Perioperative Imfinzi, Neoadjuvant Chemo Improves Survival in Muscle-Invasive Bladder Cancer

Patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC) who received neoadjuvant (treatment as the first step to shrink a tumor) Imfinzi (durvalumab) plus chemotherapy, followed by adjuvant (additional treatment) Imfinzi, had significant improvements in survival compared with neoadjuvant chemotherapy alone without compromising the completion of surgery.

Findings from the phase 3 NIAGARA study were presented at the 2024 ESMO Congress. Results showed that the median event-free survival (the time a patient remains free from complications or events that the therapy was meant to delay or prevent; EFS) was not reached in the perioperative Imfinzi arm (533 patients) versus 46.1 months in the chemotherapy comparator arm (530 patients). Of note, when EFF is not reached in a trial, this may indicate not enough information for the researchers to assess at the time, or so few patients experienced this outcome to reach a statistically significant conclusion. At a median follow-up of 42.3 months, the 12- and 24-month EFS rates with the Imfinzi regimen were 76% and 67.8%, respectively; respective rates with the placebo regimen were 69.9% and 59.8%.

A subsequent EFS sensitivity analysis excluding patients who did not undergo radical cystectomy (surgery to remove the entire bladder) showed that the median EFS was not reached in the perioperative Imfinzi arm versus not reached in the comparator arm. The 12- and 24-month EFS rates were 82.3% and 73.5%, respectively, with the Imfinzi regimen; respective rates were 79.4% and 67.9% with the placebo regimen.

Moreover, the perioperative Imfinzi regimen reduced the risk of death by 25% compared with the placebo regimen in the intention-to-treat (patients randomized to a treatment regardless of whether they actually received the treatment; ITT) population. At a median follow-up of 46.3 months, patients in the perioperative Imfinzi arm achieved 12- and 24-month overall survival (the time when a patient with cancer is still alive; 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 Imfinzi and comparator arms, respectively, had received at least one subsequent anticancer therapy following treatment discontinuation at the time of this analysis.

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

At a data cutoff of January 2022, the planned formal analysis of pathologic complete response (when all visible evidence of cancer is eliminated after treatment; pCR) rate did not show significant benefit with the Imfinzi (33.8%) versus placebo regimen (25.8%), as the data did not meet the threshold for significance. 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 Imfinzi arm. The pCR rates were 37.3% in the Imfinzi arm and 27.5% in the comparator arm.

“NIAGARA is the first global phase 3 study to evaluate a perioperative immune checkpoint inhibitor, [Imfinzi] combined with neoadjuvant chemotherapy in cisplatin-eligible patients with MIBC,” lead study author Dr. Thomas Powles, 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 [Imfinzi] 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.

NIAGARA Trial Overview

The NIAGARA trial enrolled adults with cisplatin-eligible MIBC who were evaluated and confirmed for radical cystectomy and had urothelial carcinoma (cancer that develops in the urinary tract). Patients were also required to have an ECOG performance status (PS) of 0 or 1 (fully active or some restrictions on strenuous activity, and a creatinine clearance (CrCl) of at least 40 mL/min (indicating normal kidney function).

Of the 1,530 patients enrolled onto the study, 1,063 patients were randomly assigned to receive Imfinzi plus gemcitabine/cisplatin, followed by Imfinzi alone after radical cystectomy; or gemcitabine/cisplatin alone prior to cystectomy, followed by no further treatment after surgery.

The main areas of focus in the trial were EFS and pCR rate at the time of cystectomy. Other areas of interest included OS and safety.

A total of 530 and 526 patients assigned to the Imfinzi 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 days and 38 days in these respective arms.

Cystectomy was completed in 470 patients in the Imfinzi arm and 446 patients in the placebo arm; 63 and 84 patients, respectively, elected not to undergo surgery. Of the 383 patients who started adjuvant treatment in the Imfinzi arm, 95 discontinued treatment. At the time of follow-up, 379 patients in the Imfinzi 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 [Imfinzi] to neoadjuvant chemotherapy was tolerable and manageable, with no new safety signals [observed].”

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

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

The most common any-grade side effects were nausea (Imfinzi arm, 54%; placebo arm, 49%), anemia (39%; 41%), constipation (39%; 39%), fatigue (36%; 32%), urinary tract infection (30%; 29%), decreased appetite (27%; 25%), neutropenia (low number of neutrophils, a type of white blood cell, that helps the body defend itself against infections; 26%; 31%), fever (21%; 17%), diarrhea (21%; 14%), vomiting (19%; 18%), blood creatinine increase (potentially indicating kidney damage; 19%; 15%), weakness (18%; 18%), neutrophil count decrease (decrease in the number of neutrophils, a type of white blood cell, in the blood that helps against infections; 15%; 14%) and itching (15%; 7%).

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

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