Perioperative ADC-ICI Wins Dual Survival But Faces Toxicity and Payer Scrutiny

European Commission Expands PADCEV Plus Keytruda Approval for Resectable MIBC

Astellas Pharma Inc. announced that the European Commission has granted Marketing Authorization for PADCEV (enfortumab vedotin) in combination with Keytruda (pembrolizumab) for adults with resectable muscle-invasive bladder cancer (MIBC) in the European Union, regardless of cisplatin eligibility. This expanded indication provides an approved perioperative treatment option. The approval is based on Phase 3 EV-304 results, which demonstrated statistically significant improvements in Event-Free Survival (EFS) and Overall Survival (OS) compared to neoadjuvant gemcitabine and cisplatin chemotherapy in cisplatin-eligible adults with MIBC. The combination reduced the risk of recurrence, progression, or death by 47% and the risk of death by 35%.

• The European Commission has approved PADCEV plus Keytruda as a perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC) in the EU, now regardless of cisplatin eligibility. This expands upon a previous EU indication for cisplatin-ineligible adults, offering a consistent and flexible treatment approach for a broader patient population with high unmet medical need.
• The approval is underpinned by robust data from the Phase 3 EV-304 (KEYNOTE-B15) trial. In cisplatin-eligible adults with MIBC, the combination significantly improved Event-Free Survival (EFS), reducing the risk of tumor recurrence, progression, or death by 47% (Hazard Ratio (HR) 0.53; 95% CI, 0.41–0.70; 1-sided p<0.0001) compared to standard neoadjuvant gemcitabine and cisplatin chemotherapy.
• Beyond EFS, the EV-304 trial also demonstrated a statistically significant improvement in Overall Survival (OS), reducing the risk of death by 35% (HR 0.65; 95% CI, 0.48-0.89; 1-sided p=0.0029). Additionally, the combination achieved a higher pathological complete response (pCR) rate of 55.8% at the time of surgery, compared to 32.5% with neoadjuvant chemotherapy.
• The safety profile observed in the EV-304 trial was consistent with the known profiles of enfortumab vedotin and pembrolizumab individually, with no new safety signals identified. Grade ≥3 adverse events due to any cause occurred in 75.7% of patients treated with the perioperative combination compared to 67.2% of patients treated with neoadjuvant chemotherapy.

The Unmet Need in Resectable MIBC Treatment

Current approaches for resectable muscle-invasive bladder cancer (MIBC) balance curative intent against substantial morbidity, strict eligibility requirements, and persistent risks of recurrence. Radical cystectomy (RC) remains reference standard, while trimodality bladder preservation offers comparable survival in selected patients but introduces its own locoregional and selection constraints.

• High morbidity and quality-of-life impact of radical cystectomy: Radical cystectomy plus urinary diversion associates with high complication rates and compromises quality of life as a result of long-term effects on urinary, gastrointestinal and sexual function, and changes in body image. As a society ages, the number of elderly patients unfit for radical cystectomy as a result of comorbidity will increase.

• Underutilization of potentially curative treatment and neoadjuvant chemotherapy: There is an underutilization of potentially curative treatments for patients with muscle-invasive bladder cancer. Only 11% of patients with CrCl ≥60 ml/min in 2018 and 20% in 2022 were treated before cystectomy, highlighting a scenario of low adherence to guidelines with underutilization of neoadjuvant chemotherapy. Among 394 patients included, mean age was 72.5 years and Charlson comorbidity index (CCI) 0.6, with median DFS was 0.9 years, median OS was 2.1 years with a 5-year OS rate of 43%.

• Limited benefit and restricted eligibility for cisplatin-based neoadjuvant chemotherapy: Cisplatin-based chemotherapy remains the standard neoadjuvant treatment; however, its survival benefits are limited, and its use is restricted to patients with adequate performance status and renal function. The presence of hydronephrosis - a significant marker of advanced disease - can impair renal function, potentially precluding patients from receiving cisplatin-based NAC.

• Persistent recurrence despite surgery and systemic therapy: Up to 50% of patients undergoing radical cystectomy experience recurrence within the first two years, with a 5-year overall survival reaching 50%-60%. Despite the use of neoadjuvant chemotherapy, clinical trials have failed to attain a considerable reduction in the risk of locoregional recurrence, which remains a major clinical challenge due to the limited and largely ineffective salvage treatment options.

• Limitations specific to trimodality bladder preservation: Trimodality bladder-sparing approaches consisting of transurethral resection, chemotherapy and radiotherapy (Σ 55-65 Gy) yield overall survival rates comparable with those of radical cystectomy series (50-70% at 5 years), while preserving the native bladder in 40-60% of muscle-invasive bladder cancer patients. Limitations include (i) muscle-invasive bladder cancer recurrence in the preserved bladder, which most often arises in the original muscle-invasive bladder cancer site; (ii) potential lack of curative intervention for regional lymph nodes; and (iii) increased morbidity in the event of salvage radical cystectomy for remaining or recurrent disease as a result of high-dose pelvic irradiation.

• Incomplete response, variable practice patterns, and selection complexity: There is still a significant percentage of patients who exhibit incomplete response or invasive intravesical recurrence requiring salvage RC, with patient selection factors including carcinoma in situ, hydronephrosis, debulking feasibility, and histology. Compared with the 1,447 patients who received RC, BPT patients were older, had poorer performance status, and had more comorbidities, 45% of BPT patients received concurrent chemotherapy with radiation, choice of concurrent chemotherapy regimen varied widely with no clear standard, and only 10 patients (4% of BPT patients) underwent salvage cystectomy.

EV-304: Pivotal Evidence for PADCEV + Keytruda in MIBC

Recent trials in resectable muscle-invasive bladder cancer evaluate perioperative systemic regimens, active surveillance after clinical complete response, and adjuvant radiotherapy following cystectomy. Populations include cisplatin-eligible, cisplatin-ineligible, and high-risk post-surgical patients, with endpoints spanning feasibility, event-free and recurrence-free survival, and pathologic response.

Reshaping the Resectable MIBC Treatment Landscape

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy has long been the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer, with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin demonstrating oncological benefits over gemcitabine-cisplatin in the VESPER trial in terms of pathologic complete response rates, overall survival (HR: 0.71), and progression-free survival (HR: 0.70). This paradigm has evolved toward perioperative chemoimmunotherapy, in which immune checkpoint inhibitors are added to neoadjuvant chemotherapy and continued after surgery. In the phase 3 NIAGARA trial (NCT03732677), neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles, achieved estimated event-free survival at 24 months of 67.8% (95% confidence interval [CI], 63.6 to 71.7) versus 59.8% (95% CI, 55.4 to 64.0) with neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001), and estimated overall survival at 24 months of 82.2% (95% CI, 78.7 to 85.2) versus 75.2% (95% CI, 71.3 to 78.8) (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01). Single-arm phase II data support this approach, including SAKK 06/17 with neoadjuvant gemcitabine/cisplatin plus durvalumab followed by radical surgery and adjuvant durvalumab for 10 cycles reporting event-free survival at 2 years of 76% and overall survival of 85% (95% CI, 72 to 92) at 2 years, and the NEMIO study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin combined with durvalumab ± tremelimumab reporting pathologic complete response (ypT0N0) Bayesian posterior mean rates of 48.70% (95% CI, 35.93 to 61.56) with doublet and 46.27% (95% CI, 33.92 to 58.85) with triplet.

In the adjuvant setting for high-risk disease after radical resection, immune-checkpoint blockade has changed practice. In CheckMate 274, a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma at high risk of recurrence after radical resection, disease-free survival benefit was observed in the intent-to-treat population (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and tumor PD-L1 expression ≥1% population (HR, 0.52 [95% CI, 0.37 to 0.72]) at extended median follow-up of 36.1 months, with interim overall survival HR of 0.76 (95% CI, 0.61 to 0.96) in the intent-to-treat population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1% population. Pembrolizumab in the Alliance AMBASSADOR study also produced a statistically significant improvement in disease-free survival for high-risk patients after radical cystectomy, with overall survival data still maturing. Circulating tumor DNA has emerged as a prognostic and predictive biomarker to refine adjuvant selection, with IMvigor011, a phase 3, double-blind, randomized trial of ctDNA-guided adjuvant atezolizumab versus placebo, reporting median disease-free survival of 9.9 months with atezolizumab as compared with 4.8 months with placebo (hazard ratio for first event of disease recurrence or death, 0.64; 95% CI, 0.47 to 0.87; P = 0.005) and median overall survival of 32.8 months as compared with 21.1 months (hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P = 0.01) among 250 ctDNA-positive randomized patients, while the single-arm phase II TOMBOLA trial showed that tumor-informed ctDNA testing after neoadjuvant chemotherapy and radical cystectomy predicts recurrence risk with one-year recurrence-free survival of 97% in ctDNA-negative patients and 76% in ctDNA-positive patients.

Antibody-drug conjugate-based perioperative regimens have introduced a further shift, particularly for cisplatin-eligible and cisplatin-ineligible populations. In KEYNOTE-B15/EV-304, perioperative enfortumab vedotin-pembrolizumab versus neoadjuvant cisplatin-gemcitabine in cisplatin-eligible patients yielded estimated event-free survival at 2 years of 79.4% versus 66.2% (hazard ratio for an event or death, 0.53; 95% CI, 0.41 to 0.70; P<0.001), estimated overall survival of 86.9% and 81.3%, respectively (hazard ratio for death, 0.65; 95% CI, 0.48 to 0.89), and pathologic complete response in 55.8% and 32.5% of participants (P<0.001), with grade 3 or higher adverse events of any cause in 75.7% versus 67.2%. In cisplatin-ineligible patients, SunRISe-4 reported centrally confirmed pathologic complete response rates of 42% (22 of 53 patients; 95% CI 28-56) with neoadjuvant TAR-200 plus cetrelimab versus 23% (seven of 31 patients; 10-41) with cetrelimab monotherapy, while the AURA trial reported pathologic complete response rates of 58% (95% CI: 42% to 72%) with avelumab plus dose-dense methotrexate-vinblastine-doxorubicin-cisplatin and 53% (95% CI: 37% to 68%) with avelumab plus gemcitabine-cisplatin in cisplatin-eligible patients, and 14% (95% CI: 6% to 31%) with paclitaxel-gemcitabine plus avelumab and 32% (95% CI: 18% to 51%) with avelumab alone in cisplatin-ineligible patients. Real-world uptake remains heterogeneous, with a US community oncology cohort of 138 patients undergoing radical cystectomy between 2021 and 2023 showing 46% (64/138) receiving neoadjuvant treatment mainly gemcitabine and cisplatin, 14% (20/138) receiving any adjuvant treatment including 10% (14/138) receiving adjuvant nivolumab, and 19% (12/63) of high-risk patients (ypT2-T4a or ypN+; pT3-4a or pN+) receiving nivolumab, while the Spanish MINOTAURO study reported cisplatin-based neoadjuvant chemotherapy in 40% of patients, adjuvant chemotherapy in 10.7%, and adjuvant immunotherapy predominantly nivolumab in 46.2% of eligible patients.

Perioperative EV-P: A New Standard for MIBC

The recent European Commission marketing authorization for perioperative enfortumab vedotin plus pembrolizumab in resectable muscle-invasive bladder cancer (MIBC) marks a pivotal moment in oncology. This approval fundamentally shifts the treatment paradigm, offering a highly effective, non-chemotherapy-based option for a patient population that has long faced significant challenges. Historically, cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy has been the standard for fit patients, yet over half of MIBC patients are ineligible for cisplatin due to comorbidities, leaving them with limited alternatives.

The combination of enfortumab vedotin, an antibody-drug conjugate, and pembrolizumab, an immune checkpoint inhibitor, has demonstrated remarkable efficacy. In pivotal trials, this perioperative regimen significantly improved event-free survival, overall survival, and pathological complete response rates compared to either neoadjuvant cisplatin-gemcitabine or surgery alone. This dual-action approach, combining targeted cytotoxic delivery with immune system activation, represents a powerful synergistic strategy that is now poised to become a new standard of care for both cisplatin-eligible and ineligible patients.

However, as with any potent therapy, important considerations exist. The combination is associated with a higher incidence of Grade 3 or higher adverse events compared to traditional chemotherapy or surgery alone. This underscores the need for:

• Rigorous patient selection: Identifying individuals who can best tolerate the regimen.

• Proactive toxicity management: Implementing strategies to mitigate and manage potential side effects.

• Careful monitoring: Ensuring ongoing vigilance for adverse reactions throughout treatment.

Furthermore, emerging evidence suggests that concomitant antibiotic therapy can negatively impact the efficacy of neoadjuvant pembrolizumab, potentially reducing pathological complete response rates and increasing recurrence risk. This highlights the importance of judicious antibiotic use during the perioperative period. While the literature on increased surgical difficulty following neoadjuvant immune checkpoint inhibitors remains inconclusive, it is an area warranting continued investigation.

This approval not only offers a superior treatment option but also validates the potential of combination therapies and precision medicine in MIBC. It opens doors for further research into biomarkers that can predict response and toxicity, ultimately paving the way for more personalized and potentially bladder-sparing treatment strategies.