The 40-Year Chemotherapy Paradigm in Urothelial Cancer Has Been Overturned: ASCO 2026 EV-302 Data
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ASCO 2026 EV-302 Update: Enfortumab Vedotin + Pembrolizumab Has Become an Enduring Standard in Metastatic Urothelial Cancer
The Era of Chemotherapy as First-Line Treatment in Metastatic Urothelial Cancer Is Now Being Left Behind
Urothelial cancer most commonly originates in the bladder, but it can also arise in other parts of the urinary tract, such as the ureter, renal pelvis and urethra. In locally advanced or metastatic disease, the aim is often to control the disease for a long time, prolong life and reduce symptoms. Platinum-based chemotherapy was the main initial treatment for this patient group for many years.
The field began to change with the introduction of immunotherapies and, later, antibody-drug conjugates. Enfortumab vedotin is a Nectin-4-targeted antibody-drug conjugate, while pembrolizumab is a PD-1 inhibitor immunotherapy. The EV-302 study combined these two mechanisms in the first-line setting and demonstrated superiority over chemotherapy in both progression-free survival and overall survival. The ASCO 2026 update shows that this superiority is not a short-lived effect, but is maintained with long follow-up.
Brief Concept Note: What Are Urothelial Cancer, an ADC and a PD-1 Inhibitor?
Urothelial canceris cancer that develops from the cells called the urothelium, which line the urinary tract; it occurs most often in the bladder. ADCmeans antibody-drug conjugate; it is based on the principle of an antibody binding to a target on a cancer cell and delivering a potent cytotoxic drug into the cell. A PD-1 inhibitoris a class of immunotherapy that reduces the brakes on the immune system's response to cancer cells.
Why Might Enfortumab Vedotin + Pembrolizumab Be So Effective?
Enfortumab vedotin binds to a target called Nectin-4, which is frequently expressed on urothelial cancer cells, and delivers a cytotoxic payload with microtubule-inhibiting activity into the cell. This can directly cause tumor cell death. Pembrolizumab aims to enhance the T-cell response so that the immune system works more effectively against the tumor.
This combination brings together two different biological effects: targeted cytotoxic tumor killing and release of the immune response. EV-induced tumor cell death may increase the presentation of tumor antigens to the immune system, while pembrolizumab may help make this immune response more durable.
First-Line EV + Pembrolizumab Versus Platinum-Gemcitabine Chemotherapy
EV-302/KEYNOTE-A39 is a global, open-label, randomized phase 3 study comparing enfortumab vedotin + pembrolizumab with standard platinum-gemcitabine chemotherapy in previously untreated patients with locally advanced or metastatic urothelial cancer. The inclusion of a broad patient group eligible to receive either cisplatin or carboplatin makes the study particularly relevant to clinical practice.
In the study's primary analysis, EV + pembrolizumab demonstrated clear superiority over chemotherapy in both progression-free survival and overall survival. These results paved the way for the FDA to approve the combination for first-line treatment of locally advanced or metastatic urothelial cancer at the end of 2023.
Brief Concept Note: What Do Phase 3, OS, PFS and HR Mean?
A phase 3 studyis a research stage in which a new treatment is compared with standard treatment in a large patient group and has the potential to change clinical practice. OSmeans overall survival: the time until a patient's death from any cause. PFSis the time during which the disease remains controlled without progression or death. HRmeans hazard ratio: a measure comparing the risk of an event occurring over time in two treatment arms.
| Item | EV + Pembrolizumab | Chemotherapy | Clinical significance |
|---|---|---|---|
| Treatment type | Nectin-4-targeted ADC + PD-1 inhibitor | Platinum + gemcitabine chemotherapy | Targeted cytotoxic treatment + immunotherapy was compared with conventional chemotherapy. |
| Patient group | Previously untreated locally advanced or metastatic urothelial cancer | The patient population that determines the first-line treatment standard. | |
| Primary analysis result | Superiority in both PFS and OS | Shorter disease control and survival | The combination surpassed the chemotherapy standard. |
| ASCO 2026 update | OS of 33,6 months at 42,8 months of follow-up | OS of 15,9 months | The survival difference is maintained with long follow-up. |
The Survival Difference Remains Very Clear at 3,5 Years of Follow-Up
In the updated analysis presented at ASCO 2026, median follow-up was approximately 42,8 months. At this long follow-up, median overall survival in the EV + pembrolizumab arm was 33,6 monthsand in the chemotherapy arm 15,9 months as reported. The risk of death was significantly lower in the combination arm: HR 0,53; %95 confidence interval 0,45–0,63.
More importantly, the separation of the long-term survival curves was maintained. The overall survival rate at 3,5 years in the EV + pembrolizumab arm was %44,0and in the chemotherapy arm %24,6 . This is a very strong and clinically meaningful long-term difference in metastatic urothelial cancer.
Clinical Significance of Long-Term Survival
- Median OS more than doubles: 33,6 months versus 15,9 months is a very strong difference for metastatic urothelial cancer.
- The difference does not disappear over time: The survival benefit is maintained at 42,8 months of follow-up.
- OS at 3,5 years is significantly higher: %44,0 versus %24,6 represents a marked increase in the proportion of long-term survivors.
- The new standard is strengthened: EV + pembrolizumab should now be viewed as a first-line standard with durable survival data, beyond simply a positive study result.
Response Rates and Complete Responses Also Favor the Combination
In the updated analysis, the objective response rate in the EV + pembrolizumab arm was %67,5and in the chemotherapy arm %44,2 . The complete response rate in the combination arm was %30,4and in the chemotherapy arm %14,5 as reported.
Brief Concept Note: What Are Objective Response and Complete Response?
The objective response rateindicates the proportion of patients whose tumors shrink measurably; it includes both complete and partial responses. A complete responseis the disappearance of measurable tumor findings on imaging and clinical assessment. In metastatic disease, a complete response is a rare and clinically very valuable outcome.
| Outcome | EV + Pembrolizumab | Chemotherapy | Clinical interpretation |
|---|---|---|---|
| Median overall survival | 33,6 months | 15,9 months | Survival approximately doubles in the combination arm. |
| Risk of death | HR 0,53; %95 CI 0,45–0,63 | Approximately %47 relative reduction in the risk of death. | |
| Overall survival at 3,5 years | %44,0 | %24,6 | The proportion of long-term survivors is markedly higher with the combination. |
| Objective response rate | %67,5 | %44,2 | The combination produces tumor shrinkage more frequently. |
| Complete response rate | %30,4 | %14,5 | The complete response rate is approximately twice as high with the combination. |
From Partial to Complete Response: The Treatment Effect Can Mature Over Time
One of the most notable findings of the ASCO 2026 update was the increase in complete responses over time. A substantial proportion of patients who achieved a complete response in the EV + pembrolizumab arm initially had a partial response; as treatment continued, these responses became complete. Updated summaries report that approximately two-thirds of patients who achieved a complete response first showed a partial response and subsequently converted to a complete response.
This finding is clinically important. While some treatments produce rapid but shallow responses, responses to other treatments deepen over time. The continued accumulation of complete responses with EV + pembrolizumab through week 96 suggests that the treatment effect matures over time in some patients.
Brief Concept Note: What Does Conversion From a Partial to a Complete Response Mean?
A partial responsemeans a marked reduction in tumor burden without the disappearance of all measurable disease. Conversion to a complete responsemeans the disappearance of remaining measurable tumor findings as treatment continues. This indicates that treatment may provide not only rapid shrinkage, but also deeper disease control over time.
Importance of Deepening Responses
- Early decision to continue treatment: Patients with a partial response who tolerate toxicity may develop a deeper response as treatment continues.
- Potential for long-term control: A complete response may be associated with longer disease control in some patients.
- Patient motivation: Even if the first imaging assessment shows a partial response, patients should be told that the response may deepen over time.
- Need for biomarkers: Biomarkers that predict which patients will convert to a complete response are not yet clearly established.
How Did the 40-Year Chemotherapy Paradigm in Urothelial Cancer Change?
Cisplatin-based chemotherapy was the strongest first-line option in metastatic urothelial cancer for many years. Regimens such as MVAC and, later, gemcitabine-cisplatin provided disease control, but survival gains were limited and many patients were ineligible for cisplatin. Carboplatin-gemcitabine was a more feasible but less effective option for patients unable to receive cisplatin.
In the second half of the 2010s, immunotherapies, especially PD-1/PD-L1 inhibitors, produced an important breakthrough in the post-platinum setting. Later, avelumab maintenance established a new standard by prolonging survival following a response or stable disease with platinum-based chemotherapy. However, there was still a need for a regimen that directly surpassed chemotherapy in the first-line setting and substantially improved survival in a broad patient group.
EV-302/KEYNOTE-A39 met this need. Enfortumab vedotin + pembrolizumab changed the treatment paradigm by providing, for the first time, such a marked and durable survival benefit over platinum-based chemotherapy.
| Era / approach | Main treatment | Strength | Limitation | What changed with EV-302 |
|---|---|---|---|---|
| Conventional chemotherapy era | MVAC, gemcitabine-cisplatin or gemcitabine-carboplatin | Rapid tumor shrinkage and proven efficacy | Limited survival; high toxicity; cisplatin eligibility is a major problem | Chemotherapy is no longer the sole main first-line standard. |
| Immunotherapy era | PD-1/PD-L1 inhibitors, particularly after platinum or in selected first-line groups | Patient subgroups able to achieve long-lasting responses | Limited response rate; not effective in every patient | Combining immunotherapy with an ADC produced a broader effect. |
| Avelumab maintenance era | Avelumab maintenance in patients without progression after platinum chemotherapy | Changed the survival standard following first-line treatment | Requires a response to chemotherapy or stabilization first | EV + pembrolizumab offers a stronger strategy from the outset, without waiting for chemotherapy. |
| EV + pembrolizumab era | Nectin-4-targeted ADC + PD-1 inhibitor | Clear superiority in OS, PFS, ORR and CR | Neuropathy, skin toxicity, hyperglycemia and immune adverse events require attention | A new standard that changes the first-line treatment paradigm. |
Effective Treatment Requires Careful Toxicity Management
Although EV + pembrolizumab provides high efficacy, toxicity management is critical to treatment success. The main adverse effects associated with enfortumab vedotin include peripheral neuropathy, skin reactions, hyperglycemia, ocular adverse effects and infusion reactions. Pembrolizumab requires attention to immune-related adverse events; thyroiditis, pneumonitis, colitis, hepatitis and endocrine toxicities must be monitored.
Brief Concept Note: What Are Peripheral Neuropathy, Hyperglycemia and an Immune Adverse Event?
Peripheral neuropathyis nerve damage causing numbness, tingling, burning or weakness in the hands and feet. Hyperglycemiais elevated blood sugar and is particularly important in patients with diabetes or prediabetes. An immune-related adverse eventoccurs when immunotherapy excessively activates the immune system, causing inflammation in healthy organs.
Practical Toxicity Management Note
- Neuropathy: Before treatment, patients should be asked about diabetic neuropathy, previous neurotoxic chemotherapy and daily functioning.
- Skin toxicity: Rash, blisters, widespread redness or mucosal involvement must be recognized early; severe skin reactions require urgent assessment.
- Hyperglycemia: Fasting glucose and HbA1c should be assessed at baseline; patients with diabetes require close monitoring.
- Immune toxicity: Patients should be asked about cough, diarrhea, abdominal pain, jaundice, fatigue, headache or hormonal symptoms as possible immune adverse events.
- Patient education: Early reporting of adverse effects is very important for treatment continuity with this therapy.
Which Patients Require Greater Caution?
EV + pembrolizumab is a strong first-line standard in appropriate patients, but it may not be equally easy to administer to every patient. The benefit-risk balance must be assessed more carefully in patients with marked peripheral neuropathy, uncontrolled diabetes, severe autoimmune disease, current immunosuppressive treatment, a history of severe skin disease or fragile performance status.
Issues to Consider in Patient Selection
- Performance status: The patient's capacity to tolerate treatment must be assessed.
- Peripheral neuropathy: If neuropathy is present at baseline, the EV dosing and monitoring plan requires special attention.
- Diabetes / prediabetes: Metabolic control is important because of the risk of hyperglycemia.
- Autoimmune disease: Pembrolizumab may pose a risk of immune-related adverse events.
- Risk of skin toxicity: Patients must report rash and skin reactions early.
- Access and reimbursement: In real-world practice, access to treatment is a key factor determining implementation of the algorithm.
Algorithms Need Updating, but Access Will Be Decisive
The 3,5-year update of EV-302 shows that treatment algorithms for metastatic urothelial cancer in Türkiye need to be reconsidered in light of current evidence. In appropriate patients, EV + pembrolizumab offers a higher response rate, more complete responses and significantly longer survival than chemotherapy.
Nevertheless, regulatory approval, reimbursement, drug access, toxicity management and multidisciplinary follow-up will determine the widespread use of this treatment in real-world practice. Close monitoring at experienced centers is important, particularly for peripheral neuropathy, skin reactions, hyperglycemia and immune adverse events.
How Should We Discuss This With a Patient?
“This new combination significantly improved both tumor response and survival compared with conventional chemotherapy in metastatic bladder and urothelial cancer. The benefit continues with long follow-up. However, treatment may have adverse effects involving the skin, nervous system, blood sugar and immune system. The decision must therefore consider your general condition, other conditions such as diabetes or neuropathy, access to treatment and adverse effect monitoring together.”
Durable Survival Benefit Further Clarifies the New Standard
Academic Assessment
The 3,5-year update of EV-302 shows that enfortumab vedotin + pembrolizumab is now a strong and enduring first-line standard in metastatic urothelial cancer.
The deepening of complete responses over time suggests that this treatment has the potential to truly change the natural course of the disease in some patients.
The next goal should be to bring this effective treatment to the right patients, manage toxicity well and better identify patients who will achieve long-lasting responses.
How Will We Identify Patients With Long-Lasting Responses?
EV + pembrolizumab is now a combination with strongly proven efficacy. The next research focus will be to better define the patient group that will obtain the longest and deepest benefit from this treatment. At present, Nectin-4 expression alone is not a sufficient clinical selection tool; the need for more advanced biomarkers remains.
Open Questions
- Biomarker: Which patient will achieve a long-lasting complete response, and which will develop early resistance?
- Treatment duration: How long should treatment continue in a patient with a long-lasting complete response?
- Restarting after an adverse effect: How should dose reduction and restarting algorithms be optimized after neuropathy or skin toxicity?
- Older patients and those with comorbidities: What will the real-world balance between efficacy and safety be in frail patients or those with diabetes or neuropathy?
- Sequencing: How should FGFR inhibitors, chemotherapy, other ADCs and clinical trials be sequenced following progression on EV + pembrolizumab?
- Perioperative setting: In which patients will moving this combination into earlier lines for locally advanced or muscle-invasive disease be valuable?
Truecheck Note
This update strengthens the first-line standard of EV + pembrolizumab in metastatic urothelial cancer. However, the treatment decision should not be automatic for every patient. Peripheral neuropathy, skin toxicity, hyperglycemia, immune adverse event risk, performance status and access conditions must be assessed individually.
EV-302 Redefines the Long-Term Standard in Metastatic Urothelial Cancer
The 3,5-year EV-302/KEYNOTE-A39 update presented at ASCO 2026 further consolidated the role of enfortumab vedotin + pembrolizumab in first-line treatment of metastatic urothelial cancer. At approximately 42,8 months of follow-up, median overall survival was reported as 33,6 months versus 15,9 months, and the significant reduction in the risk of death persisted.
The objective response rate was %67,5 and the complete response rate was %30,4. In the chemotherapy arm, these rates remained at %44,2 and %14,5, respectively. In addition, the deepening of complete responses over time suggests that the combination may provide not only rapid tumor shrinkage, but also more durable and deeper disease control in some patients.
These data position EV + pembrolizumab as the strongest first-line standard for metastatic urothelial cancer in appropriate patients. The next clinical goal is to deliver this effective treatment to the right patient at the right time with careful adverse effect management, and to better define the patient group that will achieve long-lasting responses.
References
- ASCO 2026. EV-302: Enfortumab vedotin plus pembrolizumab versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma.
- OncLive. Updated EV-302 Data Reinforce Enfortumab Vedotin Combo’s Durability in Urothelial Carcinoma at ASCO 2026. 21 May 2026.
- Targeted Oncology. Enfortumab Vedotin Plus Pembrolizumab Sustains Long-Term Efficacy in Advanced Urothelial Carcinoma. 2026.
- Powles T et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. New England Journal of Medicine. 2024.
- PubMed. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. 2024.
- ClinicalTrials.gov. EV-302 / KEYNOTE-A39. NCT04223856.
- U.S. FDA. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. 15 December 2023.
- Brave MH et al. FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma. Clinical Cancer Research. 2024.
- van der Heijden MS et al. Exploratory subgroup analyses of EV-302: enfortumab vedotin plus pembrolizumab versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma. 2025.
- drozdogan.com. Mesane Kanserinde Yeni Standart: Enfortumab Vedotin ve Pembrolizumab Kombinasyonu.
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