Transformative Data in Cisplatin-Ineligible MIBC: Clinical Implications of Enfortumab Vedotin Plus Pembrolizumab
Key Points
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The phase 3 KEYNOTE-905/EV-303 trial demonstrated a doubling of overall survival (OS) and a 57% pathologic complete response (pCR) rate with enfortumab vedotin (EV) plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer (MIBC).
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NIAGARA vs KEYNOTE-905: cisplatin-eligible patients should receive perioperative gemcitabine/cisplatin plus durvalumab, while cisplatin-ineligible patients should be treated with EV-pembrolizumab with surgery incorporated mid-treatment.
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Early recognition and management of toxicities, such as rash, transaminitis, and neuropathy, are critical to maintaining patients on therapy.
The approval of enfortumab vedotin (EV) combined with pembrolizumab for cisplatin-ineligible muscle-invasive bladder cancer (MIBC) has been one of the most significant advancements in bladder cancer.
Thomas Powles, MD, MBBS, MRCP, of Barts Cancer Institute, joined the Oncology Brothers, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss the landmark KEYNOTE-905/EV-303 trial and its implications for clinical practice.
Landmark Trial Results
The randomized phase 3 trial enrolled patients with T2–T4, N1 MIBC who were not candidates for neoadjuvant platinum-based chemotherapy. Historically, these patients would receive cystectomy alone, a strategy associated with high relapse rates, Dr. Powles explained. KEYNOTE-905 compared surgery alone with a perioperative regimen of EV plus pembrolizumab—three cycles before surgery and five cycles after.
Although modest in size (350 patients compared with roughly 1000 in the NIAGARA study), the results were overwhelmingly positive, he said. Two findings stood out for Dr. Powles. First, OS was doubled in the investigational arm. Second, the pCR rate reached 57%. “That high pCR tells us that systemic therapy is having a profound effect on these patients,” he said.
By contrast, outcomes in the control arm were poor, with many patients experiencing disease relapse within 2 years.
NIAGARA vs KEYNOTE-905
The doctors shared insight on how this regimen compares with the NIAGARA trial, which established perioperative gemcitabine/cisplatin plus durvalumab for cisplatin-eligible patients with MIBC.
Dr. Powles said that for now, cisplatin-eligible patients should receive gemcitabine/cisplatin with perioperative durvalumab, while cisplatin-ineligible patients should receive EV-pembrolizumab with surgery.
However, he said the field remains dynamic, and clinicians should closely monitor data from randomized phase 3 trials that are underway.
EV + Pembrolizumab: Toxicity Management
Common early toxicities of EV include skin rash and transaminitis, while neuropathy tends to emerge later, often between cycles 6 and 9, according to Dr. Powles.
Neuropathy becomes more problematic with prolonged therapy in advanced disease. However, in the perioperative setting, it is manageable, he said, adding that EV plus pembrolizumab is not more difficult to administer cycle-to-cycle than platinum chemotherapy and may even be easier.
For rash, Dr. Powles said early intervention is critical. Dose interruption allows symptoms to resolve, and then therapy can resume at a reduced dose with good tolerability.
It’s also critical for clinicians to distinguish between immune-related adverse events and those driven by the antibody-drug conjugate (ADC). Steroid use should be approached cautiously and thoughtfully, particularly during the first 3 cycles, he said.
Future Outlook
Looking ahead, Dr. Powles is excited about the next wave of perioperative trials, including second-generation studies exploring ADC-based triplets and EV-pembrolizumab as a control arm. The combination of EV-pembrolizumab with FGFR-targeted therapies and other novel agents is also an area of interest.