Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab (EVP) substantially improves event-free survival (EFS), overall survival (OS), and pathologic complete response rates vs neoadjuvant gemcitabine/cisplatin in patients with muscle-invasive bladder cancer (MIBC) eligible for cisplatin-based chemotherapy, according to the phase 3 KEYNOTE-B15 trial.

The findings mark “a pivotal moment,” lead investigator Matthew Galsky, MD, of Mount Sinai Tisch Cancer Center in New York City, said during a presentation at ASCO Genitourinary Cancers Symposium 2026.

“For the first time since cisplatin-based neoadjuvant chemotherapy was shown to improve outcomes in patients with muscle-invasive bladder cancer almost 25 years ago, a non-platinum-based regimen has surpassed it,” Galsky said.

Perioperative EVP is already approved by the FDA for cisplatin-ineligible patients based on KEYNOTE-905, which found a 2-year EFS of 74.7% with the combination vs 39.4% with surgery alone and a 2-year OS of 79.7% vs 63.1%. 

KEYNOTE-B15 tested the combination for patients who are eligible for cisplatin, pitting perioperative EVP against neoadjuvant cisplatin/gemcitabine in 808 patients undergoing radical cystectomy. 

The pathologic complete response rate was 55.8% with EVP vs 32.5% with chemotherapy. EVP also reduced the risk of an event by 47%, with a 24-month EFS of 79.4% vs 66.2% with chemotherapy. Similarly, EVP lowered the risk of death by 35%, with a 24-month OS of 86.9% vs 81.3%. 

Taken together, Galsky said, the two KEYNOTE trials support perioperative EVP as an option for patients with MIBC, regardless of cisplatin eligibility. 

Study discussant Tyler Stewart, MD, a genitourinary medical oncologist at the University of California, San Diego, was impressed by the findings. 

“On Monday, this will be my new standard for patients with muscle-invasive bladder cancer,” he said. 

Steward noted, however, that it’s impossible to know whether EVP is better than two other newer options for resectable MIBC: adjuvant nivolumab and perioperative durvalumab, both administered with neoadjuvant cisplatin/gemcitabine.

Adjuvant nivolumab was approved by the FDA for the indication in 2021, after the CheckMate 274 trial found a median disease-free survival of 20.8 months with nivolumab add-on vs 10.8 months without it. There was a strong trend towards improved OS at 5 years — a median of 75 months with nivolumab vs 50.1 months without it — but the benefit did not reach statistical significance.

Perioperative durvalumab won approval last year based on the NIAGARA trial, which showed a 24-month EFS of 67.8% with durvalumab before and after surgery vs 59.8% without it, and a 24-month OS of 82.2% with durvalumab vs 75.2%.

Commenting on KEYNOTE-B15, Kevin Kelly, DO, a urological medical oncologist at Thomas Jefferson University, in Philadelphia, agreed that the findings point to a potential new standard of care for patients with MIBC.

However, there is still a need for “rigorously designed comparative trials” of the current treatment options, Kelly noted in an ASCO press release.

KEYNOTE-B15 randomized 403 patients to four cycles of neoadjuvant cisplatin/gemcitabine followed by surgery and 405 patients to four cycles of EVP followed by surgery and then five more cycles of EVP, with pembrolizumab continuing for an additional eight cycles. Just over half of EVP patients completed the full course of treatment.

Participants had clinical stage T2-T4aN0M0 or T1-T4aN1M0 disease. The median age in both arms was 66 years. 

Grade 3 or higher treatment-emergent adverse events occurred in 75.7% of EVP and 67.2% of cisplatin/gemcitabine patients. 

In general, patients in the EVP arm had more pruritus, diarrhea, alopecia, and rash, while patients receiving cisplatin/gemcitabine experienced more neutropenia, thrombocytopenia, anemia, and nausea, Galsky said.

Skin reactions, peripheral neuropathy, and ocular disorders were the most common adverse events of special interest with enfortumab vedotin; with pembrolizumab, severe skin reactions, hypothyroidism, and pneumonitis were the most common. 

As with other perioperative therapy trials, there’s a question of how long treatment needs to continue after surgery and whether treatment both before and after surgery is even necessary. 

“It’s the question that we’re asking in the field, whether or not we can start to think about de-escalating,” Galsky said. 

He suspects circulating tumor (ct)DNA will eventually resolve the issue and noted that an ongoing trial, MODERN, is looking into using ctDNA to guide adjuvant immunotherapy after cystectomy. 

The study was funded by Merck, maker of pembrolizumab, and Astellas and Pfizer, makers of enfortumab vedotin. Galsky is an advisor for Merck and Pfizer and disclosed research funding from Merck. Tyler is an advisor to Pfizer and other companies. Kelly has received research funding from Pfizer subsidiary Seagen. 

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com