Drs. Koshkin, Basu on ctDNA and MRD Considerations for Adjuvant Therapy After Radical Cystectomy

By Arnab Basu, MD, MPH, FACP, Vadim Koshkin, MD - Last Updated: June 1, 2023

Vadim Koshkin, MD, University of California, San Francisco, and Arnab Basu, MD, MPH, FACP, University of Alabama at Birmingham, break down treatment considerations based on ctDNA status after radical cystectomy, among other factors.

Dr. Koshkin: Based on this data, do you view the data as potentially practice-changing or at least practice-impacting? And has it impacted your practice? Where do you currently use this biomarker?

Dr. Basu: That’s a great point. I think the question is, even in an exploratory analysis, how do you know and how does that impact your clinical practice when faced with a hazard of 1.3 or something?

I do discuss this data. I mention that it involved around 400 patients. It wasn’t originally part of the study design, but it raises the question of how comfortable patients are with observation if they’re MRD negative. Interestingly, we will be presenting some real-world data on this topic at ASCO in a couple of weeks. We will be discussing the outcomes of patients who did not have MRD post-cystectomy.

Based on what we find, it seems to hold true in real life as well. That has been my practice. Patients who are MRD negative may be able to enjoy a long period without therapy. A small minority might show slight biochemical changes, which you might consider in urothelial cancer as well, leading to pre-considered therapy.

Dr. Koshkin: That’s an interesting point. It’s like the PSA test for urothelial cancer, analogous to its use in prostate cancer, another common GU disease we treat.

Dr. Basu: Bladder-specific DNA, a prostate-specific analogy.

Dr. Koshkin: Indeed. So, it seems that if a patient has undergone radical cystectomy and is ctDNA positive, you would consider adjuvant therapy.

Dr. Basu: Absolutely.

Dr. Koshkin: And if they’re ctDNA negative, no adjuvant therapy. That’s the basic understanding I’m getting from your explanation.

Dr. Arnab Basu: Absolutely. You already mentioned the ongoing adjuvant trial for atezolizumab, which surveils patients and treats only those who test positive for MRD with atezolizumab. The Denmark group also conducted a similar trial called the TOMBOLA trial.

Dr. Koshkin: Okay. The first one you mentioned is IMvigor011, which is currently enrolling, mostly or probably exclusively outside the United States. The enrollment is progressing well, and we will soon see the data. You mentioned the TOMBOLA trial as well.

Dr. Basu: Yes, TONBOLA is conducted by the same group in Aarhus. It’s another trial that incorporates the biomarker, not just as an informed component, but as an integral part. We are also planning a trial called “cure MRD,” which will have an escalation design based on MRD clearance using single-agent atezolizumab.

In the IMvigor010 study, only about 18% of patients were able to clear their MRD, yet we still observed a significant hazard ratio of 0.5. This is because the survival is extremely poor otherwise, with numbers dropping off and about 75% of patients experiencing recurrence within 10 months.

The trial will investigate therapy escalation for patients who cannot clear MRD. Another adaptive design study led by Dr. Galsky’s group, through the Alliance, will be the “MODERN study.” It will explore escalation to PD-1 plus LAG-3 in patients with MRD positivity versus PD-1 alone. Patients with MRD negativity will be randomized to PD-1 treatment or surveillance, with the option to initiate nivolumab if they develop positive MRD during surveillance. That’s a non-inferiority I believe, on that arm. Those will be the next generation of escalation, de-escalation designs in the actual.

Dr. Koshkin: That’s a great overview of this dynamic field. There are numerous questions to explore and answer, especially considering the relatively new test and technology that has been available for only a few years. You have been actively involved in this space, generating excellent data.

You mentioned that you will be presenting some real-world data at the upcoming ASCO conference in a couple of weeks. While you can’t disclose the specifics, it would be helpful to get a quick overview of what you’ll be presenting and the number of patients involved.

Dr. Basu: Absolutely. Our fellow, Dr. Colopathy, will be presenting this comprehensive analysis. It’s a real-world assessment based on data from our collaborators, including Stanford, Dr. Galsky’s group, Dr. Tan, and Dr. Trush. The study involves a large cohort from multiple institutions, with approximately 120 patients. It covers various disease groups, ranging from stage 2 to stage 4, replicating the findings from Arhus. The significant difference here is the approval of adjuvant immunotherapy, allowing us to observe how DNA predicts outcomes in patients receiving this treatment. I’m thrilled to share this data on behalf of our group, and there is more to come.

View their other comments on MRD, ctDNA, and Liquid Biomarker Use in Bladder Cancer as well as Clinical Practice Patterns for Adjuvant Therapy of ctDNA-Positive MIBC.