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Cheryl T. Lee, MD: Welcome to Medscape InDiscussion for Season 2 of our Bladder Cancer Series. I'm Cheryl Lee. Today, we'll discuss circulating tumor DNA (ctDNA) biomarkers. ctDNA, also referred to as a liquid biopsy, has grown in its clinical use as a prognostic biomarker that can define the risk for recurrence after curative intent surgery for colon cancer. In bladder cancer, it may also play a role in detecting residual disease, thus sharpening our understanding of who should have adjuvant treatment after radical cystectomy. Still, there are many questions about its potential use that may be clarified by the IMvigor011 study. To further explore the utility of the ctDNA biomarker in bladder cancer management, we've invited Dr Tom Powles to the program. Dr Powles is a professor at the Center of Experimental Cancer Medicine at Barts Cancer Institute, and he's also the director of Barts Cancer Centre at St Bartholomew's Hospital in London in the UK. Welcome, Tom.
Thomas B. Powles, MBBS, MRCP, MD: Cheryl, thank you very much for inviting me.
Lee: You lead a broad array of translational studies on novel targeted and immunotherapies for several genitourinary (GU) malignancies. Importantly, you're leading the IMvigor011 trial. What sparked your interest in GU cancers and molecular medicine?
Powles: Oh, Cheryl, people have already asked me that question very often. I don't really know; I think we stumble across things in life, don't we? When I started working with patients who had GU cancer, testes cancer was largely curable. Hormone therapy worked well for prostate cancer. Bladder cancer was chemotherapy-based, and we were giving interleukin 2–interferon for kidney cancer. So there was something for everyone there. I think that's what attracted me to GU cancer.
In terms of drug development, I'm not sure I'm terrific at audits; I'm much more interested in research and development and newer things. So I kind of went into drug development in that way. I guess my interest in biomarkers goes back to my thesis, where I was looking at the mechanisms of resistance to therapy in different urology cancers. I was really interested in molecular targets, and that led to a number of trials, particularly around the HER1 to HER4 family, which started in bladder cancer with a study that ended up being randomized and negative. I'm sure you're aware that HER2-targeted therapies in the context of antibody drug conjugates has come back into fashion, dare I say it, 15 years later, which makes me feel extremely old, to be honest. I think that's where I started.
In terms of ctDNA, that story goes back to prostate and colon cancer. It's been apparent to us for some time that we can look at ctDNA. Most DNA doesn't appear in the blood; it's in cells. There is some clonal hematopoiesis. There's a small amount of DNA in the blood from the host, but as a rule, it's unusual to have circulating DNA. In fact, cancers do shed quite a lot of ctDNA, and we've known that for some time. In prostate cancer, where we use a lot of prostate-specific antigen testing, I think that's always been a good biomarker.
One of the interesting things about ctDNA, in my opinion, is that there are different ways of measuring it and it's important conceptually. There are two broad components. The first is where we get a panel-based approach, where essentially you have premade off-the-shelf testing kits that test 300 or 400 circulating mutations, somatic mutations. These are panel-based approaches that you select for the genes; the mutations have been preselected. That's sometimes good for colorectal cancer and lung cancer, where it's somewhat predictable which mutations are going to occur. But those mutations don't translate well into kidney cancer, urothelial cancer, or breast cancer. In those cancers, we need a personalized approach, in which we do very deep sequencing on the primary tumor, identify a number of mutations, normally more than 10, and try and track those mutations in the plasma by making probes to track them. It's this personalized approach that has turned out to be successful in most cancers. This panel-based, nonspecific approach probably isn't accurate enough for many cancers, such as urothelial cancer.
To summarize what I've said, we need biomarkers to identify patients at risk, not just to select patient therapy. ctDNA looks like a good biomarker. And in some of the key bladder cancer work, after cystectomy in which patients are thought to be or many have been told they're being cured but may relapse, what you can identify is that after cystectomy, 40% of patients who have no radiologic evidence of relapse of disease, using this personalized approach, you can identify 40% of them who have ctDNA. Of those patients who express ctDNA, 90% relapse. In the patients who do not express ctDNA, which is 60% of patients, the relapse rate is only about 15%. So, it's not perfect, but it's very discriminatory. It's a hazard ratio of 6 if you're ctDNA-positive or relapsing. What we also discovered is that patients become ctDNA-positive about 6 months before you can find radiologic evidence of relapse. So the ctDNA positivity predates the growth of the cancer, which follows behind. Conceptually, it's very different from what we've been telling our patients. In the past, we've said, "You'll have this operation," and then somehow the cancer comes back in the future. Many of my patients ask me when it comes back in the lungs, "Is that lung cancer or bladder cancer?" The answer to that question is that the cancer never really went away. It was always in the blood. Even at the time of the operation, it was in the blood. And it was always going to spread. After the operation, because the ctDNA is still there, it means there's micrometastatic disease. Those micrometastases will grow, and they will spread with time. The key question from our perspective is: Should we be picking adjuvant therapy based on ctDNA? And that's the last piece of IMvigor010.
Lee: I feel like we'll be getting into a period of identifying these potential micrometastases, or at least the ctDNA that may predict micrometastatic disease, treating those patients in a neoadjuvant sense as we've done anyway in bladder cancer, but maybe in a more targeted fashion, then moving forward with what we think is a definitive local therapy, and then continuing to follow the potential ctDNA that may show up in the plasma. So, I say that because in prostate cancer, we're dealing with prostate-specific membrane antigen PET scans that are showing disease that we never would have seen before. It's just an interesting period in the management of GU tumors.
Powles: I think that's right. And I can see this, dare I say, "staging creep" earlier — identifying disease earlier than previously.
Lee: Can you discuss the IMvigor010 trial and its findings and how that led to the design of IMvigor011?
Powles: IMvigor010, which was a randomized phase 3 study looking at adjuvant atezolizumab, overall was negative. It had a hazard ratio of 0.89. In unselected patients after cystectomy, atezolizumab didn't appear to delay progression-free survival or improve overall survival. One of the keys to that is 60% of patients never relapsed, so there were only 40% at risk. The ctDNA data showed that if you only selected those patients, the relapse rate was 95%. The really intriguing thing about that trial is for those patients who were treated with atezolizumab, there was a 40% reduction in the risk for relapse and a 40% reduction in the risk for death. Why would that be the case? The reason this has occurred is… We know that in urothelial cancer, by the time it's visible, the cancer is growing quickly. It's possible, conceivable, or even probable, in my opinion, that early immunotherapy, very early immunotherapy, gives a longer runway and more time for the immunotherapy to work. Potentially, the lower burden of disease is easier for the immunotherapy to deal with. We know, for example, that lymph node metastases respond better than does liver metastases. It might be these micrometastatic deposits that we can't yet see are most sensitive to immunotherapy, and that's why the trial would have been positive had we selected only the ctDNA-positive patients. That's why we're conducting IMvigor011.
But, just before, there was some more work that we did, and there were several people from Roche and the Roche Biomarker Group who were involved in this. I think it was interesting. They linked in with the biology from the primary tumor. They linked the ctDNA expression with the biology of the primary tumor that was removed surgically: the cystectomy sample. You can show that patients who are ctDNA-positive as opposed to patients who are ctDNA-negative — those who have slightly different immune biology, but, maybe more importantly, those who are ctDNA-positive and who respond to therapy but have higher tumor mutational burden and higher tumor programmed death-ligand 1 expression — respond differently.
Lee: How do you think the ctDNA relates to the primary tumor?
Powles: There's a link between the biology of the primary tumor and ctDNA expression and, indeed, the chances of responding. Those primary tumors that overexpressed transforming growth factor beta, which we know is associated with resistance to therapy, respond less well. It's not just simply that we're identifying these tumors earlier but the biology from the primary tumor is also linking in, which I think is very relevant.
Lee: Tom, we're going to obviously obtain quite a bit of information on the ctDNA, but can you just discuss the endpoints of IMvigor011?
Powles: IMvigor011 leads on from IMvigor010. IMvigor011 is a randomized, phase 3 study, and it's the confirmatory study. It's important to recognize that IMvigor010 is the adjuvant trial for unselected patients, and that trial was negative. In clinical trials, we ask a question, and if it's positive, we move forward; if it's negative, we don't. We can generate exploratory data off those trials that are negative, but you can't say, "Oh, we wish we'd done it this way, and therefore it's a positive trial." In IMvigor010, that ctDNA trial is not positive. It's a very provocative finding, but it's not statistically significant in the classic sense of a randomized trial. And the reason why that is: It's not the question we predefined that we're going to ask at the beginning. Therefore, we've done the experiment again, this time asking specifically this question. In this, we've extended the window after cystectomy. In the original trial, you had to be randomized within 12 weeks of cystectomy. Here, we're saying that if you are ctDNA-negative and become ctDNA-positive with time, you can take part in the trial. Or, if you are positive for 6 months after the operation, you can also take part in the study. We're extending the window because we're pursuing the principle that the timing is less important than is the presence of ctDNA positivity. That's the first question we're asking.
Then, of course, this time we're going against placebo. It's a randomized phase 3 study, and we're looking to randomize about 250-300 patients, somewhere around that. It's relatively modest-sized. But we're looking for quite significant results, because we're selecting this group of patients. About 40% of patients are ctDNA-positive. To get those 300 patients, we've got to screen 1000 patients or something close to that. We're tracking several patients who are ctDNA-negative as well to see if they become positive. It's a huge undertaking of ctDNA analysis to see those patients who are positive and go into study, those patients who are negative and who become positive, and the outcome of those patients who are negative and who remain negative. We're going to learn a huge amount from this study. We've already enrolled 60% of patients around the world. It's open in 200 sites. These personalized therapy studies are much more challenging than are the all-comers studies. The patients must consent to have a screening process, and so it is more complicated. Nevertheless, we're very confident we're going to finish the study, and I'm very confident that this is going to be a practice changing study. In the future, instead of doing radiologic exams after a cystectomy, we're going to be measuring ctDNA. And those patients who are positive will receive adjuvant therapy. I don't think the patients who are negative will need adjuvant therapy. So, I think we can move into a process of selection, which is relevant for the future.
Lee: Well, this is exciting. I know many are waiting for the results of this trial when the time is right. We are winding down our program today. Any last takeaways you have for our audience?
Powles: No, Cheryl, just to say thank you very much for asking me to discuss this. This is an incredibly important study, I think. And if your site is open, please take part. We're excited about moving the study forward. Bladder cancer is moving very, very quickly. It's an exciting time. And ctDNA is going to play an important role in that, in my opinion.
Lee: This has really been fantastic. I want to thank our listeners for joining in today for our conversation with Dr Tom Powles. There's much more ahead in the coming episodes, so be sure to check out the Medscape app, and share, save, and subscribe if you enjoyed this episode. I'm Cheryl Lee for Medscape InDiscussion.
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Cite this: Personalized Medicine in Bladder Cancer: Inflection Point - Medscape - May 23, 2023.