ESMO East 2024: Dr Sonpavde Discusses the NIAGARA Trial and Using ctDNA in Bladder Cancer
Presenter
Guru Sonpavde, MD, AdventHealth Cancer Institute
Conference
2024 ESMO East
In his presentation at the 2024 ESMO East Conference, Dr Guru Sonpavde highlighted findings from the NIAGARA Trial, as reported at this year’s European Society for Medical Oncology (ESMO) Congress. This landmark study investigated the efficacy of integrating immunotherapy along with chemotherapy in the perioperative setting, for patients with muscle-invasive bladder cancer (MIBC). Additional data from another trial also investigated the role of circulating tumor DNA (ctDNA) as a potential biomarker for personalizing treatment in patients with urothelial carcinoma.
Background
Muscle-invasive bladder cancer is a potentially curable but aggressive disease. The standard approach has traditionally relied on neoadjuvant cisplatin-based chemotherapy followed by surgery. Long-term survival, however, remains suboptimal, and additional strategies are needed to improve outcomes. Immunotherapy using immune checkpoint inhibitors like durvalumab help the body’s immune system to better recognize and attack cancer cells, and these agents have shown promise in other stages of bladder cancer, prompting their evaluation in combination with chemotherapy. Circulating tumor DNA (ctDNA) is a means for detecting microscopic residual cancer cells in the body after surgery, and the technology is being increasingly used to detect what is known as “minimal residual disease”, or MRD. The presence (or absence) of MRD could potentially be used to guide treatment decisions, enabling the use of tailored therapies based on real-time disease monitoring.
The NIAGARA Trial
Study Design
The NIAGARA trial is a phase III randomized trial that evaluated the addition of durvalumab, an anti-PD-L1 immune checkpoint inhibitor, to standard neoadjuvant cisplatin-gemcitabine chemotherapy in patients with MIBC. Patients received neoadjuvant (pre-surgery) durvalumab combined with chemotherapy, followed by surgery and subsequent adjuvant (post-surgery) durvalumab. Eligible participants in the trial included cisplatin-eligible patients who received gemcitabine plus conventional cisplatin, and those with borderline renal function (glomerular filtration rate [GFR] 40–60 mL/min), who received gemcitabine plus split-dose cisplatin. The primary endpoints were event-free survival (EFS) and pathological complete response (pCR), with overall survival (OS) as a secondary endpoint. Over 1,000 patients participated, with balanced demographic and clinical characteristics across the treatment arms.
Main Trial Results
Event-Free Survival (EFS):
Durvalumab combined with chemotherapy significantly improved EFS as compared to chemotherapy alone, with a hazard ratio (HR) of 0.68. This benefit was observed consistently across subgroups, including patients with varying PD-L1 expression levels.Pathological Complete Response (pCR):
Although pCR rates improved with durvalumab (37.3% vs. 27.5%), the difference did not reach statistical significance after adjustments.Overall Survival (OS):
Addition of durvalumab was associated with a notable OS benefit, with an HR of 0.75, reflecting a statistically significant survival advantage.Safety Profile:
The addition of durvalumab did not delay or compromise surgery, and the regimen was well-tolerated overall, with no unexpected safety signals.
Conclusion from NIAGARA
This is the first phase 3 trial to demonstrate that perioperative immunotherapy combined with gemcitabine-cisplatin improves both EFS and OS in MIBC. Dr. Sonpavde emphasized, “NIAGARA is a practice-changing trial, establishing the role of chemo-immunotherapy in improving long-term outcomes for patients with muscle-invasive bladder cancer.”
Using ctDNA as a Biomarker
Findings from the Tombola Study
Complementing the findings of the NIAGARA trial, the Tombola study evaluated the utility of ctDNA in guiding postoperative management for patients with MIBC. This prospective non-randomized cohort study included patients who underwent neoadjuvant (pre-surgery) cisplatin-based chemotherapy and surgery followed by post-operative ctDNA-guided atezolizumab therapy.
Detection of ctDNA:
56% of patients in the study were found to be ctDNA-positive post-surgery, suggesting the presence of residual microscopic disease. Those with negative ctDNA had an extremely low risk of recurrence (3%).Impact of Adjuvant Therapy:
Patients with detectable ctDNA who received immunotherapy with atezolizumab showed a high recurrence-free survival (RFS) rate of 75%, a substantial improvement compared to historical recurrence rates for untreated ctDNA-positive patients (typically ~95%).Key Insights:
Patients who were ctDNA-negative after surgery (suggesting no residual microscopic disease) exhibited excellent long-term outcomes, while ctDNA-positive patients were found to potentially benefit from the use of adjuvant immunotherapy. These findings highlight the potential for ctDNA to be used as a predictive biomarker and for individualizing postoperative treatments.
Implications for Clinical Practice
The NIAGARA trial establishes neoadjuvant chemo-immunotherapy as a new standard of care for MIBC, although regulatory approval are currently pending. It sets the stage for incorporating other immune checkpoint inhibitors like pembrolizumab and nivolumab in similar settings for MIBC, as well as the potential arrival of combination Enfortumab Vedotin plus pembrolizumab.
The ctDNA findings suggest a complementary approach, wherein tumor-informed biomarkers could be used to stratify patients into those who require intensified adjuvant therapy versus those who may safely forgo unnecessary treatments. The ongoing IMvigor-011 phase III trial is expected to further confirm and validate the role of ctDNA for clinical decision-making in the setting of MRD following surgery for muscle-invasive bladder cancer.
Conclusions
The integration of immunotherapy into perioperative regimens represents a transformative shift in MIBC management. The NIAGARA trial demonstrates that combining durvalumab with chemotherapy significantly improves survival outcomes without compromising safety. Additionally, ctDNA serves as a promising tool for optimizing therapy based on MRD status. Together, these advancements move the field closer to personalized treatment approaches in bladder cancer.
“This is a pivotal moment in bladder cancer care, with trials like NIAGARA paving the way for broader use of immunotherapy in curative-intent settings and ctDNA emerging as a valuable guide for treatment personalization.”
Speaker Disclosure Information: Dr Sonpavde reported the following disclosures for this presentation: Advisory Board: EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo; Consultant/Scientific Advisory Board (SAB)/Trial Steering Committee: Syapse, Merck, Servier, Syncorp, Ellipses; Institutional Research Support: EMD Serono, Jazz Therapeutics, Bayer, Sumitomo Pharma, Blue Earth Diagnostics; Speaker: Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, Merck Data Safety Monitoring Committee (Honorarium): Mereo; Employment: Spouse employed by Myriad, Exact Sciences; Travel: BMS, Astellas; CME-Certified Speaking: Research to Practice, PeerView Institute, Ideology Health, IBCU/Grand Rounds in Urology; Writing/Educational Fees: Uptodate, Practice Update, Onviv, DAVA Oncology, PrecisCa