PADCEV® (enfortumab vedotin-ejfv) Efficacy in Patients With la/mUC

CISPLATIN-INELIGIBLE, POST–PD-(L)1 EFFICACY

Set a course for response

Efficacy

Trial Design

Patient Characteristics

In the EV-201 trial (Cohort 2) of 89 cisplatin-ineligible adult patients with locally advanced or metastatic urothelial cancer (la/mUC) who had previously received a PD-(L)1 inhibitor, PADCEV® delivered a 51% ORR (95% CI: 39.8%, 61.3%), including a 22% CR and a 28% PR, with a median* DOR of 13.8 months (95% CI: 6.4, NE)^1,2

*Median DOR based on patients (n=45) with a response by BICR.¹

EFFICACY

In the EV-201 trial (Cohort 2), PADCEV achieved a clinically meaningful response in cisplatin-ineligible patients^1-4

Major efficacy outcome measure: confirmed objective response rate (ORR) by BICR^1,2

The objective response rate for PADCEV was 51%, complete response = 22%, partial response = 28%.

^†ORR consisted of confirmed CR or PR per RECIST v1.1 as evaluated by BICR.²

^‡CR was defined as the disappearance of all target and nontarget lesions. PR was defined as a ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.⁴

In the EV-201 trial (Cohort 2), PADCEV delivered a median duration of response (DOR) of almost 14 months^1,2

Major efficacy outcome measure was DOR^§ll

PADCEV delivered a median duration of response of almost 14 months.

^§Kaplan-Meier estimate of duration of response, defined as the time from first response to date of progression or death due to any cause, was assessed by BICR.^2,5

^||Based on patients (n=45) with a response by BICR.¹

Exploratory data: change in target lesions of evaluable patients (n=77) in the EV-201 trial (Cohort 2)^3¶

Additional information: change in target lesions of evaluable patients (n=77)^3¶

In the EV-201 trial (Cohort 2), the major efficacy outcome measures were confirmed ORR and DOR. The confirmed ORR was 51% (n=45/89; 95% CI: 39.8%, 61.3%), with 22% CR (n=20/89) and 28% PR (n=25/89). The median DOR was 13.8 months^1,3

Chart showing the change in individual patient tumor measurement per BICR.

^¶Data are not available for 12 subjects due to no response assessment postbaseline (n=5), incomplete assessment of target lesions postbaseline (n=1), or no measurable disease at baseline per BICR (n=6).³

^#Maximum percent reduction from baseline in target lesion sum of diameter per BICR in subjects who had measurable disease at baseline and at least one evaluable response assessment postbaseline.^3,4,6

**ORR consisted of confirmed CR or PR per RECIST v1.1 as evaluated by BICR. CR was defined as the disappearance of all target and nontarget lesions. PR was defined as a ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.^4,6

^††Per RECIST v1.1, stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.⁶

^‡‡Per RECIST v1.1, progressive disease was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.)⁶

^§§Patients evaluable for target-lesion response (n=77/89) were required to have measurable disease at baseline per BICR and adequate postbaseline assessment for target lesions.^3,4

In the EV-201 trial (Cohort 2), ORR across prespecified subgroups was an exploratory analysis²

Additional information: exploratory analysis²

Exploratory Analysis: ORR across prespecified subgroups. The study was not designed to achieve a specific sample size for these subgroups, and the findings from the subgroup analyses could be due to small sample size.

Objective response rate in the ECOG PS 1‐2 exploratory subgroup in the EV‐201 trial (Cohort 2) was 42%.

Objective response rate in the exploratory subgroup non‐responders to PD‐(L)1 inhibitor therapy in the EV‐201 trial (Cohort 2) was 48%.

Objective response rate in the liver metastases exploratory subgroup in the EV‐201 trial (Cohort 2) was 48%.

Objective response rate in the age ≥ 75 years exploratory subgroup in the EV‐201 trial (Cohort 2) was 46%.

TRIAL DESIGN

The EV-201 trial evaluated PADCEV in cisplatin-ineligible patients (Cohort 2)¹

The EV-201 trial (Cohort 2) was a single-arm, open-label, multicenter, phase 2 trial of 89 patients and included those with ECOG PS 0-2^1,2

Key inclusion and exclusion criteria for patient enrollment in the EV⁠-⁠201 trial (Cohort 2)^1,6

Key inclusion criteria

Urothelial cancer: bladder, renal pelvis, ureter, or urethra
Prior treatment with a PD-(L)1 inhibitor in the locally advanced or metastatic setting
ECOG PS of 0, 1, or 2
Cisplatin ineligible

Key exclusion criteria

Prior platinum chemotherapy in the locally advanced or metastatic setting
Ongoing sensory or motor neuropathy Grade ≥2
Uncontrolled diabetes^¶¶
Active central nervous system metastases

PATIENT CHARACTERISTICS

All patients in Cohort 2 of the EV-201 trial were cisplatin ineligible¹

Patients who had poor prognostic factors were included in the EV-201 trial (Cohort 2)¹

Baseline patient characteristics in the EV-201 trial (cohort 2).

Baseline patient characteristics in Cohort 2 of the EV-201 trial.

Reasons for cisplatin ineligibility included: 66% with baseline creatinine clearance of 30⁠-⁠59 mL/min, 7% with ECOG PS of 2, 15% with Grade ≥2 hearing loss, and 12% with more than one cisplatin-ineligibility criteria¹

Median age, years (range)

75 (49, 90)

Sex, n (%)

Male

66 (74)

Female

23 (26)

ECOG PS, n (%)

37 (42)

41 (46)

11 (12)

Renal function based on creatinine clearance, n (%)

Normal: ≥90 mL/min

5 (6)

Mild decrease: ≥60 mL/min and <90 mL/min

22 (25)

Moderate decrease: ≥30 mL/min and <60 mL/min

60 (67)

Severe decrease: ≥15 mL/min and <30 mL/min

2 (2)

Primary tumor location, n (%)

Upper tract^##

38 (43)

Bladder/other

51 (57)

Metastasis site, n (%)

Lymph node only

18 (20)

Visceral***

70 (79)

Liver

21 (24)

Preexisting peripheral neuropathy, n (%)

15 (17)

Cisplatin-ineligible,
Post–PD-(L)1 Safety

BICR=blinded independent central review; CI=confidence interval; CR=complete response; ECOG PS=Eastern Cooperative Oncology Group performance status; IV=intravenous; NE=not estimable; PD=progressive disease; PD-(L)1=programmed death receptor-1 or programmed death-ligand 1; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors.

References: 1. PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2021;22(6):872-82. Erratum in: Lancet Oncol 2021;22(6):e239. 3. Seagen Inc. and Astellas. PADCEV. Data on File. 4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. 5. Supplement to: Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV 201): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2021;22(6):872-82. 6. Supplement to: Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37(29):2592-600.

BOXED WARNING: SERIOUS SKIN REACTIONS

• PADCEV® can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.

• Closely monitor patients for skin reactions.

• Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.

• Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

INDICATION

PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (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, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

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 56% (all grades) of the 753 patients treated with PADCEV as a single agent in clinical trials. Twenty-four percent (24%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 12% 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. The median time to onset of severe skin reactions was 0.7 months (range: 0.1 to 6 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients.

When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate. Skin reactions occurred in 72% (all grades) of the 121 patients treated with PADCEV in combination with pembrolizumab in clinical trials. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 20% of patients (Grade 3: 19%, Grade 4: 0.8%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.8%). The median time to onset of severe skin reactions was 2.6 months (range: 0.3 to 16 months). Skin reactions led to discontinuation of PADCEV in 6% of patients.

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 and diabetic ketoacidosis (DKA) Hyperglycemia and 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. In clinical trials of PADCEV as a single agent, 14% of the 753 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. 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. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.4% of patients. 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. In clinical trials of PADCEV as a single agent, 2.9% of the 753 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of pneumonitis/ILD was 2.7 months (range: 0.6 to 6 months). The incidence of pneumonitis/ILD, including severe events occurred at a higher rate when PADCEV was given in combination with pembrolizumab. When PADCEV was given in combination with pembrolizumab, 9% of the 121 patients treated with combination therapy had pneumonitis/ILD of any grade and 3.3% had Grade 3. A fatal event of pneumonitis occurred in one patient (0.8%). The median time to onset of pneumonitis/ILD was 6 months (range: 0.6 to 26 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. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.

Peripheral neuropathy (PN) Peripheral neuropathy occurred in 53% of the 753 patients treated with PADCEV as a single agent in clinical trials including 40% with sensory neuropathy, 7% with muscular weakness and 7% with motor 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. The median time to onset of Grade ≥2 peripheral neuropathy was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 7% of patients. Of the patients who experienced neuropathy who had data regarding resolution (N = 319), 14% had complete resolution, 46% had partial improvement, and 40% had no improvement at the time of their last evaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade 2 or greater neuropathy at the time of their last evaluation.

The incidence of peripheral neuropathy occurred at a higher rate when PADCEV was given in combination with pembrolizumab. When PADCEV was given in combination with pembrolizumab, 65% of the 121 patients treated with combination therapy had peripheral neuropathy of any grade, 45% had Grade 2 neuropathy, and 3.3% had Grade 3 neuropathy. The median time to onset of Grade ≥2 peripheral neuropathy was 6 months (range: 0.3 to 25 months).

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 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 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19 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. Of the 753 patients treated with PADCEV as a single agent in clinical trials, 1.5% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. 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 PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

ADVERSE REACTIONS

Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy)

Rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy.

Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite and fatigue (3% each). Clinically relevant adverse reactions (<15%) include vomiting (14%), AST increased (12%), hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy.

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥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 (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increased and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased (10%), pneumonitis (4%) and infusion site extravasation (1%).

EV-103 Study: 121 patients with previously untreated locally advanced or metastatic urothelial cancer who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)

The most common adverse reactions including laboratory abnormalities (≥20%), of PADCEV in combination with pembrolizumab were glucose increased, aspartate aminotransferase increased, rash, hemoglobin decreased, creatinine increased, peripheral neuropathy, lymphocytes decreased, fatigue, alanine aminotransferase increased, sodium decreased, lipase increased, albumin decreased, alopecia, phosphate decreased, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, potassium decreased, neutrophils decreased, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%). Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%). Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (20%) and rash (6%). Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were peripheral neuropathy (18%), rash (12%), lipase increased (6%), pneumonitis (6%), diarrhea (4.1%), acute kidney injury (3.3%), alanine aminotransferase increased (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), amylase increased (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were peripheral neuropathy (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).

DRUG INTERACTIONS

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 monomethyl auristatin E 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.

SPECIFIC POPULATIONS

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

Please see full Prescribing Information, including BOXED WARNING.