal 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 fetal weight were observed.
Pediatric Use of Padcev
Pediatric Use Safety and effectiveness of PADCEV in pediatric patients have not been established.
Clinical Studies of Padcev
Urothelial Cancer Neoadjuvant and Adjuvant Treatment of Patients with MIBC Who Are Cisplatin-Eligible EV-304 The efficacy of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment and then continued after radical cystectomy (RC) as adjuvant treatment was evaluated in EV-304 (NCT04700124), an open-label, randomized, active-controlled, multicenter trial that enrolled patients with previously untreated MIBC with predominant urothelial carcinoma histology and who were candidates for RC with pelvic lymph node dissection (PLND) and were eligible for cisplatin-based chemotherapy. The study excluded patients with primary non-bladder (i.e., ureter, urethral, or renal pelvis) cancer of the urothelium and those with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression. Randomization was stratified by tumor stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), PD-L1 combined positive score (CPS ≥10 vs CPS <10), and geographic region (United States vs European Union vs Rest of World).
Treatment continued until completion of the treatment, disease progression, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase, or unacceptable toxicity. Assessment of tumor status, including CT/MRI, was performed at baseline, within 5 weeks prior to RC and PLND, and at 6 weeks post-radical cystectomy. Following RC and PLND, assessment of tumor status, including cystoscopy and urine cytology for patients who did not undergo surgery, was performed every 12 weeks up to 2 years, and every 24 weeks thereafter.
Patients had a baseline ECOG performance status of Nineteen percent were T2N0, 73% T3/T4aN0, and 8% T1-T4aN1. Eighty-nine percent of patients had pure urothelial carcinoma histology; 4.8% had urothelial carcinoma with squamous differentiation, 2.6% had urothelial carcinoma with glandular differentiation, and 3.1% had urothelial carcinoma with other variant histology. A total of 25 (6%) of patients in the chemotherapy arm received adjuvant nivolumab.
The trial was not designed to isolate the effect of PADCEV in combination with intravenous pembrolizumab in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measure was event-free survival (EFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and pathological complete response (pCR) rate as assessed by blinded independent pathology review (BIPR) were additional efficacy outcome measures.
The trial demonstrated statistically significant improvements in EFS and OS in patients treated with neoadjuvant and adjuvant PADCEV in combination with intravenous pembrolizumab compared with neoadjuvant chemotherapy. Table 20 and Figures 2-3 summarize the efficacy results for EV-304. Table 20.
Efficacy Results in EV-304 Figure 2. Kaplan-Meier Plot of Event-Free Survival, EV-304 Figure 3. Kaplan-Meier Plot of Overall Survival, EV-304 The trial demonstrated a statistically significant difference in pCR rate (55.8% vs. 32.5%; p<0.0001).
Neoadjuvant and Adjuvant Treatment of Patients with MIBC Who Are Cisplatin-Ineligible EV-303 The efficacy of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment and then continued after RC as adjuvant treatment was evaluated in EV-303 (NCT03924895), an open-label, randomized, multicenter trial that enrolled patients with previously untreated MIBC with predominant urothelial carcinoma histology and who were candidates for RC with PLND but were ineligible for or refused cisplatin-based chemotherapy. Randomization was stratified by tumor stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), cisplatin-eligibility (cisplatin-ineligible vs cisplatin-eligible but declined), and geographic region (United States vs European Union vs Rest of World). Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of Eighteen percent were T2N0, 77% T3/T4aN0, and 4.9% T1-T4aN1.
A total of 29 (17%) of patients in the RC and PLND alone arm received adjuvant nivolumab. Table 21 and Figures 4-5 summarize the efficacy results for EV-303. Table 21.
Efficacy Results in EV-303 Figure 4. Kaplan-Meier Plot of Event-Free Survival, EV-303 Figure 5. Kaplan-Meier Plot of Overall Survival, EV-303 The trial demonstrated a statistically significant difference in pCR rate (57.1% vs. 8.6%; p<0.0001).
Previously Untreated LA/mUC EV-302 The efficacy of PADCEV in combination with intravenous pembrolizumab was evaluated in EV-302 (NCT04223856), an open label, randomized, multicenter trial that enrolled 886 patients with la/mUC who received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded. Treatment was continued until disease progression or unacceptable toxicity.
Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases. Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. Eighty-five percent of patients had urothelial carcinoma (UC) histology including 6% with UC mixed squamous differentiation and 2% with UC mixed other histologic variants.
Forty-six percent of patients were considered cisplatin-ineligible and 54% were considered cisplatin-eligible at time of randomization. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures included objective response rate (ORR) as assessed by BICR.
The trial demonstrated statistically significant improvements in OS, PFS, and ORR for patients randomized to PADCEV in combination with intravenous pembrolizumab as compared to platinum-based chemotherapy. Efficacy results were consistent across all stratified patient subgroups. Table 22 and Figures 6-7 summarize the efficacy results for EV-302.
Table 22. Efficacy Results in EV-302, EV-302 Patients with Previously Untreated LA/mUC Who Are Cisplatin-Ineligible EV-103 The efficacy of PADCEV in combination with intravenous pembrolizumab was evaluated in EV-103 (NCT03288545), an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) trial in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received PADCEV 1.25 mg/kg as an IV infusion on Days 1 and 8 of a 21-day cycle followed by intravenous pembrolizumab 200 mg on Day 1 of a 21-day cycle.
Patients were treated until disease progression or unacceptable toxicity. A total of 121 patients received PADCEV in combination with intravenous pembrolizumab. Ten percent of patients were Hispanic or Latino.
Forty-five percent of patients had an ECOG performance status of 1 and 15% had an ECOG performance status of 2. At baseline, 97.5% of patients had metastatic urothelial cancer and 2.5% of patients had locally advanced urothelial cancer. Thirty-seven percent of patients had upper tract disease.
Eighty-four percent of patients had visceral metastasis at baseline including 22% with liver metastases. Thirty-nine percent of patients had transitional cell carcinoma (TCC) histology; 13% had TCC with squamous differentiation and 48% had TCC with other histologic variants. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1.
Efficacy results are presented in Table 23 below. Table 23. Efficacy Results in EV-103, Combined Dose Escalation Cohort, Cohort A, and Cohort K The median duration of response for the dose escalation cohort + Cohort A was 22.1 months (range: 1.0+ to 46.3+ months) and for Cohort K was not reached (range: 1.2 to 24.1+ months).
Previously Treated LA/mUC EV-301 The efficacy of PADCEV as a single agent was evaluated in EV-301 (NCT03474107), an open-label, randomized, multicenter trial that enrolled 608 patients with la/mUC who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Randomization was stratified by ECOG PS (0 vs 1), region of world (Western Europe vs US vs Rest of World), and presence of liver metastasis. Nine percent of patients were Hispanic or Latino.
All patients had a baseline ECOG performance status of Thirty‑four percent of patients had tumors located in the upper tract that included the renal pelvis and ureter. Seventy-six percent of patients had pure TCC histology; 14% had TCC with other histologic variants; and 10% had other tumor histologies including adenocarcinoma and squamous cell carcinoma. The median number of prior therapies was 2 (range 1 to ≥3).
Sixty‑three percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 11% received both cisplatin and carboplatin-based regimens. Patients on the control arm received docetaxel (38%), paclitaxel (36%), or vinflunine (25%). The major efficacy outcome measures were OS, PFS, and ORR assessed by investigator using RECIST v1.1.
Table 24 and Figures 8-9 summarize the efficacy results for EV-301. Table 24. Efficacy Results in EV-301, EV-301 EV-201, Cohort 1 The efficacy of PADCEV as a single agent was also investigated in Cohort 1 of EV-201 (NCT03219333), a single-arm, multi-cohort, multicenter trial that enrolled 125 patients with la/mUC who received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy.
Four percent of patients were Hispanic or Latino. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of Ninety percent of patients had visceral metastases including 40% with liver metastases. Approximately two-thirds (67%) of patients had pure transitional cell carcinoma (TCC) histology; 33% had TCC with other histologic variants.
Sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 8% received both cisplatin and carboplatin‑based regimens. The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) assessed by BICR using RECIST v1.1. Efficacy results are presented in Table 25.
Table 25. Efficacy Results in EV-201, Cohort 1 (BICR Assessment) Previously Treated Patients with LA/mUC Who Are Cisplatin-Ineligible EV-201, Cohort 2 The efficacy of PADCEV as a single agent was also evaluated in Cohort 2 of EV-201, a single-arm, multi-cohort, multicenter trial in 89 patients with la/mUC who received prior treatment with a PD-1 or PD-L1 inhibitor and were cisplatin-ineligible and did not receive platinum in the locally advanced or metastatic setting. Racial demographics were reported as White (70%), Asian (22%), or not reported (8%).
One percent of patients were Hispanic or Latino. Seventy-nine percent of patients had visceral metastases and 24% had liver metastases. Seventy percent of patients had TCC histology; 13% had TCC with squamous differentiation and 17% had TCC with other histologic variants.
The median number of prior systemic therapies was 1 (range: 1 to 4). Efficacy results are presented in Table 26 below. Table 26.
| NR = Not Reached. | ||
| Endpoint | Perioperative PADCEV with intravenous pembrolizumab n=405 | Neoadjuvant Gemcitabine with Cisplatin n=403 |
| Event-Free Survival EFS is defined as time from randomization to the first of: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery, or death. | ||
| Number (%) of patients with events | 87 (21) | 146 (36) |
| Median in months Based on Kaplan-Meier estimates. (95% CI) | NR (NR, NR) | 48.5 (43.3, NR) |
| Hazard ratio Based on stratified Cox regression model. (95% CI) | 0.53 (0.41, 0.70) | |
| p-value One-sided p-value based on stratified log-rank test. | <0.0001 | |
| Overall Survival | ||
| Number (%) of patients with events | 69 (17) | 99 (25) |
| Median in months (95% CI) | NR (NR, NR) | NR (NR, NR) |
| Hazard ratio (95% CI) | 0.65 (0.48, 0.89) | |
| p-value | 0.0029 | |
| NR = Not Reached. | ||
| Endpoint | Perioperative PADCEV with intravenous pembrolizumab n=170 | RC with PLND alone n=174 |
| Event-Free Survival EFS is defined as time from randomization to the first of: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery, or death. | ||
| Number (%) of patients with events | 48 (28) | 95 (55) |
| Median in months Based on Kaplan-Meier estimates. (95% CI) | NR (37.3, NR) | 15.7 (10.3, 20.5) |
| Hazard ratio Based on stratified Cox regression model. (95% CI) | 0.40 (0.28, 0.57) | |
| p-value Based on stratified log-rank test. | <0.0001 | |
| Overall Survival | ||
| Number (%) of patients with events | 38 (22) | 68 (39) |
| Median in months (95% CI) | NR (NR, NR) | 41.7 (31.8, NR) |
| Hazard ratio (95% CI) | 0.50 (0.33, 0.74) | |
| p-value | 0.0002 | |
| Endpoint | PADCEV with intravenous pembrolizumab n=442 | Cisplatin or carboplatin with gemcitabine n=444 |
|---|---|---|
| NE = Not Estimable. | ||
| Overall Survival | ||
| Number (%) of patients with events | 133 (30.1) | 226 (50.9) |
| Median in months (95% CI) | 31.5 (25.4, NE) | 16.1 (13.9, 18.3) |
| Hazard ratio (95% CI) Based on a stratified Cox proportional hazards model. | 0.47 (0.38, 0.58) | |
| p-value Based on stratified log-rank test., Two-sided p-value. | <0.0001 | |
| Progression-Free Survival | ||
| Number (%) of patients with events | 223 (50.5) | 307 (69.1) |
| Median in months (95% CI) | 12.5 (10.4, 16.6) | 6.3 (6.2, 6.5) |
| Hazard ratio (95% CI) | 0.45 (0.38, 0.54) | |
| p-value, | <0.0001 | |
| Confirmed Objective Response Rate Includes only patients with measurable disease at baseline (n=437 for PADCEV in combination with intravenous pembrolizumab, n=441 for chemotherapy). | ||
| ORR (%) (95% CI) | 67.7 (63.1, 72.1) | 44.4 (39.7, 49.2) |
| p-value, Cochran-Mantel-Haenszel test (CMH) controlling for stratification factors. | <0.0001 | |
| Complete response rate (%) | 29.1 | 12.5 |
| Partial response rate (%) | 38.7 | 32.0 |
| Endpoint | PADCEV in combination with intravenous pembrolizumab n=121 |
|---|---|
| Confirmed ORR (95% CI) | 68% (58.7, 76.0) |
| Complete response rate | 12% |
| Partial response rate | 55% |
| Endpoint | PADCEV n=301 | Chemotherapy n=307 |
|---|---|---|
| Overall Survival Based on log-rank test. Stratification factors were ECOG PS, region and liver metastasis. | ||
| 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) | 0.70 (0.56, 0.89) | |
| p-value | 0.0014 | |
| Progression-Free Survival | ||
| 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) | 0.62 (0.51, 0.75) | |
| p-value | <0.0001 | |
| Overall Response Rate (CR + PR) Based on Cochran-Mantel-Haenszel test. Stratification factors were ECOG PS, region and liver metastasis. | ||
| ORR (%) (95% CI) | 40.6 (34.9, 46.5) | 17.9 (13.7, 22.8) |
| p-value | <0.0001 | |
| Complete response rate (%) | 4.9 | 2.7 |
| Partial response rate (%) | 35.8 | 15.2 |
| Endpoint | PADCEV n=125 |
|---|---|
| NE = Not Estimable. | |
| Confirmed ORR (95% CI) | 44% (35.1, 53.2) |
| Complete Response Rate (CR) | 12% |
| Partial Response Rate (PR) | 32% |
| Median Based on patients (n=55) with a response by BICR. Duration of Response, months (95% CI) | 7.6 (6.3, NE) |
| NE = Not Estimable. | |
| Endpoint | PADCEV n=89 |
| Confirmed ORR (95% CI) | 51% (39.8, 61.3) |
| Complete Response Rate (CR) | 22% |
| Partial Response Rate (PR) | 28% |
| Median Based on patients (n=45) with a response by BICR. Duration of Response, months (95% CI) | 13.8 (6.4, NE) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
Ready to save on Padcev?
Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.
Compare Padcev Prices