AstraZeneca’s Imfinzi recently became the first PD-1/L1 inhibitor to deliver a patient survival win in muscle-invasive bladder cancer (MIBC). Now, detailed data show exactly how Imfinzi performed, as the company’s chief medical officer defends the immunotherapy’s continued use on both sides of surgery.
Adding Imfinzi both before and after radical cystectomy reduced the risk of death by 25% in patients with MIBC, according to results from the phase 3 NIAGARA trial unveiled at the European Society for Medical Oncology 2024 meeting. The improvement was statistically significant. Patients in both the Imfinzi and control arms of the study received cisplatin-based chemotherapy before surgery.
On one of the trial’s dual primary endpoints, event-free survival (EFS), Imfinzi also significantly reduced the risk of disease recurrence, worsening or death by 32%.
Perioperative Imfinzi is now the first PD-1/L1-based regimen to demonstrate a survival benefit in MIBC. Both Bristol Myers Squibb’s Opdivo and Merck & Co.’s Keytruda have shown in separate phase 3 trials that they can extend patients’ disease-free survival time compared with placebo when used in the adjuvant setting alone after patients have had their bladder surgically removed, but data on whether they can prolong patients’ lives remained unclear.
The phase 3 AMBASSADOR trial showed that adjuvant Keytruda pared down the risk of disease progression or death by 27% compared with observation following surgery, according to results with a median 44.8 months of follow-up presented at ESMO24 and published in The New England Journal of Medicine.
The AMBASSADOR trial looks unlikely to reach statistical significance on overall survival, one of its dual primary endpoints. By the data cut-off, the trial has undergone a second interim analysis of overall survival with 80% of death cases required for the final analysis. No obvious difference was observed between the two arms with a marginal 2% improvement in favor of Keytruda, and the two arms’ survival curves were not clearly separated. As the trial investigators noted, 15.1% of patients who progressed in the Keytruda arm, versus 52.2% in the observation group, received subsequent treatment with a checkpoint inhibitor.
While overall survival (OS) is the gold standard to evaluate a drug’s treatment profile, Imfinzi still faces questions around its separate effects before and after surgery.
The perioperative trial design—namely, testing a drug’s continuous use on both sides of surgery rather than separately—was targeted by the FDA in a closely watched advisory committee discussion in July. The protagonist of the meeting was none other than AZ with its Imfinzi.
At that time, the FDA and its external advisers voiced frustration over AZ’s AEGEAN study, which is evaluating Imfinzi as a treatment before and after surgery in early-stage resectable non-small cell lung cancer. The agency and its outside advisers specifically said the trial’s perioperative design couldn’t tease out the contribution of each phase of the regimen.
In a unanimous vote, the FDA advisory panel recommended that future trials for resectable NSCLC be designed to assess the effect of each treatment phase, with some experts calling on the FDA to consider extending the requirement to other solid tumors. The FDA eventually approved Imfinzi as a perioperative therapy for reseactable NSCLC in August.
This demand is for “next” studies, Cristian Massacesi, chief medical officer and oncology chief development officer at AstraZeneca, said in an interview with Fierce Pharma about the latest NIAGARA data. NIAGARA read out in June before the FDA advisory committee gathering.
Nevertheless, the case backing Imfinzi’s use in the neoadjuvant setting in MIBC appears a bit shaky. The NIAGARA trial failed to show a statistically significant improvement for Imfinzi on its other dual primary endpoint, pathologic complete response (pCR), which counts patients who have no sign of disease residue in resected tissues. The endpoint is considered a direct measurement of treatment effect for a presurgical treatment.
The trial did show a numerical pCR improvement in favor of Imfinzi but didn’t give the endpoint much statistical powering, Massacesi said. Besides, unlike tumors such as breast cancer, the relevance of pCR is not very well established in MIBC, he added.
“What really matters to the community, to the patients, to the regulators and to us is EFS and OS,” the AZ exec said.
Using Imfinzi before surgery didn’t appear to affect patients’ ability to undergo surgery, the trial investigators noted. Radical cystectomy was completed in 88% of patients in the Imfinzi arm, versus 83% in the control arm. Grade 3 or 4 treatment-related adverse events occurred in 41% of patients in each arm, and the rate of treatment-related deaths was the same for each group at 0.6%.
MIBC is also different from the NSCLC case, Massacesi argued. In NSCLC, the FDA has previously approved PD-1/L1 inhibitors as either neoadjuvant or adjuvant treatments.
In MIBC, BMS’ 2021 approval for Opdivo as an adjuvant therapy in MIBC established PD-1/L1 blockade’s role in the postsurgical treatment setting, but presurgical use of a checkpoint inhibitor lacks precedent.
Editor's Note: The story has been updated with additional data from Keytruda's AMBASSADOR trial.