Enfortumab Vedotin: A Comprehensive Monograph on a Paradigm-Shifting Antibody-Drug Conjugate in Urothelial Carcinoma

Executive Summary and Drug Profile

Enfortumab vedotin represents a significant therapeutic breakthrough in the management of urothelial carcinoma, the most common form of bladder cancer. As a first-in-class antibody-drug conjugate (ADC) targeting Nectin-4, it has fundamentally redefined the treatment landscape for patients with locally advanced or metastatic disease. This report provides a comprehensive analysis of enfortumab vedotin, synthesizing data on its molecular structure, mechanism of action, pharmacological profile, pivotal clinical trial evidence, safety and tolerability, and global regulatory status.

The agent's innovative design, which combines a highly specific monoclonal antibody with a potent cytotoxic payload, allows for the targeted delivery of chemotherapy directly to cancer cells, thereby maximizing efficacy while creating a distinct and manageable safety profile. In the landmark EV-302/KEYNOTE-A39 trial, the combination of enfortumab vedotin with the PD-1 inhibitor pembrolizumab demonstrated an unprecedented improvement in overall and progression-free survival compared to standard platinum-based chemotherapy, establishing this regimen as the new first-line standard of care for patients with locally advanced or metastatic urothelial carcinoma. This benefit was observed across all major patient subgroups, irrespective of cisplatin eligibility or PD-L1 expression. As a monotherapy, enfortumab vedotin has also proven its efficacy in later lines of treatment for patients who have progressed on prior chemotherapy and immunotherapy.

While highly effective, the therapy is associated with a unique spectrum of adverse events, including serious skin reactions, peripheral neuropathy, and hyperglycemia, which necessitate vigilant clinical monitoring and proactive management. Ongoing research is aggressively exploring its application in earlier stages of urothelial cancer, such as muscle-invasive disease, and in other Nectin-4-expressing solid tumors, signaling its expanding role in modern oncology. This monograph serves as an exhaustive reference for clinicians, researchers, and industry professionals on the science and clinical application of this transformative therapeutic agent.

Drug Profile Summary

The following table consolidates the essential identifiers and characteristics of enfortumab vedotin for rapid reference.

Characteristic	Details	Source(s)
Generic Name	Enfortumab vedotin (-ejfv)	1
Brand Name	Padcev®	1
DrugBank ID	DB13007	4
CAS Number	1346452-25-2	5
Type	Biotech, Antibody-Drug Conjugate (ADC)	4
ATC Code	L01FX13	2
Molecular Weight	Approximately 152 kDa	4
Target Antigen	Nectin-4	4
Cytotoxic Payload	Monomethyl Auristatin E (MMAE)	4
Developers/Marketers	Astellas Pharma, Seagen (acquired by Pfizer), Merck & Co. (for pembrolizumab combination)	7

Mechanism of Action: A Nectin-4-Directed Antibody-Drug Conjugate

Enfortumab vedotin is a sophisticated example of an antibody-drug conjugate, a class of biopharmaceuticals designed to function as a "biological missile" for targeted cancer therapy. Its efficacy is derived from a tripartite structure, where each component plays a distinct and critical role in achieving selective cytotoxicity against tumor cells.[7]

The Tripartite Structure of an Advanced ADC

1. The Antibody: The targeting component is enfortumab (also known as AGS-22C3), a fully human IgG1 kappa monoclonal antibody.[7] Produced in Chinese hamster ovary (CHO) cells, this antibody is engineered to bind with high affinity and specificity to Nectin-4, a protein highly expressed on the surface of urothelial cancer cells.[7] The selection of a fully human antibody framework is a deliberate design choice intended to reduce the likelihood of an immunogenic response in patients, which could otherwise lead to neutralization of the drug and loss of efficacy.[2]
2. The Cytotoxic Payload: The "warhead" of the ADC is monomethyl auristatin E (MMAE), a highly potent synthetic antineoplastic agent.[4] MMAE is a microtubule-disrupting agent that functions by inhibiting tubulin polymerization. This disruption prevents the formation of the mitotic spindle, a structure essential for cell division, thereby arresting the cell cycle in the G2/M phase and ultimately inducing programmed cell death, or apoptosis.[5] By itself, MMAE is too toxic for systemic administration, but its conjugation to a targeting antibody allows its potent cell-killing activity to be harnessed and directed specifically toward cancer cells.[10]
3. The Linker: Connecting the antibody to the payload is a protease-cleavable linker system.[4] Specifically, it is a maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl linker.[12] This linker is engineered for stability in the systemic circulation, ensuring the toxic MMAE payload remains attached to the antibody while it travels through the bloodstream, minimizing off-target toxicity to healthy tissues. However, upon internalization of the ADC into the target cancer cell's lysosome, the linker is efficiently cleaved by intracellular proteases, such as cathepsin, which are abundant in the lysosomal environment. This cleavage releases the MMAE payload precisely where it is needed—inside the cancer cell—to exert its cytotoxic effect.[7] The design results in a drug-to-antibody ratio (DAR) of approximately 3.8:1, meaning each antibody molecule carries, on average, just under four molecules of MMAE, optimizing the therapeutic payload delivered to the tumor.[7]

This modular design is a hallmark of the "vedotin" ADC platform, licensed from Seattle Genetics (now part of Pfizer). The same linker and MMAE payload are utilized in other successful ADCs, such as brentuximab vedotin, which targets the CD30 antigen in lymphomas.[4] This platform approach allows for the development of new targeted therapies by swapping the antibody component to direct the established cytotoxic machinery to different cancer-specific antigens. This strategy can streamline aspects of drug development and manufacturing, and provides a degree of predictability regarding the toxicities associated with the linker-payload system, although target-mediated toxicities will always be unique to the specific antibody.

The Biological Rationale and Therapeutic Process

The therapeutic strategy of enfortumab vedotin is grounded in the specific biology of its target, Nectin-4. Nectin-4 is a type I transmembrane protein that functions as a cell adhesion molecule and is a member of the immunoglobulin-like superfamily.[7] While it has roles in normal tissue, its expression is significantly upregulated in several solid malignancies, most notably in urothelial carcinoma, where it is highly and uniformly expressed.[4] This differential expression between cancer cells and most normal tissues creates a crucial therapeutic window, allowing the ADC to selectively target the tumor while largely sparing healthy cells.[7]

The antitumor activity of enfortumab vedotin unfolds through a precise, multi-step process:

1. Binding: Following intravenous administration, enfortumab vedotin circulates throughout the body. The antibody component seeks out and binds with high affinity to the Nectin-4 protein expressed on the surface of urothelial cancer cells.[10]
2. Internalization: Once bound, the entire ADC-Nectin-4 complex is drawn into the cancer cell through a process called endocytosis.[4]
3. Payload Release: The complex is trafficked to the cell's lysosomes. Within this acidic, enzyme-rich environment, the protease-cleavable linker is broken down, liberating the MMAE payload from the antibody into the cell's cytoplasm.[7]
4. Cytotoxicity: The freed MMAE molecules then bind to tubulin, disrupting the microtubule network. This action halts the cell division process (G2/M arrest) and triggers the apoptotic cascade, leading to the targeted death of the Nectin-4-expressing cancer cell.[5]

A significant clinical advantage derived from this biology is the lack of a requirement for pre-treatment biomarker testing. In the pivotal EV-201 trial, Nectin-4 expression was detected in all tested tumor samples from patients with metastatic urothelial carcinoma.[11] The expression was so consistent and widespread within the indicated patient population that routine testing for Nectin-4 was deemed unnecessary. This simplifies the clinical pathway for treatment initiation, removing a potential logistical and financial barrier, and allows eligible patients to receive this life-extending therapy more rapidly compared to other targeted agents that mandate a companion diagnostic test.[11]

Comprehensive Pharmacological Profile

The clinical behavior of enfortumab vedotin is governed by the distinct pharmacokinetic and pharmacodynamic properties of both the intact antibody-drug conjugate and its released cytotoxic payload, MMAE. Understanding these properties is essential for optimizing dosing, anticipating drug interactions, and managing toxicity.

Pharmacokinetics (PK)

The ADME (absorption, distribution, metabolism, and excretion) profile of enfortumab vedotin has been characterized in clinical studies.

• Absorption and Exposure: Following the recommended intravenous dose of 1.25 mg/kg in the first treatment cycle, the maximum plasma concentration (Cmax​) of the intact ADC reaches approximately 28 µg/mL, with a total exposure over 28 days (area under the curve, AUC0−28d​) of 111 µg·d/mL. The release of the active payload is gradual, as evidenced by the pharmacokinetics of unconjugated MMAE, which reaches a Cmax​ of 4.8 ng/mL and an AUC0−28d​ of 69 ng·d/mL. The time to reach maximum concentration (Tmax​) for MMAE is approximately 1 to 3 days after the infusion, confirming its controlled release from the ADC within the body.[5]
• Distribution: The estimated steady-state volume of distribution (Vd​) of enfortumab vedotin is approximately 11 liters.[5] This relatively small volume suggests that the large ADC molecule is primarily confined to the blood plasma and interstitial fluid, with limited distribution into deep tissues, which is typical for monoclonal antibody-based therapies.
• Metabolism: The metabolic pathways for the ADC and its payload are distinct. The enfortumab vedotin ADC is a protein and is expected to be catabolized into smaller peptides and amino acids through normal protein degradation pathways. The critical metabolic step for the active payload, MMAE, occurs after its release inside the tumor cell. MMAE is primarily metabolized by the cytochrome P450 enzyme CYP3A4 in the liver.[4] This fact has significant clinical implications for drug-drug interactions.
• Excretion: The clearance of enfortumab vedotin from the body is slow, with a mean clearance of 0.10 L/h and an elimination half-life of approximately 3.4 days. The clearance of free MMAE is faster (2.7 L/h), with a half-life of about 2.4 days; however, its overall elimination is rate-limited by its slow release from the circulating ADC. While excretion kinetics have not been fully studied for enfortumab vedotin itself, data from another MMAE-containing ADC suggest that elimination of the payload is primarily through the feces (17% of total MMAE) with a smaller portion in the urine (6%), mostly as unchanged drug.[5]
• Special Populations: Due to the central role of the liver in metabolizing the MMAE payload, patients with moderate to severe hepatic impairment should avoid enfortumab vedotin. Although not specifically studied in this population, other MMAE-containing ADCs have shown increased rates of adverse events in patients with liver dysfunction, leading to a strong precautionary recommendation.[4]

Pharmacodynamics (PD) and Exposure-Response Relationships

Analyses of data from monotherapy trials (EV-101, EV-201, EV-301) have established important relationships between drug exposure and both efficacy and safety, providing a strong rationale for the approved dosing and management strategy.[16]

• Efficacy: A clear positive exposure-response relationship for efficacy was observed. Higher initial exposure to enfortumab vedotin, particularly within the first two treatment cycles, was directly associated with a higher Objective Response Rate (ORR). This finding strongly supports the clinical strategy of initiating treatment at the full 1.25 mg/kg dose to maximize the probability of achieving a rapid and deep tumor response, which is often critical in patients with aggressive, advanced disease.[16]
• Safety: Conversely, an exposure-response relationship was also identified for key toxicities. Lower time-averaged exposure (Cavg​) was associated with a reduced risk of developing Grade ≥3 adverse events, specifically rash/skin reactions, peripheral neuropathy, and hyperglycemia. This demonstrates that managing cumulative drug exposure over time is critical for mitigating toxicity.[16]

The reliance on CYP3A4 for MMAE metabolism makes the management of drug-drug interactions a critical component of patient safety. Co-administration of enfortumab vedotin with strong inhibitors of CYP3A4, such as the antibiotics clarithromycin and erythromycin, antifungal agents like ketoconazole and itraconazole, and even dietary components like grapefruit, can significantly increase the plasma concentration of free MMAE.[15] This elevated exposure can lead to a higher incidence and severity of the drug's characteristic toxicities. Therefore, a thorough review of a patient's concomitant medications and dietary habits is an essential safety check before initiating therapy.

These pharmacological data reveal a classic "dose-toxicity-efficacy" balance. The dose required to achieve the highest likelihood of an initial response also carries a greater risk of toxicity. This is not a contradiction but a fundamental principle of potent anticancer therapy. It validates the clinical management approach of starting with a full, aggressive dose to gain control of the cancer, followed by proactive use of dose interruptions and reductions to manage emerging adverse events. This strategy allows patients to remain on a highly effective therapy for a longer duration, ultimately maximizing the overall clinical benefit. The fact that significant improvements in progression-free and overall survival were observed across all exposure quartiles in the EV-301 trial—including in patients who required dose reductions—provides robust evidence for the success of this management paradigm.[16] Dose modifications are therefore not a sign of treatment failure but rather an integral and effective tool for personalizing therapy and optimizing the long-term risk-benefit ratio for each patient.

Clinical Efficacy in Locally Advanced or Metastatic Urothelial Carcinoma

The clinical development program for enfortumab vedotin has been marked by a series of highly successful trials that have progressively established it as a cornerstone of treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). Its impact has been most profound in the first-line setting, where it has set a new standard of care.

A. First-Line Treatment: The EV-302/KEYNOTE-A39 Trial and the New Standard of Care

The EV-302/KEYNOTE-A39 trial was a global, Phase 3, open-label, randomized study that fundamentally altered the treatment paradigm for la/mUC.[17] The trial was designed to compare the efficacy and safety of enfortumab vedotin combined with the PD-1 inhibitor pembrolizumab (EV+P) against the decades-long standard of care, platinum-based chemotherapy (either gemcitabine plus cisplatin or gemcitabine plus carboplatin).[19] A total of 886 patients with previously untreated la/mUC were enrolled, critically including a broad population representative of real-world practice: both cisplatin-eligible and -ineligible patients, and patients with varying levels of PD-L1 expression.[17]

Landmark Efficacy Results

The trial met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) with results of unprecedented magnitude, leading to its rapid adoption as the preferred first-line regimen worldwide.[20]

Table 2: Summary of Key Efficacy Outcomes from the EV-302/KEYNOTE-A39 Trial

Efficacy Endpoint	Enfortumab Vedotin + Pembrolizumab (EV+P)	Platinum-Based Chemotherapy	Hazard Ratio (HR) [95% CI] / p-value
Median Overall Survival (OS)	31.5 - 33.8 months	16.1 months	0.47 - 0.51 [p<0.0001]
Median Progression-Free Survival (PFS)	12.5 months	6.3 months	0.45 - 0.48 [p<0.0001]
Objective Response Rate (ORR)	67.5% - 68%	44%	p<0.0001
Complete Response (CR) Rate	29.1% - 30.4%	12.5%	-
Median Duration of Response (DOR)	23.3 months	7.0 months	-

[17]

The EV+P combination nearly doubled the median overall survival, extending it to approximately 32-34 months compared to just 16 months with chemotherapy, which represents a 49-53% reduction in the risk of death.[20] Similarly, the risk of disease progression or death was reduced by 52-55%, with median PFS more than doubling from 6.3 months to 12.5 months.[17] The depth of response was also substantially greater, with an ORR of 68% and, remarkably, a complete response rate of nearly 30% for the EV+P arm, compared to 44% and 12.5% respectively for chemotherapy.[20]

Subgroup Analyses and Patient-Reported Outcomes

Crucially, the profound survival benefit of the EV+P combination was demonstrated consistently across all key prespecified patient subgroups. This included patients who were eligible for cisplatin and those who were not, patients with and without the presence of high-risk liver metastases, and patients with both high and low PD-L1 expression levels.[18] This broad consistency underscores the robust efficacy of the regimen and its applicability to the vast majority of patients with newly diagnosed la/mUC.

Furthermore, analysis of patient-reported outcomes (PROs) from the EV-302 trial showed that despite having a different toxicity profile, treatment with EV+P did not result in a detriment to patients' Global Health Status/Quality of Life (GHS/QoL) when compared to standard chemotherapy. For patients who entered the trial with moderate-to-severe baseline pain, the EV+P regimen led to clinically meaningful improvements in pain scores, suggesting a tangible benefit on patient well-being alongside the dramatic survival advantage.[25]

B. Later-Line Monotherapy: Evidence from the EV-201 and EV-301 Trials

Prior to its success in the first-line setting, enfortumab vedotin was first established as a valuable therapy for patients with heavily pretreated disease.

• EV-201 (Phase 2): This pivotal, single-arm trial provided the initial proof-of-concept and led to the drug's first accelerated approval from the FDA.[2] The study enrolled patients with la/mUC who had already progressed after treatment with both platinum-containing chemotherapy and a PD-1/L1 inhibitor, a population with very few effective options.[26] In this difficult-to-treat setting, enfortumab vedotin monotherapy demonstrated impressive and durable antitumor activity.

Table 3: Summary of Key Efficacy Outcomes from the EV-201 Trial (Monotherapy)

Efficacy Endpoint	EV-201 Cohort 1 (N=125)
Objective Response Rate (ORR)	44% (95% CI: 35.1-53.2)
Complete Response (CR) Rate	12%
Partial Response (PR) Rate	32%
Median Duration of Response (DOR)	7.6 months
Median Overall Survival (OS)	14.7 - 16.1 months
Median Progression-Free Survival (PFS)	5.8 - 6.7 months

[2]

• EV-301 (Phase 3): This subsequent randomized, controlled trial confirmed the findings of EV-201. It directly compared enfortumab vedotin monotherapy against standard chemotherapy (physician's choice of paclitaxel, docetaxel, or vinflunine) in the same post-platinum, post-immunotherapy patient population. The trial demonstrated a statistically significant and clinically meaningful overall survival advantage for enfortumab vedotin, with a median OS of 12.88 months versus 8.97 months for chemotherapy (HR 0.70).[13]

C. Comparative Efficacy Synthesis

A systematic review and meta-analysis of available trial data further solidifies the hierarchical efficacy of these regimens. The analysis confirmed that the EV+P combination significantly outperformed chemotherapy in both ORR (Odds Ratio 3.47) and 1-year survival (Odds Ratio 2.32).[29] In the later-line setting, enfortumab vedotin monotherapy also demonstrated a significant 1-year survival benefit over chemotherapy (Odds Ratio 1.60).[30]

The rationale for moving the combination to the forefront was supported by the randomized Cohort K of the EV-103 study. While not powered for a formal statistical comparison, this cohort provided the first head-to-head data suggesting the superiority of the EV+P combination (confirmed ORR of 64.5%) over EV monotherapy in the first-line cisplatin-ineligible population, paving the way for the definitive EV-302 trial.[31]

The transformative success of the EV+P combination in the first-line setting has effectively rendered the previous treatment algorithm—platinum chemotherapy followed by immunotherapy—obsolete for the majority of patients.[33] This paradigm shift, while a monumental step forward, has simultaneously created a new and critical unmet clinical need: determining the optimal therapeutic strategy for patients whose disease progresses after first-line EV+P. This is now a primary focus of clinical research, with potential options including platinum-based chemotherapy (for patients who are now chemo-naive), other targeted agents like the FGFR inhibitor erdafitinib for those with specific genetic alterations, or enrollment in clinical trials of novel agents.[33]

Perhaps one of the most significant implications of the EV-302 data is the nature of the responses achieved. An objective response rate is a standard endpoint, but the 30.4% complete response rate, coupled with exceptional durability—95% of these complete responders were alive at two years, and 78% remained progression-free—is remarkable.[22] For a disease like metastatic urothelial cancer, where the historical median survival was just over a year and the treatment goal was primarily palliative, these results are transformative. They suggest that for a substantial subset of patients, the EV+P combination may not just be extending life but may be altering the natural history of the disease, moving the therapeutic goal from palliation toward the possibility of long-term, durable remission.

Safety and Tolerability Profile

The potent efficacy of enfortumab vedotin is accompanied by a distinct and clinically significant safety profile that requires careful monitoring and proactive management. While considered manageable, the associated toxicities are different from those of traditional chemotherapy or immunotherapy and demand specific clinical expertise.

Boxed Warning: Serious Skin Reactions

The prescribing information for enfortumab vedotin includes a Boxed Warning, the most serious type of warning from the U.S. Food and Drug Administration, for severe and potentially fatal cutaneous adverse reactions.[3] These reactions include Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which are medical emergencies. These severe events have been observed to occur predominantly during the first cycle of treatment but can manifest at any time. The warning mandates close monitoring of all patients for skin reactions. If a severe reaction such as SJS or TEN is suspected, enfortumab vedotin must be immediately withheld and the patient referred for specialized dermatological care. The drug must be permanently discontinued in any patient with a confirmed diagnosis of SJS or TEN, or who experiences a Grade 4 or recurrent Grade 3 skin reaction.[36]

Adverse Reactions of Special Interest (AESIs)

Beyond the boxed warning, several other toxicities are characteristic of enfortumab vedotin, both as a monotherapy and in combination with pembrolizumab.

Table 4: Incidence of Key Adverse Reactions (All Grades & Grade ≥3) - Monotherapy vs. Combination Therapy

Adverse Reaction	EV Monotherapy (Any Grade / G≥3)	EV + Pembrolizumab (Any Grade / G≥3)	Source(s)
Skin Reactions	58% / 14%	68-70% / 17%	19
Peripheral Neuropathy	53% / 5%	67% / 7-8%	19
Hyperglycemia	17% / 7%	~14% / ~7%	36
Ocular Disorders	40% / G≥3 rare	29% / G≥3 rare	19
Pneumonitis/ILD	3% / 0.8%	10% / 4%	3
Fatigue	Common / ~7%	Common / G≥3 varies	3
Diarrhea	Common / G≥3 low	Common / G≥3 varies	3

• Skin Reactions: This is the most common adverse event associated with enfortumab vedotin. It typically presents as a maculopapular rash but can manifest in various forms, including bullous dermatitis and exfoliative dermatitis.[36] Management of mild-to-moderate reactions often involves the use of topical corticosteroids and oral antihistamines. Dose interruption or reduction may be necessary for more severe cases.[36]
• Hyperglycemia: Elevated blood glucose is a significant metabolic toxicity that can occur in patients with or without a prior history of diabetes mellitus. In rare cases, it can progress to diabetic ketoacidosis (DKA), which can be fatal.[3] The risk of hyperglycemia is increased in patients with a higher body mass index (BMI) and a higher baseline hemoglobin A1c (HbA1c).[39] Close monitoring of blood glucose levels is mandatory for all patients. If a patient's blood glucose rises above 250 mg/dL, treatment should be withheld until it is controlled.[4]
• Peripheral Neuropathy: This is a common and potentially dose-limiting toxicity. It is primarily sensory in nature, presenting as tingling, numbness, or pain in the hands and feet, but can also have a motor component causing muscle weakness.[10] The neuropathy is often cumulative, worsening with continued treatment. Patients must be monitored for new or worsening symptoms, and dose interruption or reduction is a key management strategy. Grade ≥3 neuropathy necessitates permanent discontinuation of the drug.[36]
• Ocular Disorders: A range of adverse ocular events has been reported, primarily affecting the cornea. These include dry eye, keratitis (inflammation of the cornea), blurred vision, and in rare cases, limbal stem cell deficiency.[19] The symptoms are often manageable, and prophylactic use of preservative-free artificial tear substitutes is recommended for all patients to prevent or mitigate dry eye. Patients experiencing new or worsening ocular symptoms should be referred for an ophthalmologic evaluation.[36]
• Pneumonitis/Interstitial Lung Disease (ILD): While rare with enfortumab vedotin monotherapy, the incidence and severity of pneumonitis/ILD are notably increased when combined with pembrolizumab, as this is a known immune-related adverse event of PD-1 inhibitors. This condition can be severe, life-threatening, or fatal.[3] Patients should be monitored for respiratory symptoms such as cough, dyspnea, and hypoxia. Any suspected case requires immediate evaluation and management, typically involving withholding treatment and administering corticosteroids.[36]
• Infusion Site Extravasation: If the drug leaks out of the vein during infusion, it can cause severe skin and soft tissue reactions at the site. These reactions may be delayed, with erythema, swelling, and pain worsening for up to a week after the event. Careful administration through a secure venous access line is critical to prevent this complication.[36]

Drug Interactions

As the MMAE payload is metabolized by CYP3A4, co-administration of enfortumab vedotin with strong inhibitors of this enzyme must be avoided or undertaken with extreme caution and close monitoring for increased toxicity. Common strong CYP3A4 inhibitors include certain antibiotics (e.g., clarithromycin), antifungal agents (e.g., ketoconazole, itraconazole), and some antiviral medications.[15]

While the list of potential adverse events is extensive and includes serious risks, the overall safety profile is considered manageable within the context of treating a life-threatening malignancy.[27] Successful administration requires a high degree of clinical vigilance, a multidisciplinary approach involving specialties like dermatology and ophthalmology, and a well-educated patient who can report symptoms early.

A noteworthy finding from the pivotal EV-302 trial was that the rate of Grade ≥3 treatment-related adverse events was actually lower in the EV+P arm (56-57%) compared to the standard chemotherapy arm (69.5%).[18] This may seem counterintuitive for a novel, potent combination. However, it highlights the fundamental difference between targeted therapy and conventional chemotherapy. While EV+P has a unique profile of specific toxicities that require new management skills, traditional chemotherapy induces more widespread and severe systemic toxicities, such as profound myelosuppression, debilitating nausea, and severe fatigue. This suggests that while the

type of toxicity with EV+P is different, the overall burden of severe adverse events on the patient may be less than with chemotherapy, a critical factor for quality of life and a strong supporting argument for its adoption as the new standard of care.

Dosing, Administration, and Clinical Management

The safe and effective use of enfortumab vedotin hinges on adherence to recommended dosing regimens, proper administration techniques, and a proactive strategy for managing adverse events through dose modifications.

Recommended Dosing Regimens

The dosage and schedule for enfortumab vedotin differ depending on whether it is administered as a monotherapy or in combination with pembrolizumab.

• Monotherapy: For patients receiving enfortumab vedotin as a single agent (e.g., in the later-line setting), the recommended dose is 1.25 mg/kg, with a maximum dose of 125 mg for patients weighing 100 kg or more. It is administered as a 30-minute intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day treatment cycle.[3]
• Combination Therapy: When given in combination with pembrolizumab for first-line treatment, the enfortumab vedotin dose remains 1.25 mg/kg (up to a 125 mg maximum) administered as a 30-minute IV infusion. However, the schedule is adjusted to Days 1 and 8 of a 21-day cycle. Pembrolizumab is administered on Day 1 of the same cycle, typically after the enfortumab vedotin infusion is complete.[9]

Administration Guidelines

To ensure safe delivery, enfortumab vedotin, which is supplied as a lyophilized powder, must be reconstituted and then diluted prior to infusion. It should be diluted in an appropriate volume of either 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to achieve a final concentration between 0.3 mg/mL and 4 mg/mL.[38] The diluted solution should be mixed by gentle inversion to avoid foaming. Given the risk of severe tissue damage from extravasation, it is imperative to ensure adequate and secure intravenous access before and during the 30-minute infusion.[36]

Management of Adverse Events

Proactive and systematic management of adverse events is crucial for keeping patients on this highly effective therapy. The primary strategy involves dose interruptions, dose reductions, or, in severe cases, permanent discontinuation.

Table 5: Recommended Dose Modifications for Key Adverse Events

Adverse Event	Severity (Grade)	Recommended Action	Source(s)
Skin Reaction	Grade 2	Hold until Grade ≤1, resume at same dose. Consider dose reduction.	36
	Grade 3	Hold until Grade ≤1, resume at reduced dose or discontinue.	36
	Grade 4 or confirmed SJS/TEN	Permanently discontinue.	36
Hyperglycemia	Blood Glucose >250 mg/dL	Hold until ≤250 mg/dL, then resume at the same dose.	36
Peripheral Neuropathy	Grade 2	Hold until Grade ≤1, then resume at a reduced dose.	36
	Grade ≥3	Permanently discontinue.	36
Hematologic Toxicity	Grade 3 Thrombocytopenia	Hold until Grade ≤1, then resume at same or reduced dose.	15
	Grade 4	Hold until Grade ≤1, then resume at a reduced dose or discontinue.	15

[15]

In addition to dose modifications, specific supportive care measures are recommended. Patients should be advised to use preservative-free artificial tear substitutes to prevent or manage dry eye symptoms.[38] Blood glucose levels must be monitored regularly, especially in patients with risk factors for hyperglycemia.[38] Patients should be educated on the signs and symptoms of all major toxicities—including skin rash, neuropathy, hyperglycemia, and ocular issues—and instructed to report them to their healthcare provider immediately.[38] Effective contraception is required for both female and male patients of reproductive potential during treatment and for a specified period after the last dose due to the risk of fetal harm.[38]

Global Regulatory Landscape and Development Timeline

The development and approval of enfortumab vedotin is a case study in modern, collaborative, and accelerated drug development, driven by compelling clinical data in an area of high unmet medical need.

Collaborative Development

Enfortumab vedotin was co-developed through a strategic partnership between Astellas Pharma and Seattle Genetics (which was subsequently acquired by Pfizer).[7] Astellas, through its subsidiary Agensys, was responsible for the development of the anti-Nectin-4 antibody, while Seattle Genetics provided its proprietary antibody-drug conjugate technology, including the linker and the MMAE payload.[2] For the development of the combination therapy, these companies entered into a further collaboration with Merck & Co., the developer of the PD-1 inhibitor pembrolizumab (Keytruda®).[9] This multi-company collaboration was essential to designing and executing the pivotal trials that established the EV+P combination as a new standard of care.

Regulatory Journey

The path to global approval for enfortumab vedotin was remarkably rapid, reflecting the strength of the clinical evidence and the recognition by regulatory agencies of the need for better treatments for urothelial cancer. The timeline highlights a "land and expand" strategy, beginning with an accelerated approval in a later-line setting and culminating in full approval as a first-line therapy.

Table 6: Timeline of Major Regulatory Milestones (FDA, EMA)

Date	Agency	Action	Indication	Source(s)
Dec 18, 2019	FDA	Accelerated Approval	Later-line la/mUC (post-platinum, post-CPI)	2
Jul 9, 2021	FDA	Regular Approval	Expanded later-line la/mUC indications	2
Apr 13, 2022	EMA	Marketing Authorization	Later-line la/mUC (monotherapy)	2
Apr 3, 2023	FDA	Accelerated Approval	First-line la/mUC (cisplatin-ineligible) + Pembrolizumab	19
Dec 15, 2023	FDA	Full (Traditional) Approval	First-line la/mUC (all-comers) + Pembrolizumab	17
Aug 28, 2024	EC (on EMA recommendation)	Marketing Authorization	First-line la/mUC + Pembrolizumab	9

The initial U.S. approval in December 2019 was granted under the FDA's accelerated approval program, based on the impressive tumor response rates seen in the single-arm EV-201 trial.[2] This was converted to a full, regular approval in July 2021 after the confirmatory Phase 3 EV-301 trial demonstrated a clear survival benefit over chemotherapy.[2]

The most significant regulatory action occurred in December 2023, when the FDA granted full approval for the combination of enfortumab vedotin with pembrolizumab for all previously untreated patients with la/mUC, regardless of cisplatin eligibility.[17] This decision was based on the overwhelming efficacy data from the EV-302 trial and was granted nearly five months ahead of the scheduled Prescription Drug User Fee Act (PDUFA) date, underscoring the agency's view of the data's importance and the urgency of the clinical need.[20] Similar approvals followed from the European Medicines Agency (EMA) and the European Commission (EC), solidifying the EV+P regimen as the global standard of care.[39] The drug is also approved in other jurisdictions, including Australia.[43]

Emerging Applications and Future Research Directions

With enfortumab vedotin firmly established as a standard of care in advanced urothelial carcinoma, the focus of its clinical development program has shifted toward two main strategic goals: expanding its use into other Nectin-4-expressing cancers and moving it into earlier stages of urothelial cancer to improve cure rates.

Expansion into Other Nectin-4 Expressing Solid Tumors (The EV-202 Trial)

The biological rationale for enfortumab vedotin is not limited to urothelial cancer. Nectin-4 is known to be expressed in a variety of other solid tumors, including breast cancer, non-small cell lung cancer (NSCLC), head and neck cancer, and gastroesophageal cancers.[44] The EV-202 trial (NCT04225117) is a Phase 2, multi-cohort "basket" study designed to systematically evaluate the efficacy and safety of enfortumab vedotin in these other tumor types.[44]

Early results from several cohorts have been presented:

• Head and Neck Squamous Cell Carcinoma (HNSCC): In a cohort of heavily pretreated patients with recurrent or metastatic HNSCC, enfortumab vedotin monotherapy demonstrated promising antitumor activity, achieving a confirmed Objective Response Rate (ORR) of 23.9%.[46] The safety profile was consistent with that seen in urothelial cancer. These encouraging results have prompted further investigation, and a new cohort within EV-202 is now evaluating the combination of enfortumab vedotin plus pembrolizumab as a first-line therapy for patients with R/M HNSCC.[48]
• Breast Cancer: In cohorts of heavily pretreated patients, enfortumab vedotin monotherapy showed more modest activity. The ORR was 19.0% in patients with triple-negative breast cancer (TNBC) and 15.6% in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer.[49]
• Other Cohorts: The trial continues to enroll patients and evaluate enfortumab vedotin in other solid tumors, including NSCLC and gastroesophageal cancers, with results anticipated in the future.[44]

Moving into Earlier Stages of Urothelial Cancer

The next major frontier for improving outcomes in urothelial cancer is to apply this highly active therapy in earlier, potentially curable stages of the disease, particularly muscle-invasive bladder cancer (MIBC).

• Neoadjuvant Therapy for MIBC: The goal of neoadjuvant (pre-surgical) therapy is to shrink the tumor, eradicate micrometastatic disease, and improve surgical outcomes and long-term survival.
• Early evidence from Cohort H of the EV-103 trial showed that three cycles of neoadjuvant enfortumab vedotin monotherapy in cisplatin-ineligible patients with MIBC was highly effective. It resulted in a pathological complete response (pCR) rate—meaning no residual cancer found at the time of surgery—of 36.4% and a pathological downstaging rate of 50%. Critically, the therapy was well-tolerated and did not cause any delays to definitive surgery (radical cystectomy).[50] The 2-year event-free survival (EFS) rate was a promising 62.0%.[50]
• Building on this success, several large-scale Phase 3 trials are now underway to definitively establish the role of enfortumab vedotin plus pembrolizumab in the perioperative setting, including EV-304/KEYNOTE-B15 and EV-303/KEYNOTE-905.[8]
• The EV-ECLIPSE trial (NCT05239624) is a Phase 2 study specifically designed to investigate neoadjuvant EV+P in a high-risk population: patients with MIBC that has already spread to the lymph nodes (node-positive), prior to radical cystectomy.[51]
• Non-Muscle Invasive Bladder Cancer (NMIBC): Research is also exploring the potential of enfortumab vedotin in the earliest stage of bladder cancer. An active clinical trial is investigating the direct intravesical administration of the drug into the bladder to treat NMIBC, aiming for a potent local effect with minimal systemic exposure.[51]

Novel Combination Strategies

The remarkable synergy observed between enfortumab vedotin and pembrolizumab has spurred extensive research into other novel combinations in la/mUC. Active clinical trials are investigating enfortumab vedotin in combination with other targeted agents, such as the FGFR inhibitor erdafitinib, the multi-tyrosine kinase inhibitor cabozantinib, and even other ADCs like sacituzumab govitecan, in an effort to overcome resistance and further improve outcomes.[51]

Table 7: Overview of Key Ongoing Clinical Trials

Trial ID (Name)	Phase	Setting	Intervention(s)	Focus
NCT04225117 (EV-202)	2	la/m Solid Tumors	EV Monotherapy or EV + Pembrolizumab	Expansion into HNSCC, BC, NSCLC, etc.
NCT05239624 (EV-ECLIPSE)	2	Neoadjuvant MIBC	EV + Pembrolizumab	High-risk, node-positive disease
NCT04700124 (EV-304)	3	Perioperative MIBC	EV + Pembrolizumab	Establishing role in curative-intent setting
NCT04963153	1	la/mUC	EV + Erdafitinib	Combination with FGFR inhibitor post-chemo/CPI
NCI-Sponsored Trial	Active	NMIBC	Intravesical EV	Treatment of early-stage, non-invasive disease

[8]

The breadth of the ongoing clinical development program demonstrates a clear and aggressive two-pronged strategy to maximize the therapeutic value of enfortumab vedotin. The "vertical" integration strategy aims to move the drug earlier into the urothelial cancer treatment course—from the metastatic setting to the potentially curative muscle-invasive and even non-muscle-invasive settings. The "horizontal" expansion strategy, exemplified by the EV-202 trial, seeks to leverage the Nectin-4 biomarker to establish enfortumab vedotin as a treatment for a portfolio of different solid tumors. This dual approach represents a classic biopharmaceutical lifecycle management strategy, designed to transform a single successful product into a broad oncology franchise. Furthermore, the overwhelming success of the EV+P combination has firmly established it as the new therapeutic backbone in urothelial cancer. Future research is largely focused not on replacing this combination, but on building upon it by adding other agents, such as radiation or other targeted drugs, to further improve outcomes for specific patient subgroups.

Synthesis and Concluding Remarks

Enfortumab vedotin has unequivocally transformed the therapeutic landscape for urothelial carcinoma. Its development and rapid ascent to a first-line standard of care represent a triumph of rational drug design, leveraging a well-validated tumor antigen, Nectin-4, with a potent and proven antibody-drug conjugate platform.

The combination of enfortumab vedotin with pembrolizumab has delivered unprecedented survival outcomes in patients with previously untreated locally advanced or metastatic disease, nearly doubling both progression-free and overall survival compared to the long-standing chemotherapy standard. The depth and durability of these responses, particularly the high rate of complete remissions, have shifted the therapeutic goals for a subset of patients from palliation toward the prospect of long-term disease control. The drug's efficacy is robust, holding true across diverse patient populations, and is further supported by a manageable, albeit demanding, safety profile that appears to confer a lower burden of severe toxicity than conventional chemotherapy.

The successful establishment of enfortumab vedotin in the advanced setting has catalyzed an ambitious and logical clinical development program. The key future directions are clear: first, to improve cure rates by integrating this highly active agent into the treatment of earlier-stage, potentially curable urothelial cancer, such as muscle-invasive disease; and second, to expand its application to other Nectin-4-expressing solid tumors, potentially offering a new therapeutic option for patients with other difficult-to-treat cancers.

Key challenges remain. The clinical community must continue to refine its expertise in managing the unique toxicities associated with the therapy, particularly skin reactions, neuropathy, and hyperglycemia. Furthermore, the success of the EV+P combination in the first-line setting has created an urgent need to define the optimal treatment sequence for patients who eventually progress. Enfortumab vedotin stands as a prime example of the power of precision oncology and serves as a benchmark for future therapeutic development in genitourinary cancers and beyond.

Works cited

1. www.padcev.com, accessed August 8, 2025, [https://www.padcev.com/#:~:text=PADCEV%C2%AE%20(enfortumab%20vedotin%2Dejfv,Advanced%20Bladder%20Cancer%20%7C%20Safety%20Info](https://www.google.com/url?q=https://www.padcev.com/%23:~:text%3DPADCEV%25C2%25AE%2520(enfortumab%2520vedotin%252Dejfv,Advanced%2520Bladder%2520Cancer%2520%257C%2520Safety%2520Info&sa=D&source=editors&ust=1754639349948385&usg=AOvVaw2tN64fw6JlBpNZxbLYn6IS)
2. Enfortumab vedotin - Wikipedia, accessed August 8, 2025, https://en.wikipedia.org/wiki/Enfortumab_vedotin
3. Padcev (enfortumab vedotin-ejfv) FDA Approval History - Drugs.com, accessed August 8, 2025, https://www.drugs.com/history/padcev.html
4. Enfortumab vedotin: Uses, Interactions, Mechanism of Action ..., accessed August 8, 2025, https://go.drugbank.com/drugs/DB13007
5. Enfortumab Vedotin - PubChem, accessed August 8, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Enfortumab-Vedotin
6. Enfortumab Vedotin | 1346452-25-2 - ChemicalBook, accessed August 8, 2025, https://www.chemicalbook.com/ChemicalProductProperty_IN_CB58080892.htm
7. Enfortumab Vedotin Drug Description » ADC Review, accessed August 8, 2025, https://www.adcreview.com/enfortumab-vedotin-drug-description/
8. Enfortumab vedotin | Pfizer Oncology Development Website, accessed August 8, 2025, https://www.pfizeroncologydevelopment.com/molecule/enfortumab-vedotin
9. European Commission Approves Merck's KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) as First-Line Treatment of Unresectable or Metastatic Urothelial Carcinoma in Adults, accessed August 8, 2025, https://www.merck.com/news/european-commission-approves-mercks-keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-as-first-line-treatment-of-unresectable-or-metastatic-urothelial-carcinoma-in-ad/
10. How Does PADCEV® (enfortumab vedotin-ejfv) Work?, accessed August 8, 2025, https://www.padcev.com/about-padcev
11. Advancements in Therapy for Bladder Cancer: Enfortumab Vedotin - PMC, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7863123/
12. Enfortumab vedotin-ejfv Antibody-Drug Conjugate inhibitor - Selleck Chemicals, accessed August 8, 2025, https://www.selleckchem.com/products/enfortumab-vedotin-ejfv.html
13. European Commission Approves PADCEV™ (enfortumab vedotin) for Locally Advanced or Metastatic Urothelial Cancer - Apr 13, 2022 - the Astellas US Newsroom, accessed August 8, 2025, https://newsroom.astellas.us/2022-04-13-European-Commission-Approves-PADCEV-TM-enfortumab-vedotin-for-Locally-Advanced-or-Metastatic-Urothelial-Cancer
14. Padcev | European Medicines Agency (EMA), accessed August 8, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/padcev
15. Padcev (enfortumab vedotin) dosing, indications, interactions, adverse effects, and more, accessed August 8, 2025, https://reference.medscape.com/drug/padcev-enfortumab-vedotin-4000028
16. Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer. - ASCO, accessed August 8, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT447020
17. FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma - PubMed, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/39230571/
18. Survival Benefit of Enfortumab Vedotin and Pembrolizumab Compared with Chemotherapy in Patients with Previously Untreated Locally Advanced or Metastatic Urothelial Cancer | ESMO, accessed August 8, 2025, https://www.esmo.org/oncology-news/survival-benefit-of-enfortumab-vedotin-and-pembrolizumab-compared-with-chemotherapy-in-patients-with-previously-untreated-locally-advanced-or-metastatic-urothelial-cancer
19. FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma - PubMed Central, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11530298/
20. FDA Approves Expanded Indication for KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) for the First-Line Treatment of Adult Patients With Locally Advanced or Metastatic Urothelial Cancer - Merck.com, accessed August 8, 2025, https://www.merck.com/news/fda-approves-expanded-indication-for-keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-for-the-first-line-treatment-of-adult-patients-with-locally-advanced-or-metastatic-uroth/
21. Groundbreaking EV-302 Trial Significantly Extends Overall Survival and Progression-Free Survival in Patients Treated with PADCEV® (enfortumab vedotin-ejfv) and KEYTRUDA® (pembrolizumab) in First-Line Advanced Bladder Cancer - PR Newswire, accessed August 8, 2025, https://www.prnewswire.com/news-releases/groundbreaking-ev-302-trial-significantly-extends-overall-survival-and-progression-free-survival-in-patients-treated-with-padcev-enfortumab-vedotin-ejfv-and-keytruda-pembrolizumab-in-first-line-advanced-bladder-cancer-301963132.html
22. EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). | Journal of Clinical Oncology - ASCO Publications, accessed August 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.664
23. EV-302: Long-term subgroup analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). | Journal of Clinical Oncology - ASCO Publications, accessed August 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4571
24. Enfortumab Vedotin Combo Doubles PFS vs Chemo in Urothelial Cancer, accessed August 8, 2025, https://www.targetedonc.com/view/enfortumab-vedotin-combo-doubles-pfs-vs-chemo-in-urothelial-cancer?utm_source=dataLayer&medium=cmi_oss&campaign=newsDeck
25. Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomised, controlled, phase 3 study - PubMed, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/40449498/
26. A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (EV-201) - ClinicalTrials.gov, accessed August 8, 2025, https://clinicaltrials.gov/study/NCT03219333
27. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy - PubMed, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/31356140/
28. Health-related Quality of Life of Patients with Locally Advanced or Metastatic Urothelial Cancer Treated with Enfortumab Vedotin after Platinum and PD-1/PD-L1 Inhibitor Therapy: Results from Cohort 1 of the Phase 2 EV-201 Clinical Trial, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9385268/
29. Enfortumab Vedotin With or Without Pembrolizumab in Metastatic ..., accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/40067303/
30. Enfortumab Vedotin-Based Approaches to Metastatic Urothelial Carcinoma, accessed August 8, 2025, https://ascopost.com/news/march-2025/enfortumab-vedotin-based-approaches-to-metastatic-urothelial-carcinoma/
31. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer | Journal of Clinical Oncology - ASCO Publications, accessed August 8, 2025, https://ascopubs.org/doi/10.1200/JCO.22.02887
32. Enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC): Subgroup analyses of confirmed objective response rate (cORR) from EV-103 cohort K. - ASCO, accessed August 8, 2025, https://www.asco.org/posters/POSTER394566
33. Optimizing Treatment Strategies for Advanced Urothelial Cancer: What Comes After Frontline Enfortumab Vedotin and Pembrolizumab? - ASCO Daily News, accessed August 8, 2025, https://dailynews.ascopubs.org/do/optimizing-treatment-strategies-advanced-urothelial-cancer-comes-after-frontline
34. Enfortumab Vedotin Combo Yields 'Transformative' Urothelial Cancer Outcomes, accessed August 8, 2025, https://www.cancernetwork.com/view/enfortumab-vedotin-combo-yields-transformative-urothelial-cancer-outcomes
35. EV-302 Supports Enfortumab Vedotin Plus Pembrolizumab as Bladder Cancer SOC, accessed August 8, 2025, https://www.cancernetwork.com/view/ev-302-supports-enfortumab-vedotin-plus-pembrolizumab-as-bladder-cancer-soc
36. Official HCP Site for PADCEV® (enfortumab vedotin-ejfv), accessed August 8, 2025, https://www.padcevhcp.com/
37. Toxicity profile of enfortumab vedotin with or without pembrolizumab in patients with metastatic urothelial carcinoma: A systematic review and meta-analysis. - ASCO, accessed August 8, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT506914
38. Enfortumab Vedotin-ejfv Monograph for Professionals - Drugs.com, accessed August 8, 2025, https://www.drugs.com/monograph/enfortumab-vedotin-ejfv.html
39. European Medicines Agency Validates Type II Variation Application for PADCEV® (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) for First-Line Treatment of Advanced Bladder Cancer | Pfizer, accessed August 8, 2025, https://www.pfizer.com/news/press-release/press-release-detail/european-medicines-agency-validates-type-ii-variation
40. First-Line Enfortumab Vedotin, Pembrolizumab Superior to Chemotherapy in Patients With Urothelial Carcinoma - Pharmacy Times, accessed August 8, 2025, https://www.pharmacytimes.com/view/first-line-enfortumab-vedotin-pembrolizumab-superior-to-chemotherapy-in-patients-with-urothelial-carcinoma
41. FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma - PubMed, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/38441576/
42. European Commission Approves Astellas' PADCEV TM (enfortumab vedotin) in Combination with KEYTRUDA ® (pembrolizumab) for First-Line Treatment of Advanced Urothelial Cancer News, accessed August 8, 2025, https://www.astellas.com/en/news/29371
43. Padcev | Therapeutic Goods Administration (TGA), accessed August 8, 2025, https://www.tga.gov.au/resources/auspmd/padcev
44. EV-202: A phase II study of enfortumab vedotin in patients with ..., accessed August 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.TPS3647
45. A Study to Evaluate Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) | ClinicalTrials.gov, accessed August 8, 2025, https://www.clinicaltrials.gov/study/NCT04225117
46. Phase II Trial of Enfortumab Vedotin in Patients With Previously Treated Advanced Head and Neck Cancer - ASCO Publications, accessed August 8, 2025, https://ascopubs.org/doi/10.1200/JCO.24.00646
47. Enfortumab vedotin in the previously treated advanced head and neck cancer (HNC) cohort of EV-202. - ASCO, accessed August 8, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT409920
48. Enfortumab vedotin and pembrolizumab as first-line treatment in recurrent or metastatic head and neck squamous cell carcinoma: A cohort of the EV-202 trial. - ASCO Meeting Program Guide, accessed August 8, 2025, https://meetings.asco.org/abstracts-presentations/238511
49. Enfortumab vedotin (EV) in triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer (BC) cohorts of EV-202. - ASCO Meeting Program Guide, accessed August 8, 2025, https://meetings.asco.org/abstracts-presentations/233643
50. Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC)—2-year event-free survival and safety data for Cohort H. - ASCO Publications, accessed August 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4564
51. Clinical Trials Using Enfortumab Vedotin - NCI, accessed August 8, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/enfortumab-vedotin?pn=1
52. Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced and/or Node Positive Urothelial Cancer, The EV-ECLIPSE Trial - NCI, accessed August 8, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-04854
53. Enfortumab Vedotin and Pembrolizumab in People with Bladder Cancer - ClinicalTrials.gov, accessed August 8, 2025, https://clinicaltrials.gov/study/NCT05239624
54. Enfortumab vedotin Recruiting Phase 1 Trials for Metastatic Urothelial Carcinoma (UC) Treatment | DrugBank Online, accessed August 8, 2025, https://go.drugbank.com/drugs/DB13007/clinical_trials?conditions=DBCOND0073677&phase=1&purpose=treatment&status=recruiting
55. Enfortumab vedotin Recruiting Phase 1 Trials for metastatic Urothelial Carcinoma of the Bladder / Metastatic Urothelial Carcinoma (UC) / Urothelial Carcinoma Ureter Recurrent / Urothelial Carcinoma Bladder Recurrent / Urothelial Carcinoma Recurrent Treatment - DrugBank, accessed August 8, 2025, https://go.drugbank.com/drugs/DB13007/clinical_trials?conditions=DBCOND0073677%2CDBCOND0154595%2CDBCOND0117327%2CDBCOND0119267%2CDBCOND0150764&phase=1&purpose=treatment&status=recruiting
56. Official HCP Site - PADCEV™ (enfortumab vedotin-ejfv), accessed August 8, 2025, https://padcev-hcp.azurewebsites.net/hcp
57. A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer - larvol clin, accessed August 8, 2025, https://clin.larvol.com/trial-detail/NCT03219333
58. Enfortumab vedotin shrinks bladder tumours in Phase II study, accessed August 8, 2025, https://www.clinicaltrialsarena.com/news/enfortumab-vedotin-phase-ii-data/