Andrea Necchi: Thank you, Ashish, and thanks today for the invitation. I always appreciate joining your discussion. Yes, SURE-02 was an investigative initiative study. It was conducted entirely in San Raffaele in Milan as a single site. It's a single-arm phase two study that was built at the beginning as a classical perioperative study with the pre-surgical phase, the radical cystectomy approach, and the adjuvant period treatment. The combination therapy was the sacituzumab govitecan plus pembrolizumab. So the ADC targeting TROP-2 and immunotherapy approach and neoadjuvant relief for full cycles, surgery, and then the adjuvant with pembrolizumab for one year. As I said, initially the study conceived the possibility for the patient to go cystectomy, and the primary endpoint was initially the pathological complete response. But soon realized that the first 10 patients that the rate of refusal to overall cystectomy based on the fact that most frequently, based on the fact that the patient responded well to treatment with the clinical complete response was very high. Based on the initial protocol deviations, we changed and we amended the study. Implying the possibility for the patient to receive a reTURBT, so an endoscopic resection with a bladder-sparing option in case they refused post-neoadjuvant therapy cystectomy. So we shifted the primary endpoint for the classical pathological complete response to a newer approach named clinical complete response. The response that was assessed with reTURBT, no evidence of residual disease via reTURBT added to a negative imaging, negative cytology, negative cystoscopy.
Ashish Kamat: If I could just, for our audience, when you say negative imaging, explain that a little bit more.
Andrea Necchi: Yeah. It's a work in progress. As you know, and you are part of the endeavor that we are doing in order to find a shared definition of what is meant with the negative imaging. Let's say we use systematically and we use in this trial MRI to assess disease in the bladder. And we previously reported a bit different definition of VI-RADS, introducing the so-called VI-RADS at zero category. Which means actually that the radiologists that do not see any signal in the multiparametric approach, any signal of residual disease. Which is actually what is, to me, the most important point to make, besides the technicalities, besides the details, the residual disease that may be muscle invasive or non-muscle invasive or not. What is important for us as clinicians is if the disease is present or not. So black and white. It's a way of simplifying a little bit the way we assess response. VI-RADS zero means imaging complete response for us, and for clinical trials at least. The trial overall reported a clinical CR rate of about 40%, which is good. Of course, we are accumulating data from other therapies, EV + pembrolizumab most importantly. That stands at the forefront of the drug development. So everything is being reconsidered based on the data that we got with EV + pembrolizumab in the B15, KEYNOTE-905, and CHAARTED and so on. The development of non-EV + ADC combination has become complicated. But this study is still the first of its kind introducing ADC + IO combination in a bladder-sparing approach, kind of response adapted.
And the second point is that as compared to other classical response adaptive approach like medical study or retain studies. Here we do not provide bladder-sparing approach and necessarily to patients in clinical CR. The decision was fully driven by the patient. Of course, the majority of refusals fall into the category of clinical complete responders, but there were patients without a clinical complete response who refused cystectomy and received TURBT and maintenance immune therapy. It is interesting to see that overall in the category of patients who received reTURBT, not just those with clinical CR, but the reTURBT category which comprises 25 patients out of 49 overall, none of them have relapsed into the bladder or distal metastasis at the latest follow-up time. So follow-up duration is still short, but the study overall suggests that delay in cystectomy, at least when it comes to the use of newer therapies, in particular maintenance immune therapy approach, could be feasible without exposing patients to the extra risk of development of metastatic disease. The metastasis-free survival in the reTURBT population was 100%. It's a good preliminary data. Of course, next step will imply the possibility to make some fine-tuning in patient selection. And this is the reason why we, as we usually do in our academic research, in academic trials, we enrich the trials with a lot of biomarkers. And it's interesting to see. And we have presented in the post-session the updates on this trial with this regard, an interesting signal of enrichment in responses in luminal subtype tumors.
Classically endowed with an inferior response to immune therapy, the luminal subtype, the cold tumors, FGF receptor three alteration, and so drop to expression. And here, in this category, we found enrichment in 57 or 60% of clinical CR rate. Meaning that there is that could be a contribution of sacituzumab over pembrolizumab activity. It's interesting that from the biological standpoint, the combination therapy and the combination of a TROP-2 ADC and immunotherapy may also shape a little bit of the profile of the tumor who may be highly responding to this approach or completely responding to this approach.
Ashish Kamat: Yeah. I think it's very interesting. Because, again, in the real world, pragmatically speaking, not every patient is going to want to have a radical cystectomy, as we know from multiple decades of experience. And if you limit bladder preservation strictly in the clinic to those that have clinical complete response, ideally that's pure, that's what we would like to see. But you're going to see patients where they may not have had a VI-RADS at zero, may have had some tumor and you resect it. So data such as this is very, very important. Just briefly, can you compare numerically in short, what is the bladder-intact event-free survival in those that had a TUR and those with CCR? Do you have those numbers?
Andrea Necchi: Yes. We presented this number, and we also will be released soon in full manuscript. The overall one-year projection of event-free survival in the intention-to-treat populations overcome this is around the 70%. So not too bad as compared to other trials with the most effective combinations. Event-free survival rises up to 90% in complete responders. It goes down to 50% in those who are not complete responders. Bladder intact event-free survival, we put the design point and there's an exploratory endpoint, which was a post-doc assessment, which was not included formally in the protocol, because it is not actually a classical bladder-saving design. The data and the BI-EFS in our trial is around 40% in one year. That does not mean that the treatment is inferior to the rates reported by chemo radiation because we do include radical cystectomy as an option. It's a patient decision. In a trial, which starts basically as a surgical trial, patient had to accept the possibility to undergo radical cystectomy. So it's not a classical bladder-sparing trial like a chemo radiation trial. And we included a bit different definition of BI-EFS, which is to me the most reliable one. Classically, BI-EFS in chemo radiation trials includes all the muscle invasive relapse, distal metastasis development and death as events. Not intravesical relapses, non-muscle-invasive relapses as events. We did include superficial relapses as events. We counted them as events because they could expose the patient to a risk of doing radical cystectomy.
To me, it's important to provide an all-inclusive endpoint that captures also this kind of relapses that are the majority of the relapses that occur in this kind of adapted design. This is the reason why the numbers and the estimates cannot be fully compared with other trials. We don't have much literature of this kind to make comparison with regards to this particular endpoint. But I agree with you that clinical CR by itself is a good biomarker, is a good way of studying biomarkers, testing the tumor biology for certain biomarkers, or screening the activity of new drugs, but it's not actually a good way, a good biomarker to incorporate necessarily in clinical trials. What you mean, what you need is an event-free survival endpoint, and the clinical CR just as a surrogate, possible surrogate for survival, but flexibility is the key. So leaving the patient the decision after the induction and the induction course of any kind is the key for the success of accrual conclusion of the trial, and to adapt our intent to the patient desire, most frequently based on how they respond to the treatment. But not necessarily, because the state of mind may change, they position towards impactful operations like surgery, like cystectomy, may change not necessarily due to response, but may change also due to safety profile, may change for whatever reason. You have to be flexible enough to adapt your plans to their desire.
Ashish Kamat: Yeah, no, absolutely. Andrea, I think you summarized also, in addition to the trial that we're talking about, the whole concept of bladder sparing. That, again, thank you for all that you're doing and collaborating together, both of us. I think that's really important, this whole bladder-preservation strategy. Thank you very much.
Andrea Necchi: Thank you.