Results of the phase III NIAGARA study support perioperative durvalumab with neoadjuvant chemotherapy as a potential new standard treatment for patients with cisplatin-eligible muscle-invasive bladder cancer.
Neoadjuvant cisplatin-based chemotherapy (NAC) with radical cystectomy (RC) improves overall survival (OS) versus RC alone and has been the recommended treatment for muscle-invasive bladder cancer (MIBC) for the past 40 years. Unfortunately however, approximately half of the patients experience recurrence within three years. In the setting of MIBC, immune checkpoint inhibitors (ICIs) as adjuvant monotherapy have demonstrated improved disease-free survival in phase III studies in patients at high risk of recurrence after surgery and perioperative ICIs could improve long-term clinical outcomes by priming anti-tumour immunity before surgery and eradicating micrometastatic disease after surgery. NIAGARA is the first global phase III study to evaluate a perioperative ICI, durvalumab, combined with NAC in cisplatin-eligible patients with MIBC.
In the international, randomised, open-label, phase III NIAGARA study, adult patients with MIBC (type cT2-T4aN0/1M0) were enrolled if they were eligible for treatment with cisplatin and radical cystectomy was planned. Patients were then randomised 1:1 to 4 cycles of neoadjuvant durvalumab (1500 mg, IV, Q3W) plus cisplatin and gemcitabine (IV, Q3W), followed by radical cystectomy and subsequent 8 cycles of adjuvant monotherapy with durvalumab (1500 mg, IV, Q4W) or only neoadjuvant cisplatin and gemcitabine and a radical cystectomy. The study had two primary endpoints: the EFS and the pathological complete response (pCR), with OS and safety being secondary endpoints. The current analysis is a pre-planned interim analysis of the EFS and OS data collected until April 2024. A previous analysis of the pCR data showed no statistically significant differences between the study groups for this outcome measure.
A total of 1,063 patients were randomised to the durvalumab group (N= 533, median 65 years; 82% male) or the control group (N= 530, median 66 years; 82% male). After a median follow-up of 42.3 months, EFS was not reached in the durvalumab group, while the median EFS was 46.1 months in the placebo group (HR[95%CI ]: 0.68[0.56-0.82]; p< 0.0001). OS at the 24-month landmark analysis was 82.2% in the durvalumab group, compared with 75.2% in the placebo group (HR[95%CI]: 0.75[0.59-0.93], p= 0.0106). Although the pCR did not differ between the two study groups in the planned formal analysis for pCR (January 2022, OR[95%CI]: 1.49[1.14-1.96], p= 0.0038), the re-analysis of April 2024 showed nominal statistical significance in favour of the durvalumab arm (37.3% vs. 27.5%; OR[95%CI]: 1.60[1.23-2.08], p= 0.0005).
Treatment-related adverse events (TRAEs) of grade 3 or 4 occurred in 41% of patients in both study groups. In the durvalumab group, 8% of patients discontinued adjuvant durvalumab treatment due to AEs. In both arms, 0.6% of patients died from a treatment-related cause. Any-grade immune-mediated AEs were reported in 21% of patients in the durvalumab arm and in 3% of patients in the comparator arm.
NIAGARA is the first phase III perioperative immunotherapy study in MIBC and has demonstrated a statistically significant and clinically meaningful improvement in EFS and OS. Furthermore, the addition of perioperative durvalumab to neoadjuvant chemotherapy was tolerable and manageable, with no new safety signals.
Reference
Powles TB, et al. A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). Presented at ESMO 2024; Abstract LBA5.
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