Perioperative Therapy, ctDNA for Advanced Bladder Cancer

Guru Sonpavde, MD, of AdventHealth Cancer Institute, shares his general thoughts on first-line perioperative PD-L1 therapy for advanced bladder cancer, including how trials like CheckMate 274, AMBASSADOR, and NIAGRA are shaping the management approach.

He also comments on research initiatives to better optimize ctDNA use in the patient care continuum.

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Can you share your general thoughts on first-line perioperative PD-L1 therapy for advanced bladder cancer? How are trials like CheckMate 274, AMBASSADOR, and NIAGRA shaping the management approach?

Dr. Sonpavde: In the perioperative setting, we currently have adjuvant nivolumab approved based on the results of the CheckMate 274 trial. This trial showed an improvement in both overall disease-free survival and, more notably, in disease-free survival among patients with high PD-L1 expression. A recent update at the EAU meeting in 2024 also indicated an improvement in overall survival, which was a secondary endpoint of the trial. Although the statistical threshold was not fully met, there was a clear trend toward improved survival. In Europe, nivolumab is approved for adjuvant therapy in PD-L1 high patients only, while in the US, it is approved for all patients.

Additionally, we have the adjuvant pembrolizumab trial, known as the AMBASSADOR trial, which demonstrated an improvement in disease-free survival across all patients. Although this has not yet been approved, there is anticipation that it may be in the near future.

More recently, the NIAGARA trial has reported positive results. This neoadjuvant trial compared gemcitabine-cisplatin versus gemcitabine-cisplatin plus durvalumab, with an adjuvant component of durvalumab alone in the experimental arm. The trial showed improvements in both event-free survival and overall survival, according to a press release. This positive outcome suggests that other chemo-immunotherapy trials could also yield favorable results. For instance, the combination of EV and pembrolizumab, which has shown dramatic results in advanced disease and first-line settings, might also prove beneficial in the perioperative setting.

Overall, we are likely to see significant changes in the perioperative management of bladder cancer based on the outcomes of these trials.

Can you elaborate on NIAGRA? Does it have the potential to be paradigm-shifting in the way immunotherapy is utilized pre- and post-surgery?

Dr. Sonpavde: The NIAGARA trial is likely to be practice-changing. While we are still awaiting the full presentation of the results—hopefully at the ESMO Congress 2024—it seems promising. Given that NIAGARA has shown positive outcomes, I anticipate that other trials testing similar cisplatin-based chemotherapy combined with PD-L1 inhibitors will also yield positive results. Additionally, I expect the EV-pembrolizumab combination to be effective as well, potentially leading to the adoption of several regimens that include immune checkpoint inhibition in this space.

Can you comment on research efforts or initiatives to better optimize ctDNA use in the patient care continuum?

Dr. Sonpavde: Currently, we still lack prospective validation of circulating tumor DNA (ctDNA) for minimal residual disease (MRD) assessment. However, there is promising retrospective data indicating that post-operative ctDNA, particularly when using tumor-informed ctDNA with whole exome sequencing, shows potential. This approach involves sequencing the tumor’s exome and selecting key genes to monitor in the blood. Retrospective analysis of the IMvigor010 trial demonstrated that patients who are ctDNA-positive post-operation have a very high chance of recurrence: over 90%. Conversely, those who are ctDNA-negative have a significantly lower risk, approximately 25%, though not zero. This suggests that ctDNA could potentially be used to determine which patients might benefit from adjuvant therapy.

Prospective validation of this platform is ongoing in the IMvigor011 trial. Preliminary data from this trial shows that patients who remained ctDNA-negative continuously for up to about 16 months had a low risk of radiographic recurrence, around 10%. This suggests that continuous ctDNA negativity is a strong prognostic factor, indicating a low, though not zero, chance of recurrence. Further data from IMvigor011 is needed, and additional validation is being sought in the TOMBOLA trial.

Moreover, new platforms are emerging that could further refine ctDNA detection. One of these involves whole genome sequencing of the tumor to select ctDNA molecules in the blood, offering a broader analysis than whole exome sequencing. Another emerging approach is fragmentomics, which examines not only the genetic alterations in ctDNA but also the way DNA fragments are broken up in tumor cells compared to normal cells. Tumor cells produce smaller DNA fragments, and this characteristic can be used as a biomarker. These innovations in ctDNA analysis, including whole genome sequencing and fragmentomics, are expected to play a significant role in the future of MRD assessment.