Enfortumab Vedotin Plus Pembrolizumab Sustains Survival Advantage at 3.5 Years

Enfortumab vedotin (EV, Padcev; Astellas Pharma US, Inc/Seagen Inc) plus pembrolizumab (pembro, Keytruda; Merck Sharp & Dohme LLC) has established itself as the preferred standard of care for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC), following the landmark EV-302/KEYNOTE-A39 trial (NCT04223856).

Updated data with 3.5 years of median follow-up now reinforce the regimen’s long-term efficacy and shed new light on the clinical significance of complete response conversion.

"Now with 3 and a half years of follow-up, EV-pembro continues to be this transformative regime,” said Thomas Powles, MBBS, MD, PhD, MRCP, FCPS, professor of genitourinary oncology, director at Barts Cancer Centre at St. Bartholomew's Hospital in London, England, and lead for Solid Tumor Research. “I think it's curing patients; it's doubling survival, doubling progression-free survival (PFS), and has a 70% response rate."¹

Redefining the Standard of Care

Nectin-4, a protein highly expressed on the surface of muscle-invasive bladder cancer (MIBC) cells, serves as the therapeutic target of EV—an antibody-drug conjugate that has reshaped the treatment landscape for UC. Upon binding, EV delivers monomethyl auristatin E directly into cancer cells, triggering cell cycle arrest and apoptosis. Beyond its established role in locally advanced or metastatic disease, EV has now demonstrated meaningful clinical benefit in earlier-stage settings.^2-4

In November 2025, the FDA approved EV in combination with pembrolizumab for a new perioperative indication: neoadjuvant treatment followed by adjuvant treatment after cystectomy in adult patients with MIBC who are ineligible for cisplatin-containing chemotherapy. The approval was driven by results from the phase 3 EV-303 trial (NCT03924895), in which perioperative EV plus pembrolizumab reduced the risk of recurrence, progression, or death by approximately 60% compared with surgery alone.⁵

"The first trial I did, a number of very unsuccessful trials in my past...those early trials showed 5-year overall survival [OS] somewhere around 5%,” explained Powles. “So, we really have come a long way with this disease, and I think that's terrific for our patients."¹

Measuring EV’s Efficacy

The global, open-label, randomized phase 3 EV-302 trial compared the efficacy and safety of EV and pembro versus that of platinum-based chemotherapy in patients with previously untreated la/mUC. Patients were randomly assigned to receive EV (1.25 mg/kg intravenous [IV] on days 1 and 8 of each 3-week cycle) plus pembro (200 mg IV on day 1) or gemcitabine (gem) with cisplatin (cis) or carboplatin (carbo). Treatment continued until disease progression, unacceptable toxicity, or completion of the maximum number of cycles. The dual primary end points were PFS by blinded independent central review and OS; safety was a secondary end point.⁶

With a median follow-up of 42.8 months (data cutoff, October 6, 2025), the OS benefit favoring EV plus pembro over chemotherapy was sustained. Median OS was about 33.6 months in the EV plus pembro arm (n = 442) vs 15.9 months in the chemotherapy arm (n = 444), representing a 47% reduction in the risk of death (HR, 0.53; 95% CI, 0.45-0.63). The 42-month OS rate was approximately 44.0% with EV plus pembro compared with 24.6% with chemotherapy. No new safety signals were identified with extended follow-up.⁶

Notable Partial-to-Complete Response Conversions

Among responding patients, 45.1% in the EV plus pembro arm and 32.8% in the chemotherapy arm achieved a complete response (CR). A notable finding from this updated analysis is the frequency and impact of CR conversion: Among patients who achieved a confirmed CR in the EV plus pembro arm, 66.2% initially achieved a partial response (PR) before converting to a CR, doing so after a median of 5 additional EV cycles (IQR, 3.0-8.0).⁶

The survival outcomes in this subgroup were notable. Among all CR patients in the EV and pembro arm, median OS was not estimable, with a 42-month OS rate of 83.6% (95% CI, 75.6-89.1). For patients who converted from PR to CR specifically, median OS was similarly not estimable, and more than 80% remained alive at 3.5 years, with a 42-month OS rate of 82.4% (95% CI,71.8-89.4). Median total EV and pembro cycles were higher in the PR-to-CR subgroup (15.0 and 31.0, respectively) compared with all CR patients (13.0 and 28.0), reflecting the longer treatment duration required to achieve conversion.⁶

Subsequent Therapy Following EV Progression

Following discontinuation of study treatment, approximately 70% of patients who progressed on EV plus pembro received subsequent therapy. Platinum-based chemotherapy was the most common subsequent regimen in the EV plus pembro arm (30.5%), with investigator-assessed responses in 20.7% of those patients. No meaningful difference in outcomes was observed between gem-cis and gem-carbo in this post-EV setting. In the chemotherapy arm, a PD-L1 inhibitor was the most frequently used subsequent regimen (59.7%), with approximately 32% of patients receiving maintenance avelumab.¹

Median OS following subsequent therapy was 11 months. Powles suggested that platinum chemotherapy is likely becoming the de facto standard of care after EV plus pembro progression, noting that the 11-month OS figure should serve as "the benchmark of our ongoing randomized phase 3s in this space."¹

Emerging Signals With Long-Term Toxicity Data

The follow-up data revealed various adverse effects associated with EV plus pembro, which occur in earlier and later courses of treatment. Skin toxicity, hyperglycemia, and rare immune-related events (eg, adrenal insufficiency, pancreatitis, arthritis) appeared to occur relatively early, though arthritis showed a possible increasing trend over time.¹

Regarding later treatment courses, peripheral neuropathy trends increased with longer treatment duration, with the most critical management window being between 3 and 12 months but typically stabilizing beyond that point. Hypothyroidism appeared to become more common after 1 to 2 years.¹

"I think this long-term toxicity data [are] important if we're curing our patients,” said Powles.

Dose Modifications Crucial for AE Management

Dose modifications were common throughout the trial, with 60% of patients in the EV plus pembro arm requiring dose reductions or interruptions for EV and 43% requiring dose reductions specifically. Rather than viewing this as a treatment failure, Powles framed proactive dose management as central to keeping patients on therapy.

"Almost all my patients have dose reductions or dose interruptions," he noted. "I think it's a really important part of what we do, and I am very relaxed, particularly with that early skin toxicity and the peripheral neuropathy, to intervene to make sure we can give the drug safely."

The data reflected this reality in treatment duration as well. Median duration of EV therapy was 7 months, and for pembro, 8 months across the overall population, with only approximately 25% of patients reaching the 2-year maximum pembro duration and 41% remaining on therapy at 1 year.

"We haven't yet come to a conclusion about the optimal duration of therapy,” Powles said. “There's more work to be done here."

New Horizons for Urothelial Carcinoma Care

These data further support the growing role of EV plus pembro across the bladder cancer treatment spectrum, extending beyond MIBC to earlier and later stages of disease. As frontline facilitators of care, pharmacists will continue to play a crucial role in managing the nuanced toxicity profile of this regimen and ensuring patients remain on therapy long enough to achieve the deep, durable responses this data has shown are possible.

"When one looks back in time...” pondered Powles, “the thought of having 30% of patients in CR, 85% of [whom] are alive at 2 years, does suggest to us that we're curing some of those patients, and I'm now maybe for the first time really confident that we're doing that."

REFERENCES

1. Mckay R, Chen J, Choueiri TK, et al. Genitourinary cancer—kidney and bladder. Presented at 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL

2. Karam J, Galsky M, Powles T, et al. Oral abstract session B: urothelial carcinoma. Presented at: 2026 ASCO GU Cancers Symposium; February 26-28, 2026; San Francisco, CA.

3. Muscle-invasive bladder cancer. Urology Care Foundation. Updated August 2024. Accessed December 18, 2025. https://www.urologyhealth.org/urology-a-z/m/muscle-invasive-bladder-cancer

4. Chang BY, Khou T, Contreras A, McQuiston FL, Shin PJ. A review of antibody-drug conjugates for the treatment of urothelial carcinoma: the rise of enfortumab vedotin. Pharmacy Times. November 6, 2025. Accessed February 27, 2026. https://www.pharmacytimes.com/view/a-review-of-antibody-drug-conjugates-for-the-treatment-of-urothelial-carcinoma-the-rise-of-enfortumab-vedotin

5. US FDA approves Padcev plus Keytruda for certain patients with bladder cancer. News release. Pfizer Inc. November 21, 2025. Accessed November 21, 2025. https://www.businesswire.com/news/home/20251117031627/en/U.S.-FDA-Approves-PADCEV-plus-Keytruda-for-Certain-Patients-with-Bladder-Cancer

6. Powles T, Van Der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the phase 3 EV-302 study. Presented at 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 4507.