Neoadjuvant cisplatin-based chemotherapy is a standard therapy for muscle-invasive bladder cancer. The efficacy and safety of neoadjuvant and adjuvant (perioperative) enfortumab vedotin–pembrolizumab as compared with neoadjuvant cisplatin-based chemotherapy in persons with this cancer are unclear.
We conducted a phase 3, open-label, randomized trial involving adults with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection (cystectomy). Participants were assigned to receive neoadjuvant enfortumab vedotin–pembrolizumab (4 cycles; enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] and pembrolizumab [200 mg on day 1] every 3 weeks), cystectomy, and 5 cycles of enfortumab vedotin and 13 cycles of pembrolizumab as adjuvant therapy or to receive neoadjuvant cisplatin–gemcitabine (4 cycles; cisplatin [70 mg per square meter of body-surface area on day 1] plus gemcitabine [1000 mg per square meter on days 1 and 8] every 3 weeks) and cystectomy. The primary end point was event-free survival; key secondary end points were overall survival and pathological complete response. Safety was assessed. Research Summary Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer
A total of 405 participants were assigned to receive enfortumab vedotin–pembrolizumab and 403 to receive cisplatin–gemcitabine. The median time from randomization to the data-cutoff date was 33.6 months (range, 22.5 to 53.6). A total of 86.7% of the participants in the enfortumab vedotin–pembrolizumab group and 89.6% of those in the cisplatin–gemcitabine group underwent cystectomy. 2 years, estimated event-free survival was 79.4% with enfortumab vedotin–pembrolizumab and 66.2% with cisplatin–gemcitabine (hazard ratio for an event or death, 0.53; 95% confidence interval [CI], 0.41 to 0.70; P
Among participants with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy, perioperative enfortumab vedotin–pembrolizumab led to significantly better event-free and overall survival outcomes and a significantly higher incidence of pathological complete response than neoadjuvant cisplatin–gemcitabine, but with more adverse events of grade 3 or higher. (Funded by Merck Sharp and Dohme and others; KEYNOTE-B15/EV-304 ClinicalTrials.gov number, NCT04700124.) Quick Take Enfortumab Vedotin–Pembrolizumab in Bladder Cancer 2m 59s
At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin–pembrolizumab group and 39.4% in the control group (hazard ratio) HR 0.4 estimated overall survival was 79.7% and 63.1% HR 0.50. Perioperative enfortumab vedotin plus pembrolizumab new standard of care for cisplatin ineligible patients who are candidates for surgery.
Circulating tumor DNA (ctDNA) was used to identify patients who may benefit from adjuvant immunotherapy. Among ctDNA-positive patients, those who received adjuvant atezolizumab demonstrated improved progression-free survival (PFS) and overall survival (OS) compared with placebo (median OS, 32 vs 24 months). Patients with persistently negative ctDNA results had 1-year disease-free survival (DFS) of 95% and 2-year DFS of 88%.
Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder.
Perioperative durvalumab showed an improvement of 2-year OS of 82.2 vs 75.2%, 2-year PFS was improved 67.8 vs 59.8%. There was interestingly no difference in the rates of grade 3-4 toxicity in the SOC vs periop-IO group. This is likely going to become the SOC in resectable bladder cancer.
Many had neoadjuvant therapy, still no difference between standard or extended lymphadenectomy for muscle-invasive bladder cancer. So, it seems more is not better.