NIAGARA: Durvalumab plus chemo improves EFS and OS in cisplatin-eligible MIBC

Results of a large phase 3 study support the use of perioperative durvalumab (Imfinzi) plus neoadjuvant chemotherapy followed by radical cystectomy and adjuvant chemotherapy in patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC), according to data presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain and published in The New England Journal of Medicine.^1,2

Thomas B. Powles, MBBS, MRCP, MD

Describing the background for the phase 3 NIAGARA study (NCT03732677), Thomas B. Powles, MBBS, MRCP, MD, said “The perioperative approach, particularly that in the neoadjuvant phase…has a strong biological rationale and has been explored successfully in other cancers such as lung cancer and breast cancer.³ Indeed, perioperative durvalumab with cisplatin-based chemotherapy has been tested in a phase 2 study…by a Swiss group successfully. It appears safe and efficacious.”⁴

In his presentation, Powles called the current study “a massive undertaking.”

“I don’t think we’ve ever done a study this size in muscle-invasive bladder cancer before,” said Powles, director of the Barts Cancer Centre at St. Bartholomew’s Hospital in London, United Kingdom.

The patient population consisted of adults with cisplatin-eligible MIBC (cT2-T4aN0/1M0), urothelial cancer or urothelial cancer with divergent differentiation or histologic subtypes, evaluated and confirmed for radical cystectomy, and with creatine clearance of 40 mL/min or lower. Patient were randomly assigned 1:1 to either the durvalumab arm or the comparator arm. Patients in the durvalumab arm received neoadjuvant durvalumab, 1500 mg intravenously Q3W and gemcitabine plus cisplatin for 4 cycles followed by radical cystectomy and 8 cycles of adjuvant durvalumab. Patients in the comparator arm received 4 cycles of gemcitabine plus cisplatin for 4 cycles followed by radical cystectomy. The 2 primary end points were event-free survival (EFS) and pathological complete response (pCR).

“Event-free survival is different from disease-free survival because it includes those patients who did not have a cystectomy, and that was counted as an event,” Powles noted.

The trial was “considered positive if either of the dual primary end points were met,” wrote the authors.

A total of 1530 patients were enrolled and 1063 patients were randomly assigned, with 533 patients assigned to the durvalumab arm and 530 assigned to the comparator arm.

“A very similar proportion of patients completed the neoadjuvant period—about 80%. About 85% of patients in both arms had a successful cystectomy. We were worried that it might be a lower rate than that,” Powles said. In addition, 70% of patients went on to receive adjuvant durvalumab.

The 2 arms were “very balanced” in terms of patient characteristics, Powles reported. In both arms, 73% of patients had high PD-L1 expression, and histology was urothelial carcinoma in 86% of patients in the durvalumab arm compared with 83% in the comparator arm.

Regarding EFS, there was a significant reduction in risk (HR=0.68, 95% CI, 0.56-0.82). Median follow-up was 42.3 months (range 0.03-61.3 months).

“At 2 years, the landmark EFS is 68% vs 60%, an 8% delta,” Powles said.

The investigators also conducted an EFS sensitivity analysis in which patients who did not undergo radical cystectomy were censored. In this analysis, the HR was 0.69 (95% CI, 0.56-0.86), which Powles said was “reassuring.”

“The overall survival showed a 25% reduction in the risk of death. This is statistically significant,” Powles said. There were 136 deaths (25.5%) in the durvalumab arm vs 169 deaths (31.9%) in the comparator arm (HR=0.75, 95% CI, 0.59-0.93, P = .0106).

Powles reported that adverse events (AEs) “were balanced in both arms.” Grade 3 or 4 AEs occurred in 368 (69%) patients in the durvalumab arm vs 355 (68%) patients in the comparator arm. The rate of grade 3 or 4 treatment-related AEs was 41% in both arms. AEs leading to discontinuation of neoadjuvant chemotherapy occurred in 72 (14%) patients in the durvalumab arm vs 80 (15%) patients in the comparator arm.

In his concluding remarks, Powles said, “[NIAGARA] shows a significant event-free survival advantage. It shows a 25% reduction in the risk of death. It’s working across broad subgroups of patients. The path-CR results and the significant overall survival benefit and the shape of the curves underline the importance of both periods of therapy…NIAGARA supports perioperative durvalumab with neoadjuvant chemotherapy as a potential new standard treatment for patients with cisplatin-eligible muscle-invasive bladder cancer.”

REFERENCES

1. Powles TB, van der Heijden MS, Galsky MD, 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: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA5. https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=LBA5

2. Powles T, Catto JWF, Galsky MD. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. Published online September 15, 2024. Accessed September 15, 2024. https://www.nejm.org/doi/abs/10.1056/NEJMoa2408154

3. Vansteenkiste J, Wauters E, Reymen B, Ackermann CJ, Peters S, De Ruysscher D. Current status of immune checkpoint inhibition in early-stage NSCLC. Ann Oncol. 2019;30(8):1244-1253. doi:10.1093/annonc/mdz175

4. Cathomas R, Rothschild SI, Hayoz S, et al. Perioperative chemoimmunotherapy with durvalumab for muscle-invasive urothelial carcinoma: primary analysis of the single-arm phase II trial SAKK 06/17. J Clin Oncol. 2023;41(33):5131-5139. doi:10.1200/JCO.23.00363