'Keytruda+Padcev' proposed as a new standard trt for MIBC

The Phase 3 KEYNOTE-905/EV-303 studies have confirmed a survival benefit

Has improved all EFS·OS·pCR indexes in MIBC patients ineligible to receive cisplatin

Perioperative combination therapy is expected to bring a paradigm shift

Keytruda (pembrolizumab) and Padcev (enfortumab vedotin) have demonstrated synergistic effects in muscle-invasive bladder cancer (MIBC), opening up new possibilities.

 

Analysis suggests that the combination of enfortumab vedotin and pembrolizumab may shift the perioperative standard of care for MIBC patients who are ineligible for or refuse cisplatin.

 

The KEYNOTE-905/EV-303 results were presented at the ESMO Congress 2025.

On October 18 (local time), the Phase 3 KEYNOTE-905/EV-303 results (LBA2) were presented at the ESMO Congress 2025 (European Society for Medical Oncology).

 

The study evaluated the combination of Padcev and Keytruda before and after radical cystectomy + pelvic lymph node dissection (RC+PLND), the current standard of care, in MIBC patients who were ineligible for or refused cisplatin.

 

Perioperative EV + pembrolizumab combination therapy improved the survival index significantly선 Professor Christof Vulsteke of AZ Maria Middelares Hospital in Belgium delivered the Phase 3 clinical trial results as an oral presentation during the Presidential Symposium I.

 

Professor Christof Vulsteke of AZ Maria Middelares Hospital in Belgium

The study randomized 344 patients ineligible for or refusing cisplatin, comparing the Padcev + Keytruda combination therapy group (170 patients) with the surgery-only control group (174 patients).

 

Patients were tracked for a median follow-up of 25.6 months.

 

The study results showed that the Padcev + Keytruda combination therapy demonstrated statistically significant improvements in event-free survival (EFS), overall survival (OS), and pathological complete response rate (pCR) compared to RC+PLND monotherapy.

 

First, EFS was significantly improved in the combination group, with the median not yet reached, compared to 15.7 months in the control group (Hazard Ratio [HR] 0.40; 95% CI 0.28–0.57; P < 0.0001).

 

Overall survival (OS) also showed a statistical advantage in the combination group, with the median not yet reached, compared to 41.7 months in the control group (HR 0.50; 95% CI 0.33–0.74; P = 0.0002).

 

This performance garnered significant applause during the presentation of EFS and OS results.

 

The pCR also showed a stark difference: 57.1% in the combination arm versus 8.6% in the control arm, a difference of nearly 48 percentage points (P < 0.000001).

 

Event-free survival (EFS) was significantly improved in the combination group, with the median not yet reached, compared to 15.7 months in the control group (Hazard Ratio [HR] 0.40; 95% CI 0.28–0.57; P < 0.0001).

Professor Vulsteke said, "This study is the first randomized Phase 3 result to clearly demonstrate a survival benefit from perioperative combination therapy in patients with resectable, cisplatin-ineligible MIBC," and explained that "the Padcev + Keytruda combination demonstrated the potential to replace the existing chemotherapy-centric treatment paradigm." The median age of the patients was 74, and the reasons for cisplatin ineligibility varied, including reduced kidney function, hearing impairment, and neuropathy.

 

However, the benefit of the Padcev + Keytruda combination was consistently maintained across subgroup analyses by age and comorbidity.

 

However, the incidence of Grade 3 or higher adverse events was higher in the combination group (71.3%) compared to the control group (45.9%), emphasizing the importance of patient selection and management during clinical application.

 

"Clarity needed on stage-specific contribution of treatment before and after surgery"

Jonathan Rosenberg, Professor at Memorial Sloan Kettering Cancer Center in the U.S.

Jonathan Rosenberg, Professor at Memorial Sloan Kettering Cancer Center in the U.S., who participated as a guest speaker, said, "This study showed impressive results with an HR for both EFS and OS in the range of 0.4-0.5 in elderly and cisplatin-ineligible or refusing patients," and assessed that "the Padcev + Keytruda combination is ready to become a realistic new standard of care." Professor Rosenberg further stressed, "Clearly defining the contribution of treatment in the neoadjuvant and adjuvant stages, and optimizing therapy through circulating tumor DNA (ctDNA) analysis, will be important future tasks." Regarding the management of relapsed and metastatic patients, he suggested, "Platinum-based chemotherapy may still be considered the standard for patients who relapse early after Padcev + Keytruda," and proposed that "research into new treatment orders is needed in the post-EV combination era." Experts analyzed that, based on these results, the focus of bladder cancer treatment is shifting from traditional cisplatin chemotherapy to EV-based combination therapy, assessing this as a signal for a paradigm shift in the treatment of MIBC.