The Phase III NIAGARA study evaluating AstraZeneca‘s Imfinzi (durvalumab) for neoadjuvant and adjuvant cisplatin-eligible muscle-invasive bladder cancer (MIBC) results were presented at European Society for Medical Oncology (ESMO) Congress 2024.
For decades, perioperative platinum-based chemotherapy regimens have been the standard of care (SOC). Still, disease recurrence following bladder removal occurs in roughly half of the patients within several years. In the study, Imfinzi was administered in combination with chemotherapy in the neoadjuvant setting and alone, postoperatively. At 24 months, the study met its primary endpoint of event-free survival, besting the SOC with 67.8% versus 59.8% (hazard ratio [HR], 0.68). There was a 25% reduction in the risk of death with Imfinzi, and 82% of patients were alive at the two-year mark compared to 75% of patients in the control arm (HR, 0.75). The safety profile was consistent with the chemotherapy comparator arm, as 41% of patients had treatment-related adverse events. GlobalData’s analyst consensus forecast estimates that Imfinzi’s sales will surpass $7bn by 2030.
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Based on disease-free survival (DFS) in the Checkmate-274 study, Bristol Myers Squibb’s Opdivo (nivolumab) became the first and only immunotherapy to be approved in the adjuvant setting. Opdivo provided a benefit of 19.4 months in median overall survival (OS) compared to placebo. However, the NIAGARA trial is the first study to show an OS benefit in both the neoadjuvant and adjuvant settings.
Although expected to be practice-changing in Europe, key opinion leaders are cautiously optimistic about whether or not the FDA will greenlight the regimen in the US. The FDA recently delayed an approval for perioperative stage II–IIIb non-small-cell lung cancer (NSCLC) based on positive results from the AEGEAN trial. The study, which shares the same trial design as NIAGARA, led to the FDA’s advisory committee questioning whether positive studies that contain both neoadjuvant and adjuvant settings should be evaluated for their split contribution rather than their combined benefit. Regulators are concerned that overtreatment of the immunotherapy may cause unnecessary toxicity if there is no real added benefit to dosing pre- and postoperatively. The FDA suggested that in the future, perioperative studies across indications will require a three- or four-arm trial design to evaluate each component of the study separately. The time and budget associated with conducting such trials may be considerably higher due to the added recruitment requirement. While the NIAGARA study is most mature, several other studies are underway.
Similar to NIAGARA, the MSD-sponsored KEYNOTE-866 trial for Keytruda (pembrolizumab) and chemotherapy has a primary completion date scheduled for 2025. The addition of pembrolizumab to Pfizer’s antibody-drug conjugate Padcev (enfortumab vedotin-ejfv) for untreated, advanced/metastatic bladder cancer was a highlight of last year’s ESMO conference, where the combination showed a drastically improved progression-free survival and made it the new SOC for these patients. The combination is being evaluated in the perioperative setting in two Phase III studies for cisplatin-eligible (EV-304) and ineligible (EV-303) patients. A substantial improvement over NIAGARA should be warranted, as a label in this setting could have significant drug sequencing implications for patients who relapse if redosing is not viable. Finally, the Phase III VOLGA perioperative trial combining Padcev with Imfinzi and Imjudo (tremelimumab) is the first triplet to be evaluated in this setting.
Aside from questions about the benefit of adding adjuvant treatment following neoadjuvant therapy, some physicians in the field question whether a different agent, such as Opdivo, should be administered rather than using the same drug as currently done in all the trials mentioned. The industry is grappling with many such considerations, and the forthcoming years are expected to clarify these currently outstanding questions.
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