Phase 3 KEYNOTE-905 and IMvigor011 Trials Signal New Standards in MIBC

Data that were presented from the phase 3 KEYNOTE-905/EV-303 (NCT03924895) and IMvigor011 (NCT04660344) trials during the 2025 ESMO Congress have the potential to alter the treatment paradigm of muscle-invasive bladder cancer (MIBC), according to Daniel P. Petrylak, MD. Specifically, data from KEYNOTE-905 demonstrated the first instance of improved efficacy outcomes with perioperative therapy relative to surgery for the treatment of patients with MIBC who are ineligible for cisplatin-based chemotherapy and results from IMvigor011 indicated that serial circulating tumor DNA (ctDNA) monitoring can identify patients with MIBC who may benefit from adjuvant atezolizumab (Tecentriq).1,2

“To me, [KEYNOTE-905] is the most important study that came out of ESMO,” Daniel P. Petrylak, MD, the chief of genitourinary oncology as well as a professor of medicine (medical oncology) and of urology at the Yale School of Medicine in New Haven, Connecticut, said in an interview with OncLive. “[These data] showed that this [regimen] is going to be the new standard of care for neoadjuvant therapy. We’ve never had neoadjuvant therapy in the past for cisplatin-ineligible patients.”

What were the key findings from KEYNOTE-905 presented at ESMO?

KEYNOTE-905 evaluated the perioperative combination of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in patients with MIBC who were not eligible for or declined cisplatin-based chemotherapy.1 Additional inclusion criteria included having at least 50% urothelial histology, an ECOG performance status of 0 to 2, and clinical stage T2 to T4aN0M0 or T1 to T4AN1M0 disease per central assessment.

Patients were randomly assigned 1:1 to receive intravenous (IV) enfortumab vedotin at 1.25 mg/kg on days 1 and 8 every 3 weeks for 3 cycles plus IV pembrolizumab at 200 mg every 3 weeks for 3 cycles or no therapy prior to radical cystectomy and pelvic lymph node dissection. Following surgery, patients in the investigational arm received enfortumab vedotin at 1.25 mg/kg on days 1 and 8 every 3 weeks for 6 cycles plus pembrolizumab at 200 mg every 3 weeks for 14 cycles; those in the control arm underwent observation.

The primary end point was event-free survival (EFS) per blinded independent central review. Key secondary end points consisted of overall survival (OS) and pathologic complete response (pCR) rate per central pathologist review.

Patients in the intention-to-treat population of the investigational arm (n = 170) achieved a median EFS that was not reached (NR; 95% CI, 37.3-NR) compared with 15.7 months (95% CI, 10.3-20.5) in the observation arm (n = 174; HR, 0.40; 95% CI, 0.28-0.57; 1-sided P < .0001). The 12-month EFS rates were 77.8% and 55.1% with the combination and observation, respectively; the 24-month EFS rates were 74.7% and 39.4%, respectively.

The median OS in the investigational and control arms was NR (95% CI, NR-NR) vs 41.7 months (95% CI, 31.8-NR), respectively (HR, 0.50; 95% CI, 0.33-0.74; 1-sided P = .0002). The 12- and 24-month OS rates in the investigational arm were 86.3% and 79.7%, respectively; these respective rates were 75.7% and 63.1% in the observation arm. The pCR rates were 57.1% (95% CI, 49.3%-64.6%) and 8.6% (95% CI, 4.9%-13.8%), respectively, representing an estimated difference of 48.3% (95% CI, 39.5%-56.5%; 1-sided P < .000001).

The safety profile of enfortumab vedotin plus pembrolizumab was found to be manageable and consistent with prior data with the regimen in patients with advanced/metastatic urothelial carcinoma. All patients in the investigational arm experienced any-grade treatment-emergent adverse effects (TEAEs); grade 3 or higher TEAEs (71.3%), and serious TEAEs (58.1%) were also reported in this arm. Notably, adverse effects (AEs) leading to a delay in surgery in the combination arm occurred at a low rate (4.0%).

How could the new data from IMvigor011 inform the role of ctDNA testing in MIBC?

IMvigor011 enrolled patients with MIBC within 6 to 24 weeks of radical cystectomy who had no evidence of radiographic disease and an ECOG performance status of 0 to 2; neoadjuvant chemotherapy was permitted. Eligible patients underwent ctDNA monitoring until 1-year post-cystectomy, which included ctDNA testing every 6 weeks and radiographic imaging every 12 weeks.

Patients who were ctDNA positive at any time during the 1-year monitoring period were randomly assigned 2:1 to receive IV atezolizumab at 1680 mg every 4 weeks for up to 1 year or matching placebo after no evidence of radiographic disease was confirmed. Those who achieved ctDNA negativity until 1 year received no further treatment. The primary end point was investigator-assessed disease-free survival (DFS) and OS represented the key secondary end point.

At a median follow-up of 16.1 months, patients who received atezolizumab (n = 167) experienced a median DFS of 9.9 months (95% CI, 7.2-12.7) compared with 4.8 months (95% CI, 4.1-8.3) among those in the placebo arm (n = 83; HR, 0.64; 95% CI, 0.47-0.87; stratified P = .0047). The 12- and 24-month DFS rates in the investigational arm were 44.7% and 28.0%, respectively; these respective rates in the placebo arm were 30.0% and 12.1%.

Moreover, the median OS in the atezolizumab arm was 32.8 months (95% CI, 27.7-not evaluable [NE]) vs 21.1 months (95% CI, 14.7-NE) in the placebo arm (HR, 0.59; 95% CI, 0.39-0.90; stratified P = .0131). The 12-month OS rates were 85.1% and 70.0% in the atezolizumab and placebo arms, respectively. The respective 24-month OS rates were 62.8% and 46.9%.

“[IMvigor011] used ctDNA to determine whether a patient should go on adjuvant atezolizumab or not, and we saw that in patients who were ctDNA positive post-cystectomy there was a survival benefit in favor of atezolizumab vs observation which is an important finding,” Petrylak explained. “[Additionally], among patients who were ctDNA negative, the relapse rate was very low, although there was a relapse rate, so you still have to consider using conventional imaging. But from a risk standpoint, [ctDNA] will help us to determine who should receive adjuvant therapy post-cystectomy.”

In terms of safety, the profile of atezolizumab was found to be tolerable with no new safety signals. Patients in the atezolizumab and placebo arms experienced similar rates of any-grade AEs (83.6% vs 85.5%), any-grade treatment related AEs (49.1% vs 50.6%), and grade 3 or 4 AEs (28.5% vs 21.7%).

Where can I learn more about the clinical effects of the new data presented during ESMO?

During the 19th Annual New York GU Cancers Congress™, hosted by Physicians’ Education Resource®, LLC, which is being held in New York, New York, from March 13 to 14, 2026, Petrylak will be joined by his cochair Maha Hussain, MD, FACP, FASCO, to further contextualize the key data updates presented during the 2025 ESMO Congress in MIBC and beyond.3 The meeting will focus on treatment selection considerations based on patient and disease characteristics considering updated data in prostate cancer, renal cell carcinoma, and bladder cancer. It will include expert presentations, panel discussions, and interactive tumor board-style case presentations. 

Hussain is the Genevieve E. Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, as well as the deputy director, and leader of the GU Oncology Program at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“We are going to have a special symposium on theranostics, which will be very interesting,” Petrylak explained. “There will [also] be a special symposium on urothelial carcinoma management, [which will highlight] the new data with enfortumab vedotin. These will be important, [but] the other [important aspect of] this meeting is the interaction between those practicing in the community and us [in the academic setting]; [the community oncologists] often bring their most difficult cases to discuss. [Virtual] meetings are good, but face-to-face meetings are better. [The New York GU Cancers Congress] is a unique interaction between patient care, the academic world, and the [pharmaceutical] world.”

References

1. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
2. Powles T, Kann AG, Castellano D, et al. IMvigor011: a phase 3 trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA8.
3. 19th Annual New York GU Cancers Congress. Physicians’ Education Resource, LLC. Accessed November 4, 2025. https://www.gotoper.com/courses/new-york-gu