Dear Readers,
In this issue, we highlight recently presented and published trials from the 2025 ESMO Annual Meeting. In the future, please reach out to us directly in order to highlight any specific clinical trials at pkagarwal@bsd.uchicago.edu or cns9006@med.cornell.edu and/or at blc.pra@sagepub.com
Sincerely,
Study Title: KEYNOTE-905/EV-303: A Phase 3, randomized study of perioperative Pembrolizumab plus Enfortumab Vedotin (EV) for muscle-invasive bladder cancer (MIBC) in cisplatin-ineligible patients.
Clinicaltrials.gov identifier: NCT03924895
Sponsor: Merck Sharp & Dohme Corp./Astellas Pharma/Seagen Inc. (Pfizer)
Enrollment: 359 (Randomized population for efficacy analysis in presented cohorts)
Rationale: There is a critical unmet need for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or decline cisplatin-based chemotherapy. Approximately half of patients are ineligible for cisplatin-based chemotherapy due to comorbidities or impaired renal function. The current standard of care for this population is radical cystectomy (RC) alone, which is associated with high recurrence rates and poor long-term survival. Enfortumab vedotin (EV) plus pembrolizumab (Pembro) has previously demonstrated profound efficacy and a survival benefit in the metastatic setting (EV-302). KEYNOTE-905 evaluates whether this potent combination, given perioperatively (neoadjuvant and adjuvant), can improve outcomes compared to surgery alone in this high-risk, cisplatin-ineligible population.
Study Design: This is a randomized, open-label, Phase 3 study. Patients with MIBC (T2-T4aN0M0 or T1-T4aN1M0) who were cisplatin-ineligible (per Galsky criteria) or declined cisplatin were randomized to treatment. The presented data focused on the comparison between Arm C (Perioperative Combination) and Arm B (Surgery Alone).
Arm C (Experimental): Neoadjuvant EV (1.25 mg/kg Days 1, 8) + Pembrolizumab (200 mg Day 1) Q3 W for 3 cycles, followed by Radical cystectomy (RC)+ pelvic lymph node dissection (PLND), followed by Adjuvant EV (6 cycles) + Pembrolizumab (up to 14 cycles).
Arm B (Control): Radical cystectomy (RC) + pelvic lymph node dissection (PLND) alone.
(Note: The study also included an ARM A: Pembrolizumab monotherapy arm followed by RC + PLND, but the primary comparison presented was Combination vs. Control as ARM A was stopped in 2022).
Endpoints: The primary endpoint was Event-Free Survival (EFS) by blinded independent central review. Secondary endpoints included Overall Survival (OS), Pathological Complete Response (pCR) rate, and safety.
Results: Overall, 344 patients were randomized (170 to the combination arm and 174 to the control arm). Results from the interim analysis presented at ESMO 2025 showed a statistically significant and clinically meaningful benefit for the combination arm.
Event-Free Survival (EFS): The median EFS was Not Reached in the combination arm vs. 15.7 months in the control arm. This corresponded to a Hazard Ratio (HR) of 0.40 (95% CI: 0.28–0.57; p < 0.0001), representing a 60% reduction in the risk of progression or death.
Overall Survival (OS): The median OS was Not Reached in the combination arm vs. 41.7 months in the control arm, with a Hazard Ratio (HR) of 0.50 (95% CI: 0.33–0.74; p = 0.0002). This analysis further incorporated the differential use of subsequent therapies, with 4.7% of patients in the combination arm and 26.4% in the control arm receiving treatment for recurrent or metastatic disease.
Pathological Complete Response (pCR): The pCR rate was 57.1% in the combination arm compared to 8.6% in the control arm (Difference: 48.3%; p < 0.00001).
Safety: Grade ≥3 treatment-related adverse events occurred in 71.3% of the combination group vs. 45.9% in the control group. Skin reactions and peripheral neuropathy were the most common adverse events, consistent with the known profiles of EV and Pembro. Neoadjuvant treatment did not delay surgery or increase surgical complications.
Comments: KEYNOTE-905 represents a practice-changing milestone, being the first phase III trial to show an overall survival (OS) and event-free survival (EFS) benefit with perioperative systemic therapy in cisplatin-ineligible MIBC patients.The pCR rate of 57.1% is the highest ever reported in a Phase 3 MIBC trial, significantly outperforming historical controls. In addition, this was a generally older population than other perioperative MIBC trials, with a median age of 74 years in the combination arm as compared to 72.5 years in the cystectomy arm. Notably, adjuvant immunotherapy was largely absent in the control arm, with only 16.7% of patients receiving adjuvant immune checkpoint therapy. While the toxicity is higher in the combination arm than surgery alone, it was reported as manageable and did not preclude curative-intent surgery. These results established the EV + Pembro regimen as a new standard of care for cisplatin-ineligible patients, leading to FDA approval in November 2025.
Reference: Presented by Christof Vulsteke, MD, PhD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA2.
Study Title: IMvigor011: A Phase 3 trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer (MIBC).
Clinicaltrials.gov identifier: NCT04660344
Sponsor: F. Hoffmann-La Roche Ltd/Genentech, Inc.
Enrollment: 761 (Surveillance Phase); 250 (Randomized Treatment Phase)
Rationale: High-risk muscle-invasive bladder cancer (MIBC) patients often face recurrence after radical cystectomy (RC). Previous trials (e.g., IMvigor010) failed to show a benefit for adjuvant atezolizumab in an unselected population, but retrospective analyses suggested that only patients with detectable circulating tumor DNA (ctDNA) derived benefit. IMvigor011 was designed to prospectively validate whether serial ctDNA testing could identify patients with molecular residual disease (MRD) who would benefit from adjuvant therapy, while sparing ctDNA-negative patients from unnecessary treatment.
Study Design: This was a global, double-blind, randomized Phase 3 study. Patients with high-risk MIBC (pT2-4aN0M0 or pT1-4aN1-3M0) post-cystectomy were enrolled in a surveillance phase with serial ctDNA testing (Signatera™) performed every 6 weeks for up to 12 months. Prior neoadjuvant chemotherapy was allowed.
ctDNA-Positive: Patients who tested positive for ctDNA (either at baseline or during surveillance) were randomized 2:1 to receive Atezolizumab (1200 mg q3w for up to 1 year) or Placebo.
ctDNA-Negative: Patients who consistently tested negative for ctDNA continued surveillance without adjuvant treatment.
Endpoints: The primary endpoint was investigator-assessed Disease-Free Survival (DFS) in the intent-to-treat (ITT) population of randomized (ctDNA+) patients. Secondary endpoints include Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), and Safety.
Results: At the ESMO 2025 interim analysis, data was presented on 607 patients (250 patients with ctDNA positivity (167 randomized to atezolizumab and 83 to placebo) and 357 patients with ctDNA negativity) as the study met its primary and key secondary endpoints:
Disease-Free Survival (DFS): In the randomized ctDNA + population, the median DFS was 9.9 months with Atezolizumab vs. 4.8 months with Placebo. This resulted in a Hazard Ratio (HR) of 0.64 (95% CI: 0.47–0.87; p = 0.0047). The 12-month DFS rate was 44.7% vs 30.0%.
Overall Survival (OS): Adjuvant atezolizumab demonstrated a statistically significant improvement in OS with a median of 32.8 months vs. 21.1 months for placebo (HR 0.59; 95% CI: 0.39–0.90; p = 0.0131).
ctDNA-Negative Cohort: Patients who remained ctDNA-negative during surveillance had excellent outcomes without treatment, with a 12-month DFS of 95.4% and a 12-month OS of 100%.
Safety: The safety profile was consistent with prior atezolizumab studies. Grade 3-4 treatment-related adverse events occurred in 7.3% of the atezolizumab arm vs. 3.6% in the placebo arm.
Comments: IMvigor011 is a landmark, practice-changing study providing the first Level 1 evidence for ctDNA-guided intervention in MIBC post cystectomy. It fundamentally shifts the treatment paradigm from treating “risk” (pathological stage) to treating “disease” (molecular presence). The authors concluded that the data confirmed that ctDNA + patients derive significant survival benefit from immunotherapy, while ctDNA-negative patients can be safely spared the toxicity and cost of treatment, as their recurrence risk is exceptionally low. However, in the ctDNA-negative cohort, 102 patients (22%) subsequently converted to ctDNA-positive status, and 39 (8%) experienced clinical recurrence before ctDNA positivity. Thus, approximately 30% of patients had unfavorable outcomes. Importantly, the question of treatment versus placebo at the time of molecular recurrence is conceptually distinct from whether treatment at molecular recurrence is non-inferior to conventional adjuvant therapy. This study validates the use of serial ctDNA monitoring as a standard of care for post-cystectomy management.
Reference: Presented by Thomas Powles, MD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA8 and Powles T et al., N Engl J Med. 2025 Dec 18;393(24):2395–2408.
Study Title: POTOMAC: A Phase 3, randomized study of Durvalumab in combination with Bacillus Calmette-Guérin (BCG) for BCG-naive, high-risk, non-muscle-invasive bladder cancer (NMIBC).
Clinicaltrials.gov identifier: NCT03528694
Sponsor: AstraZeneca
Enrollment: 1018
Rationale: Standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) involves transurethral resection followed by intravesical BCG. However, recurrence and progression rates remain high. Durvalumab (an anti-PD-L1 antibody) has shown efficacy in advanced urothelial carcinoma. The POTOMAC trial hypothesized that combining systemic checkpoint inhibition with local BCG immunotherapy could enhance the antitumor immune response and improve disease control in the BCG-naive, high-risk setting.
Study Design: This was a randomized, open-label, global Phase 3 study. Patients with histologically confirmed, BCG-naive, high-risk NMIBC (including CIS, T1, or high-grade Ta) were randomized 1:1:1 to three arms:
Arm A (Experimental): Durvalumab (1500 mg IV q4w for 13 cycles/1 year) + BCG Induction (6 weeks) + BCG Maintenance (Standard SWOG protocol for 24 months).
Arm B (Experimental): Durvalumab (1 year) + BCG Induction (6 weeks) only (No BCG maintenance).
Arm C (Control): BCG Induction + BCG Maintenance (Standard SWOG protocol for 24 months).
Endpoints: The primary endpoint was Disease-Free Survival (DFS), defined as the time to recurrence of high-grade NMIBC, progression to muscle-invasive or metastatic disease, or death. Secondary endpoints include Overall Survival (OS) and safety.
Results: Data was presented on 1018 patients at a median follow-up of 60.7 months as the study met its primary endpoint for the combination maintenance arm.
Disease-Free Survival (DFS): Durvalumab + BCG (Induction + Maintenance) reduced the risk of recurrence or progression by 32% compared to BCG alone (Hazard Ratio 0.68; 95% CI: 0.50–0.93; p = 0.0154).
DFS Rates: The estimated 24-month DFS rate was 86.5% for the combination arm vs 81.6% for the control arm.
Induction-Only Arm: Interestingly, the arm receiving Durvalumab with only BCG induction (Arm B) did not show a benefit over standard BCG maintenance (HR 1.14), suggesting that omitting BCG maintenance is inferior even with systemic immunotherapy.
Overall Survival (OS): While not formally powered for OS, descriptive analysis showed no detriment to survival (HR 0.80; 95% CI: 0.53–1.20).
Safety: Grade 3/4 treatment-related adverse events occurred in 21% of the combination arm compared to 4% in the BCG-only arm. Immune-mediated adverse events were observed but were generally manageable.
Comments: POTOMAC is a significant positive trial in the NMIBC space, demonstrating that adding systemic durvalumab to full BCG maintenance improves outcomes for high-risk patients. Crucially, the failure of the “Induction only” arm reinforces that systemic therapy cannot simply replace local BCG maintenance; rather, they work synergistically. These results are in line with the CREST trial (sasanlimab + BCG) presented earlier in the year at the AUA 2025 Annual Meeting. However, these results contrast with the ALBAN trial (also presented at ESMO 2025), which failed to show a benefit with atezolizumab + BCG, potentially due to differences in study population risk or BCG dosing schedules. Durvalumab + BCG represents a potential new standard of care for patients at the highest risk of recurrence.
Reference: Presented by Maria De Santis M, MD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA108 and De Santis M et al., Lancet 2025 Nov 8;406(10516):2221–223.
Study Title: ALBAN (GETUG-AFU 37): A Phase 3, randomized, open-label trial of intravenous Atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) versus BCG alone in BCG-naive high-risk, non-muscle invasive bladder cancer (NMIBC).
Clinicaltrials.gov identifier: NCT03799835
Sponsor: Unicancer (GETUG-AFU)
Enrollment: 517
Rationale: Intravesical BCG is the standard of care for high-risk NMIBC, but treatment failure occurs in 30–40% of patients. Preclinical data suggests that PD-L1 expression is associated with BCG resistance and that combining immune checkpoint inhibition with BCG could overcome this resistance. The ALBAN trial was designed to evaluate whether adding systemic atezolizumab (anti-PD-L1) to standard BCG therapy could improve event-free survival in patients who had not previously received BCG.
Study Design: This was a randomized, open-label, international Phase 3 study. Patients with histologically confirmed, BCG-naive, high-risk NMIBC (High-grade Ta, T1, or CIS) were randomized 1:1 to two arms:
Arm A (Control): Intravesical BCG induction (6 weekly instillations) + BCG Maintenance (3 weekly instillations at months 3, 6, and 12). Note: This represents a 1-year maintenance schedule, shorter than the 3-year SWOG protocol used in POTOMAC.
Arm B (Experimental): Atezolizumab (1200 mg IV q3w for 1 year) + Intravesical BCG (Induction + Maintenance as in Arm A).
Endpoints: The primary endpoint was investigator-assessed Event-Free Survival (EFS), defined as the time to high-grade recurrence, progression to muscle-invasive or metastatic disease, or death. Secondary endpoints include High-Grade Recurrence-Free Survival (RFS), Overall Survival (OS), and Safety.
Results: At a median follow-up of 35.3 months, the study failed to meet its primary endpoint.
Event-Free Survival (EFS): There was no statistically significant difference in EFS between the combination arm and the BCG-only arm. The Hazard Ratio (HR) was 0.98 (95% CI: 0.71–1.36; p = 0.9106).
High-Grade RFS: Similarly, there was no benefit in preventing high-grade recurrence (HR 1.06; 95% CI: 0.73–1.55).
Overall Survival (OS): Data remains immature, but preliminary analysis showed no survival advantage (HR 1.73; 95% CI: 0.76–3.92).
Safety: The addition of atezolizumab increased toxicity. Grade ≥3 treatment-related adverse events occurred in 22.7% of the combination group versus 8.8% in the BCG-only group.
Comments: The ALBAN trial is a negative study, standing in stark contrast to the positive POTOMAC trial (Durvalumab + BCG). Several factors may explain the discrepancy:
BCG Schedule: ALBAN used a 1-year BCG maintenance protocol, whereas POTOMAC used the standard 3-year SWOG protocol.
Patient Population: ALBAN enrolled a population with different risk characteristics (lower proportion of T1 tumors compared to POTOMAC), which may have diluted the potential signal of the immunotherapy.
Drug Differences: It remains possible that there are intrinsic differences between atezolizumab and durvalumab in this setting, though “class effect” is usually assumed. These results suggest that the addition of systemic immunotherapy to BCG is not universally beneficial and may be dependent on the specific regimen and maintenance duration used.
However, both trials also demonstrate how effective BCG induction and maintenance therapy is as a single agent for BCG-naïve high NMIBC.
Reference: Presented by Morgan Rouprêt, MD, PhD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA107.
