The IMvigor011 study is, in fact, a consequence of the IMvigor010. IMvigor010 was one of the trials that were conducted maybe four or five years ago about the use of adjuvant immunotherapy after surgery in patients being at high risk of recurrence. There have been three trials exploring the role of giving adjuvant immunotherapy, meaning after surgery, in this setting. We have the AMBASSADOR trial that is using pembrolizumab, this trial was positive for disease free survival; we have the nivolumab trial that was proven, it’s being used in the States and in Europe after surgery. Then the third trial was the atezolizumab trial and this atezolizumab trial, the IMvigor010, was randomising patients to receive atezolizumab or follow-up, it was not placebo. This was the only trial, I was the PI of that study, this was published in Lancet Oncology, this was the only trial that was negative.

As we all learn from negative things, we went back to these patients receiving atezolizumab and we had ctDNA, circulating tumour DNA, from these patients. When retrospectively analysing patients that the ctDNA was positive receiving atezolizumab, we saw that patients having ctDNA positive receiving atezolizumab derived benefit in terms of disease free survival and overall survival. This was a retrospective analysis but in fact this retrospective analysis of IMvigor010 was finally published in Nature. Then, obviously, the next step was we need to design a prospective trial and then the IMvigor011 is a consequence of that and is a prospective trial where the role of ctDNA is being explored in this setting of high-risk muscle-invasive bladder cancer patients and testing the role of atezolizumab in these patients having ctDNA positivity. So that’s how the IMvigor011 trial started.

What was the study design?

The study design for IMvigor011 is the eligibility criteria – patients at high risk of recurrence after radical cystectomy having muscle-invasive disease. Patients could have received even neoadjuvant chemotherapy but then the pathology is showing that there was still active disease,  those patients of high risk were screened for ctDNA.

So we started screening around 800 patients and then we selected the patients that tested positive for ctDNA. These ended up being around 250 patients and these 250 patients that in the follow-up didn’t recur, the imaging was negative, so those were the patients with no disease recurrence after surgery having only ctDNA positive. These patients having ctDNA positive were randomised to receive atezolizumab or placebo. So all these patients that were registered in the trial after surgery, we were allowed to monitor these patients during a year, meaning some patients the ctDNA came back positive immediately after surgery but for other patients we were following all these patients with ctDNA every six weeks meaning that if they developed positivity in ctDNA even after two, three, four months, it was up to six months, these patients were also allowed to be randomised and included in the trial.

So we have two cohorts of patients: patients that immediately after surgery you see that there is no evidence of disease, imaging is negative but they are testing positive for ctDNA, and these patients that in the follow-up they became positive. So the main endpoint of this trial, the comparison of atezolizumab versus placebo, was disease free survival investigator initiated. This was the main endpoint and the secondary endpoint was overall survival; the overall survival was analysed if the disease free survival endpoint was met.

In fact, the disease free survival endpoint was met, so there was a hazard ratio of 0.65, meaning the median disease free survival was 5 months in the placebo arm versus 10 months in the treatment arm, and this was statistically significant. Then when analysing, because the main endpoint was positive, analysing survival we saw that there was also a survival benefit in patients being ctDNA positive receiving atezolizumab, so with a hazard ratio of 0.58, or close to 0.60.

So based on that, obviously, we can conclude for the first time that in patients with ctDNA positive atezolizumab derives benefit on disease free survival and overall survival. So that’s one part of the trial.

But obviously the other cohort of patients that were negative, sequentially negative, because, as mentioned, it was allowed just to monitor these patients for at least one year. So we have data on what has happened in these patients that have sequentially tested negative for a period of up to one year. What we can see is that these patients that obviously were not randomised in the trial, we have seen that these patients that are negative after a period of 12 months, only 12% of patients are recurring. Meaning if you have surgery, being high risk, and the ctDNA is being monitored, if you are negative the likelihood of recurring is very low, meaning that you can potentially, and this is one of the messages that we can take from this trial, maybe you can spare some patients of receiving adjuvant immunotherapy, the side effects and obviously the cost of this treatment.

Also, we analysed the side effects because this was treatment versus placebo. We didn’t see any out of expected side effects. We expect to see some immune-related side effects but there were no toxic deaths, for example, during this trial.

Is there anything else you would like to add?

The main thing is benefit in disease free survival and overall survival. The benefit is seen in patients testing immediately positive and in patients having delayed testing of positivity for ctDNA. Then the message: you can spare, potentially, adjuvant treatment in patients that are sequentially, not at a single timepoint; in these patients that after a year the ctDNA is negative then you can spare giving them adjuvant immunotherapy.

One thing that we have also learned, it doesn’t mean that you can stop monitoring the ctDNA after one year because still we have other patients out of the trial and still there is a risk of recurrence after one year. But the trial was designed just to monitor these patients for one year.

The results of these trials have concomitant with being published in The New England Journal, and now there are additional analyses for more granularity, for example. So the ctDNA test that was used is the Natera Signatera test and it’s important because the ctDNA stands for circulating tumour DNA. There are different ways to measure the circulating tumour DNA; this is the concept of liquid biopsy. In this trial we used the Natera Signatera, the Natera Signatera is built in the beginning like sequencing the tumour and sequencing the germline and then you select 16 genes that are tumour specific. This is doing next generation sequencing, but then for the follow-up you create a qPCR platform where you are testing if any of these 16 genes are showing up in the blood. Then it’s negative or positive based on that.

So this test that is pretty well established and is now being used widely in the States, this test also could have some granularity because you can report the NPM, that is the amount of risk that you see, and now there are studies done to say maybe if the risks are higher maybe these patients are going to do worse. Then also the pathways of recurrence are being analysed in these patients and the pathologic features at the time of surgery are being correlated with the kinetics of the ctDNA, meaning that this is going to provide a lot of information about how to monitor in blood the minimal residual disease using this platform.

How this can impact on other trials because at the time this trial was designed it was 2022 but since then we have had some changes in the treatment landscape of bladder cancer in the perioperative space. We got the positivity for the NIAGARA trial, the NIAGARA trial is also in this perioperative space where patients are receiving chemoimmunotherapy followed by immunotherapy with durvalumab. We have heard in this meeting the results of the KEYNOTE-905 in patients who are ineligible for platinum-based therapy. These patients have received enfortumab vedotin that is being used in the metastatic setting in the perioperative space before the surgery and then after surgery in the adjuvant. We have seen for the first time a survival benefit in these patients receiving EV+pembrolizumab perioperatively.

 So the question is how are we going to handle these patients after surgery if they, for example, become with a pathologic complete response? Do you need to give adjuvant treatment to all our patients that are receiving chemoimmunotherapy or enfortumab vedotin pembrolizumab? We don’t know. But it might happen.

So, one of the things that was discussed yesterday in this publication of the KEYNOTE is that having this highly active regimen, the EV-pembrolizumab, given in the perioperative space, with a rate of pathologic complete responses of up to 60% maybe bladder preservation might come subsequently and then maybe the ctDNA is going to be used to select which patients. So now all this data is creating a lot of expectation and we need to design trials to address all these questions.