Managing Adverse Reactions to Help Optimize Outcomes in Certain Urothelial Cancers

This article is a collaboration between Astellas Pharma US, Inc., Pfizer Inc., and Dr. Nizam. Dr. Nizam was paid for her participation in writing this article.

The treatment of locally advanced or metastatic urothelial cancer (la/mUC) is complex and requires coordinated, multidisciplinary care with oncology nurses playing a critical role in patient education and toxicity management. The 2023 FDA approval of the combination of PADCEV® (enfortumab vedotin-ejfv) plus Keytruda® (pembrolizumab) advanced the treatment of la/mUC by demonstrating significantly superior outcomes compared to platinum-based chemotherapy.ⁱ Whether a patient is starting or continuing treatment, proactive assessment and management of adverse reactions is essential to supporting treatment continuation and optimization of outcomes.ⁱⁱ

The Evolution of la/mUC Treatment

For decades, cisplatin-based chemotherapy was the standard-of-care first-line treatment for patients with la/mUC.ⁱ Given the historically poor prognosis of la/mUC with five-year survival rates of approximately 9%ⁱⁱⁱ, there was a need for novel therapies that could improve patients’ survival outcomes.

Based on results from the EV-302 trial, the approval of PADCEV plus pembrolizumab for the treatment of adult patients with la/mUC led to an alternative to platinum-based chemotherapy, offering patients a first-line treatment option capable of meaningfully improving outcomes.ⁱ

The EV-302 study was an open-label, randomized, Phase 3 trial that evaluated the combination of PADCEV plus pembrolizumab (n=442) compared to platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine, n=444) in patients with previously untreated la/mUC.ⁱ Primary endpoints were overall survival (OS) and progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death from any cause.ⁱ Select secondary endpoints were overall response and safety.ⁱ PADCEV was dosed at 1.25 mg/kg intravenous (IV) on Days 1 and 8 of a 21-day cycle and IV pembrolizumab was dosed at 200 mg on Day 1 of a 21-day cycle.ⁱⁱ Treatment was continued until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, pembrolizumab was continued for up to 2 years. Gemcitabine was dosed at 1000 mg/m² IV on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m² or carboplatin (AUC = 4.5 or 5) IV on Day 1 of a 21-day cycle.ⁱⁱ Treatment was continued until disease progression or for up to 6 cycles in the absence of disease progression or unacceptable toxicity. In the trial, PADCEV plus pembrolizumab nearly doubled median OS and PFS compared to platinum-based chemotherapy.ⁱ Median OS was 31.5 months (95% confidence interval (CI): 25.4, NE) for the combination of PADCEV plus pembrolizumab versus 16.1 months (95% CI: 13.9, 18.3) for platinum-based chemotherapy (hazard ratio (HR): 0.47 (95% Cl: 0.38, 0.58); p-value: <0.0001).ⁱⁱ Median PFS was 12.5 months (95% CI: 10.4, 16.6) for the combination of PADCEV plus pembrolizumab versus 6.3 months (95% CI: 6.2, 6.5) for platinum-based chemotherapy (HR: 0.45 (95% Cl: 0.38, 0.54); p-value: <0.0001).ⁱⁱ Median follow-up time for survival was 17.2 months.ⁱ

Current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for bladder cancer recommend enfortumab vedotin-ejfv plus pembrolizumab as the only NCCN Category 1 preferred first-line treatment option for patients with la/mUC, regardless of cisplatin eligibility.^iv

Adverse Reactions of PADCEV Plus Pembrolizumab

Although this targeted combination therapy has become the standard of care for first-line la/mUC, it can cause serious adverse reactions and includes a boxed warning for severe skin reactions.^{ii, v,vi} Additional warnings and precautions associated with the combination regimen include hyperglycemia, pneumonitis or interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.ⁱⁱ At treatment initiation, it is important to develop a clear plan with patients and their caregivers to monitor for adverse reactions and set expectations that dose interruptions or modifications may be required throughout the course of treatment to help manage side effects. The PADCEV prescribing information includes dose modification guidance, directing care teams to adjust dosing to address select side effects. The EV-302 trial included full and modified dosing regimens, and adverse reactions led to PADCEV dose interruption in 73% of patients, PADCEV dose reduction in 42% of patients, and PADCEV discontinuation in 35% of patients.

• The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were peripheral neuropathy (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased alanine aminotransferase (3%), and pruritus (2.5%). ⁱⁱ
• The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), peripheral neuropathy (13%), and fatigue (2.7%). ⁱⁱ
• The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (15%), rash (4.1%), and pneumonitis/ILD (2.3%). ⁱⁱ

In the EV-302 clinical trial, serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with intravenous pembrolizumab.ⁱⁱ The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).ⁱⁱ Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with IV pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).ⁱⁱ

For more information on adverse reactions associated with the combination of PADCEV plus pembrolizumab, as well as resources for clinicians, patients, and clinical practices, please visit https://www.padcevhcp.com/resources.

Monitoring Adverse Reactions

Given the adverse reaction profile for PADCEV plus pembrolizumab, proactive monitoring before and throughout treatment is essential, with nurses playing a critical role.ⁱⁱ Proactive monitoring can enable early detection and prompt intervention, which are key to addressing adverse reactions and supporting patients’ ability to remain on therapy.ⁱⁱ

Prior to treatment initiation, a comprehensive assessment of patient-specific risk factors, including comorbidities, prior conditions, and previous treatments, can be helpful to gauge which adverse reactions a patient may be most at risk for. Equally important is patient and caregiver education about potential adverse reactions, early symptoms to monitor for, the importance of timely reporting, and the role of dose modification in addressing select side effects. This proactive communication empowers patients to be active partners in their care and enables timely clinical intervention.

Risk assessment should include a review of the patient’s past medical history for a variety of factors including, but not limited to, skin reactions, peripheral or motor neuropathy, obesity, diabetes, ocular conditions, relevant medications, and other medical conditions. During treatment, patients should be assessed before each infusion with careful attention to any new or worsening symptoms.ⁱⁱ

The measures taken to address adverse reactions may include supportive measures targeted to specific toxicities, referral to appropriate specialists, temporary dose interruptions or reductions, and when indicated, permanent treatment discontinuation, depending on the severity and persistence of the adverse reaction.ⁱⁱ

Table: Recommended PADCEV Dose Modificationsⁱⁱ

Note: Recommended dose reduction schedule can be found in the Prescribing Information.

Managing Select Adverse Reactions

Addressing certain adverse reactions related to treatment with PADCEV plus pembrolizumab requires a proactive approach centered on early recognition and prompt intervention.

Skin Reactions: Patients should be closely monitored for skin reactions beginning with the first treatment cycle and throughout treatment. Management may include topical corticosteroids and anti-histamines, specialist referrals, and dose modifications, as clinically indicated.ⁱⁱ With proper management, skin reactions may improve or resolve; of the patients who were treated with PADCEV in combination with pembrolizumab for la/mUC in EV-302 and EV-103 (n=564) and 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.ⁱⁱ

Peripheral Neuropathy (PN): Patients should be monitored for new or worsening PN with consideration of dose interruption, reduction, or discontinuation when clinically indicated.ⁱⁱ Symptoms vary by affected nerve type with sensory neuropathy being associated with pain, burning, numbness, or tingling in the hands and feet and motor neuropathy being associated with loss of coordination, gait instability, or muscle weakness.^vii

Patients should be encouraged to self-monitor and promptly report any symptoms of PN to enable early identification and intervention.ⁱⁱ Of the patients who were treated with PADCEV in combination with pembrolizumab for la/mUC in EV-302 and EV-103 (n=564) and who experienced neuropathy and had data regarding resolution (n=373), 13% had complete resolution, and 87% of patients had residual neuropathy at last evaluation. Of the patients with residual neuropathy at last evaluation, 45% (146/326) had Grade ≥2 neuropathy.ⁱⁱ

PADCEV plus pembrolizumab represents a major step forward in the treatment of advanced urothelial cancer, but its benefits must be carefully balanced against the risk of potentially serious adverse reactions. Oncology nurses and nurse practitioners can play a critical role through patient and caregiver education, vigilant monitoring, early identification, and prompt intervention. Through addressing adverse reactions, using supportive care and appropriate dose modifications, oncology nurses and nurse practitioners can directly support patients’ ability to remain on therapy, when clinically appropriate.

For more information on the management of adverse reactions associated with the combination of PADCEV plus pembrolizumab, as well as resources for clinicians, patients, and clinical practices, please visit https://www.padcevhcp.com/resources.

IMPORTANT SAFETY INFORMATION AND INDICATION

BOXED WARNING: SERIOUS SKIN REACTIONS

• PADCEV (enfortumab vedotin-ejfv) 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, 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 (mUC).

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 70% (all grades) of the 564 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC in clinical trials. The majority of skin reactions that occurred included maculo-papular rash, macular rash, and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), 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 (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients. 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.

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), 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, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). 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.

When PADCEV was given in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 10% of the 564 patients had pneumonitis/ILD of any grade and 4% had Grade 3-4. 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).

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) When PADCEV was given in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 67% of the 564 patients had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months). Of the patients who experienced neuropathy and had data regarding resolution (n=373), 13% had complete resolution, and 87% of patients had residual neuropathy at last evaluation. Of the patients with residual neuropathy at last evaluation, 45% (146/326) had Grade ≥2 neuropathy.

Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade >3 PN.

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. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% 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 in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC: increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), 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.

EV-302 Study: 440 patients with previously untreated locally advanced or mUC (PADCEV in combination with intravenous pembrolizumab)

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with intravenous pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with intravenous pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%).

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 3 weeks after the last dose.

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

For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here.

References

^i. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888.

^ii. Padcev. Package insert. Northbrook, IL: Astellas Pharma US, Inc.; 2025.

^iii. National Cancer Institute. Urinary bladder (invasive & in situ) SEER 5-year relative survival rates, 2015-2021. Updated April 16, 2025. Accessed May 27, 2025. https://seer.cancer.gov/statistics-network/explorer/application.html?site=71&data_type=4&graph_type=5&compareBy=stage&chk_stage_104=104&chk_stage_105=105&chk_stage_106=106&chk_stage_107=107&series=9&sex=1&race=1&age_range=1&advopt_precision=1&advopt_show_ci=on&hdn_view=1&advopt_show_apc=on&advopt_display=2#resultsRegion1

^iv. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer v.1.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed March 16, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

^v. Powles T, Bellmunt J, Comperat E, et al; for the ESMO Guidelines Committee. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024;35(6):485-490.

^vi. Powles TB, Van der Heijden MS; Loriot Y, et al. Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial. Ann Oncol. 2025;36(10):1212-1219.

^vii. National Institute of Neurological Disorders and Stroke. Peripheral neuropathy. Updated August 7, 2024. Accessed June 2, 2025. https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy.

MAT-US-PAD-2025-00299 | 06/26