Addition of Perioperative Durvalumab to Neoadjuvant Chemo Generates Survival Benefits in Cisplatin-Eligible MIBC

Neoadjuvant durvalumab (Imfinzi) plus chemotherapy, followed by adjuvant durvalumab, produced statistically significant and clinically meaningful improvements in event-free survival (EFS) and overall survival (OS) vs neoadjuvant chemotherapy plus placebo without compromising the ability to complete radical cystectomy in patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC), according to data from a pre-planned interim analysis of the phase 3 NIAGARA trial (NCT03732677).

Results presented at the 2024 ESMO Congress showed that the median EFS was not reached (NR; 95% CI, NR-NR) in the perioperative durvalumab arm (n = 533) vs 46.1 months (95% CI, 32.2-NR) in the chemotherapy comparator arm (n = 530; HR, 0.68; 95% CI, 0.56-0.82; P < .0001). At a median follow-up of 42.3 months (range, 0.03-61.3) in censored patients, the 12- and 24-month EFS rates with the durvalumab regimen were 76.0% and 67.8%, respectively; corresponding rates with the placebo regimen were 69.9% and 59.8%.

A subsequent EFS sensitivity analysis excluding patients who did not undergo radical cystectomy showed that the median EFS was NR (95% CI, NR-NR) in the perioperative durvalumab arm vs NR (95% CI, 53.2-NR) in the comparator arm (HR, 0.69; 95% CI, 0.56-0.86). The 12- and 24-month EFS rates were 82.3% and 73.5%, respectively, with the durvalumab regimen; respective rates were 79.4% and 67.9% with the placebo regimen.

Moreover, the perioperative durvalumab regimen reduced the risk of death by 25% compared with the placebo regimen (HR, 0.75; 95% CI, 0.59-0.93; P = .0106) in the intention-to-treat (ITT) population. At a median follow-up of 46.3 months (range, 0.03-64.7) in censored patients, patients in the perioperative durvalumab arm achieved 12- and 24-month OS rates of 89.5% and 82.2%, respectively. Corresponding rates in the comparator arm were 86.5% and 75.2%. Notably, 53 and 93 patients in the durvalumab and comparator arms, respectively, had received at least 1 subsequent anticancer therapy following treatment discontinuation at the time of this analysis.

Both the EFS and OS benefits with the durvalumab regimen were reported across all subgroups.

At a data cutoff of January 2022, the planned formal analysis of pathologic complete response (pCR) rate did not show significant benefit (odds ratio [OR], 1.49; 95% CI, 1.14-1.96; P = .0038) with the durvalumab (33.8%; 95% CI, 29.8%-38.0%) vs placebo regimen (25.8%; 95% CI, 22.2%-29.8%), as the data did not meet the threshold for significance (P = .001). However, 59 evaluable samples from the ITT population were incorrectly attributed as non-responders.

A re-analysis of pCR including these omitted samples was accordingly conducted. At a data cutoff of April 2024, nominal statistical significance was reported in favor of the durvalumab arm (OR, 1.60; 95% CI, 1.23-2.08; nominal P = .0005). The pCR rates were 37.3% (95% CI, 33.2%-41.6%) in the durvalumab arm and 27.5% (95% CI, 23.8%-31.6%) in the comparator arm.

“NIAGARA is the first global phase 3 study to evaluate a perioperative immune checkpoint inhibitor, durvalumab combined with neoadjuvant chemotherapy in cisplatin-eligible patients with MIBC,” lead study author Thomas Powles, MBBS, MRCP, MD, noted during an oral presentation of the data. “The pCR results and significant OS benefit [observed in this analysis] support the perioperative approach, and neoadjuvant durvalumab did not delay surgery [nor] impact the ability of patients to undergo or complete surgery.”

Powles is a professor of Genitourinary Oncology, lead for Solid Tumor Research, and director of Barts Cancer Centre at St. Bartholomew’s Hospital in London, United Kingdom.

NIAGARA Trial Overview

The randomized, open-label, multicenter, global NIAGARA trial enrolled adult patients with cisplatin-eligible MIBC with a clinical stage of T2-T4aN0/1M0 who were evaluated and confirmed for radical cystectomy and had urothelial carcinoma with or without divergent differentiation or histologic subtypes. Patients were also required to have an ECOG performance status (PS) of 0 or 1, and a creatinine clearance (CrCl) of at least 40 mL/min.

Patients were stratified according to clinical tumor stage (T2N0 vs >T2N0), renal function (CrCl ≥ 60 mL/min vs ≥40 to <60 mL/min) and PD-L1 status (high vs low or negative expression).

Of the 1530 patients enrolled onto the study, 1063 patients were randomly assigned 1:1 to receive 1500 mg of intravenous durvalumab every 3 weeks plus gemcitabine/cisplatin for 4 cycles, followed by durvalumab alone every 4 weeks after radical cystectomy for 8 cycles; or 4 cycles of gemcitabine/cisplatin alone prior to cystectomy, followed by no further treatment after surgery.

The dual primary end points were EFS by blinded independent review and pCR rate at the time of cystectomy. Secondary end points included OS and safety. Other end points not reported in the current analysis included disease-free survival, disease-specific survival, metastasis-free survival, heath-related quality of life, and 5-year OS.

In this pre-planned interim analysis, the estimated number of events in the ITT population across both arms was 410 for EFS and 288 for OS. One pCR analysis was planned approximately 6 months after the last patient was randomly assigned to a study arm. The study was considered positive if either of the primary end points were met.

Powles notes that baseline characteristics in the ITT population were well-balanced across both study arms. The median age was 65 year (range 34-84) in the durvalumab arm and 66 years (range, 32-83) in the comparator arm. The majority of patients across both arms were male (82% in the durvalumab arm; 82% in the comparator arm), White (66%; 68%), had an ECOG PS of 0 (78%; 78%), were current or former smokers (71%; 75%), had CrCl of at least 60 mL/min (81%; 81%), were a tumor stage greater than T2N0 (60%; 60%), had high PD-L1 expression (73%; 73%), had urothelial carcinoma histology (86%; 83%), and no regional lymph node metastasis (95%; 94%).

A total of 530 and 526 patients assigned to the durvalumab and comparator arms, respectively, started neoadjuvant treatment; 113 and 137 discontinued treatment prior to surgery. The median time from the last dose of neoadjuvant therapy to cystectomy was 39.0 days (range, 8-118) and 38.0 days (range, 12-333) in these respective arms.

Cystectomy was completed in 470 patients in the durvalumab arm and 446 patients in the placebo arm; 63 and 84 patients, respectively, elected not to undergo surgery. Among the 383 patients who started adjuvant treatment in the durvalumab arm, 95 discontinued treatment. At the time of follow-up, 379 patients in the durvalumab arm and 333 patients in the placebo arm were ongoing in the study. No patients were still on study treatment at the data cutoff.

Safety Analysis

Powles noted that, “The addition of perioperative durvalumab to neoadjuvant chemotherapy was tolerable and manageable, with no new safety signals [observed].”

The majority of patients in both arms experienced adverse effects (AEs) of any cause (99% in the durvalumab arm; 100% in the comparator arm). Of these, 69% and 68%, respectively, were grade 3/4; serious AEs were reported in 62% and 55% of patients, respectively. AEs leading to death (5%; 6%), discontinuation of study treatment (21%; 15%), discontinuation of neoadjuvant durvalumab (9%; not applicable [NA]); discontinuation of neoadjuvant chemotherapy (14%; 15%), not undergoing radical cystectomy (1%; 1%), a delay in surgery (2%; 1%), and discontinuation of adjuvant durvalumab (8%; NA) were reported. Forty-one percent of patients in both arms experienced potential treatment-related AEs (TRAEs), 0.6% of which resulted in death in both arms. Any-grade immune-mediated AEs were reported in 21% of patients in the durvalumab arm vs 3% of patients in the comparator arm.

Specifically within the adjuvant phase, AEs of any cause were observed in 86% and 71% of patients who received perioperative durvalumab vs the placebo regimen. Grade 3/4 AEs were reported in 31% and 24% of patients, respectively. Serious AEs occurred in 26% and 22% of patients, and AEs led to death in 2% of patients across both groups. Potential TRAEs were seen in 41% and 6% of patients in the durvalumab and placebo arms, respectively; 6% and 1% of these were grade 3/4. No potential adjuvant TRAEs led to death in either arm.

The most common any-grade AEs were nausea (durvalumab arm, 54%; placebo arm, 49%), anemia (39%; 41%), constipation (39%; 39%), fatigue (36%; 32%), urinary tract infection (30%; 29%), decreased appetite (27%; 25%), neutropenia (26%; 31%), pyrexia (21%; 17%), diarrhea (21%; 14%), vomiting (19%; 18%), blood creatinine increase (19%; 15%), asthenia (18%; 18%), neutrophil count decrease (15%; 14%), and pruritis (15%; 7%).

“[Overall,] NIAGARA supports perioperative durvalumab with neoadjuvant chemotherapy as a potential new standard treatment for patients with cisplatin-eligible MIBC,” Powles concluded.

Reference

Powles T, Van der Heijden MS, Galsky M, 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 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA5.