The European Commission approved perioperative pembrolizumab plus enfortumab vedotin for patients with cisplatin-ineligible resectable MIBC.
Pembrolizumab (Keytruda) plus enfortumab vedotin-ejfv (Padcev) has been approved by the European Commission as neoadjuvant treatment and then as adjuvant treatment after radical cystectomy for the treatment of adult patients with resectable muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.¹ The approval also covers subcutaneous pembrolizumab (Keytruda SC) and applies across the 27 European Union (EU) member states, Iceland, Liechtenstein, and Norway.
The regulatory decision was supported by data from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895). Findings from KEYNOTE-905 revealed that perioperative pembrolizumab plus enfortumab vedotin reduced the risk of event-free survival (EFS) events by 60% vs surgery alone (HR, 0.40; 95% CI, 0.28-0.57; P < .0001). The median EFS was not reached (NR; 95% CI, 37.3 months-NR) with the combination compared with 15.7 months (95% CI, 10.3-20.5) with surgery alone.
“Patients with resectable MIBC who are ineligible for cisplatin‑containing chemotherapy face an aggressive disease and few effective therapies, with surgery alone as the longstanding standard of care,” Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent and Clinical Trial Unit Oncology Ghent in Belgium, as well as the KEYNOTE-905 principal investigator, stated in a news release. “Based on robust data from the KEYNOTE-905 trial, this approval marks a turning point in bladder cancer care. It introduces a potentially practice-changing perioperative treatment option that may significantly improve outcomes and extend survival for this underserved patient population across the EU.”
KEYNOTE-905 was an open-label, randomized, multi-arm trial that evaluated perioperative pembrolizumab with or without enfortumab vedotin vs surgery alone in patients with MIBC who were either not eligible for or declined cisplatin-based chemotherapy. Additional eligibility criteria included an ECOG performance status of 0 to 2, adequate organ function, and having clinically nonmetastatic disease per imaging.2
The trial enrolled 595 patients.¹ Patients were randomly assigned to 1 of 3 groups. Arm A received 3 cycles of neoadjuvant pembrolizumab followed by radical cystectomy and 14 cycles of adjuvant pembrolizumab; arm B underwent surgery alone; and arm C received 3 cycles of neoadjuvant pembrolizumab plus enfortumab vedotin followed by radical cystectomy, then 6 adjuvant cycles of pembrolizumab plus enfortumab vedotin and 8 cycles of pembrolizumab alone.
The primary objective was to compare EFS outcomes between arms C and B. Key secondary objectives included overall survival (OS) and pathologic complete response (pCR) rate for arm C vs arm B, as well as EFS, OS, and pCR comparisons for arm A vs arm B.
Pembrolizumab plus enfortumab vedotin reduced the risk of death by 50% vs surgery alone (HR, 0.50; 95% CI, 0.33-0.74; P = .0002). The median OS was NR (95% CI, NR-NR) in the combination arm vs 41.7 months (95% CI, 31.8-NR) in the surgery-alone arm. The pCR rate was also higher with the combination arm, at 57.1% (95% CI, 49.3%-64.6%) compared with 8.6% (95% CI, 4.9%-13.8%) with surgery alone (P < .0001).
Among safety-evaluable, cisplatin-ineligible patients with MIBC treated with pembrolizumab plus enfortumab vedotin (n = 167), the most common adverse effects (AEs) occurring in at least 20% of patients were rash (54%), fatigue (47%), pruritus (47%), peripheral neuropathy (39%), dysgeusia (35%), alopecia (35%), diarrhea (34%), decreased appetite (28%), constipation (28%), nausea (26%), urinary tract infection (24%), dry eye (21%), and weight loss (20%).
During the neoadjuvant phase, serious AEs occurred in 27% of patients; the most frequent were urinary tract infection (3.6%) and hematuria (2.4%). Fatal AEs occurred in 1.2% of patients and included myasthenia gravis and toxic epidermal necrolysis (0.6% each). Seven patients (4.2%) did not undergo surgery because of AEs, and 6 of 146 patients who underwent radical cystectomy (4.1%) had surgery delayed more than 8 weeks after the last neoadjuvant treatment because of AEs.
Among safety-evaluable patients who received enfortumab vedotin in the adjuvant phase, serious AEs occurred in 43%. Fatal AEs occurred in 7% of patients, and permanent discontinuation of pembrolizumab due to AEs occurred in 28% of patients; the most frequent events leading to discontinuation were diarrhea (5%), as well as peripheral neuropathy, acute kidney injury, and pneumonitis (2% each).
“For patients with resectable MIBC in Europe, this approval represents a meaningful advance after years of limited progress in the field,” Marjorie Green, MD, senior vice president and head of oncology and global clinical development, at Merck Research Laboratories, added in the news release. “As the first PD-1 inhibitor plus antibody-drug conjugate regimen approved in this setting, this treatment is poised to address a crucial unmet need, reflecting our continued commitment to delivering innovative [pembrolizumab]-based therapies to patients with bladder cancer worldwide.”
The European approval follows a
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