Thomas Powles: So, the ctDNA space is evolving very quickly and IMvigor011 is probably leading the charge because it's a positive randomized phase three study testing ctDNA. The design of IMvigor011 is actually quite straightforward and it's based off retrospective data from IMvigor010. Essentially, after an operation for urothelial cancer in the adjuvant setting, the cancer comes back in about half the patients, and as it happens, about half the patients are ctDNA positive. And what we showed in IMvigor010 is there was really, really strong enrichment, has a ratio of about eight, for those patients who were positive, relapsed. Almost all the positive patients relapsed. And indeed, if you look at the negative patients, about 20, 25% of those patients relapsed. So, you can have a big enrichment using ctDNA. And the IMvigor010 prospectively tested that.
So, in the positive patients, they were randomized to atezolizumab or placebo, but also the negative patients, we tracked those patients, and if they were negative and became positive, they were also randomized, and then we had the third group, the negative that remained negative. The outcomes of the negative patients was excellent, I think we can spare those patients' therapy. Remember, these adjuvant trials have never achieved overall survival before. So, it's not like we're saving every patient from [inaudible 00:01:36] cancer chemotherapy. Immune therapy is not particularly effective in unselected patients. So, those patients who are not at risk, we're helping those, sparing them life changing toxicity, and then the positive patients or those that are negative become positive, we showed a significant overall survival advantage.
And that's important because we've never shown survival in the adjuvant setting before. So, from my perspective, this changes our approach to urothelial cancer. Now, don't get me wrong, everything's moving up into neoadjuvant setting, and the results of IMvigor011 don't apply in the neoadjuvant setting. It doesn't tell you when you can stop immune therapy, but it does tell you you've got a test that's now strongly prognostic, and I believe better than CT scanning and imaging, for example. Because starting therapy early in these patients is super important.
So, that's what we did. We defined the test using the Signatera assay, and I've talked about positivity and negativity, and I've been very quick to describe that, but actually it's more complicated. We track up to 16 mutations, and if you have two or more mutations, you're defined as positive. Now, these mutations are given at different levels in the blood, and you'd have tiny weeny low levels of two and that's positive. And so, what we did here is we looked at MTM levels, like PSA. PSA five versus PSA 5000, PSA 5000 do better than PSA five, but you're still positive. And we basically showed the same thing.
Tian Zhang: So, tell us about MTM.
Thomas Powles: MTM is essentially, it's the concentration, it's the concentration of ctDNA within a particular per mil. And essentially you can get a value, and it goes 0.02 up to about three. And three is... So, we had cut points of 0.13, 1.0, 3.0, to separate-
Tian Zhang: So, much more of a continuous variable than binary.
Thomas Powles: It is a continuous variable, you get a value. And the higher the value, guess what? The higher the chance of the cancer is aggressive, it's prognostic, the higher levels are more prognostic. You would expect that. And so, those patients with more aggressive disease have higher levels. We also showed actually that pathological T stage is really unpredictable in saying what level you're going to have. So, we know that pathology, if you got T2, T3, T4, it's not particularly reliable predicting on whether the cancer's going to come back. And actually, ctDNA trumps that, and you can look at that by looking at the MTM levels. And then, of course, you have clearance, and we talked about clearance are going to positive to negative, but here we've shown that actually you're going to have clearance that way, but you can also have reduction from your MTM levels, a twofold reduction, for example, and that is strongly prognostic as well.
And then, the final bit, of course, is you can then subsequently track biomarkers with time, and you can watch dynamic changes occurring. So, essentially, the take home message with this is IMvigor011 is a study that's positive, we may not be using that because adjuvant therapy is less popular than it was, but it still has a role to play there, but actually it has broader applications, and now we're showing it's not just positive and negative using the Signatera assay, it's also the MTM level that's useful, and having higher levels is prognostically important. The last thing I'd like to say, if I may, is that the negative patients still do really well.
And the positive patients, even the patients who are low positive, they relapse in the end. So, it's not like there's a three groups of patients, there's the negative patients, there's the super high risk, and there's this gray area in the middle. If you're positive, it's bad news. You will relapse, but you might relapse two times, it might take twice as long as if you're only just borderline positive.
Tian Zhang: So, Tom, ctDNA ready for prime time, should we be using it in our routine practices now?
Thomas Powles: I think it is ready. Honestly, I do. And I'm not just saying that because it's a study, because sometimes you got... I just feel like we have it at our center and it's useful. I had a patient the other day, he had a diverticular tumor, he had surgery, it turned out to be T3... It was thought to be T1, but it was T3. He just had an operation because it was thought to be a T1 and a diverticulum, and that's a bit unusual. We did a test beforehand, it was positive. And then we did a test afterwards, and it's positive.
Tian Zhang: So, you're thinking adjuvant treatment for sure for him?
Thomas Powles: Well, he's got MRD, he's going to relapse, and we got to get treatment in effectively, get treatment in early. And instead of that uncertainty, and I said, "Well, nivolumab and maybe going, maybe you haven't..." The big question is what is the right treatment for these patients? Atezolizumab, the trial was done with that, but in the future, in 10 years time, if we're going to cure... I think we'll cure more patients with more intensive therapy, and these patients are at risk. So, the answer to your question is yes, it's part of my thinking.
Tian Zhang: And finding those patients with minimal residual disease, maybe intensifying their therapies early rather than later?
Thomas Powles: I think at the moment we should go, personally, I think at the moment we should go with the data we have, but I'd love to do studies where we explore combinations in that, because at the moment the ctDNA clearance rate with atezolizumab is about 30%, what about if we've got 100%?
Tian Zhang: Yeah, absolutely. We'd love to cure more patients for sure. Talk a little bit about that clearance. So, timing, does timing matter for the clearance?
Thomas Powles: So, we did, in IMvigor010, the original trial, we only looked at one time point, and IMvigor011, we looked at multiple time points. And when you look at the timing of clearance, most, the vast majority... So it goes from 26 on the first cycle, on the first test, and we do every six weeks, and then six weeks later, you go up nearly about 32%. So, most of the clearance is happening early. And by the first two samples, almost all the clearance is done actually. So, one of the things we are learning is ctDNA clearance happens quite quickly.
Tian Zhang: Right.
Thomas Powles: So, if you haven't got visible disease, your tumor burden overall is quite low, and clearance occurs quite quickly. We haven't done the experiments in metastatic disease, I'd imagine if you've got lots of liver metastasis, and you have incredibly active therapy, I imagine it would take longer than six to 12 weeks to get clearance.
Tian Zhang: Yeah. Fantastic. Congratulations on your work.
Thomas Powles: Thank you. It's a big team. It's a big team. It's a big team.