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Alicia Morgans: Hi, I'm thrilled to have with me here today Dr. Andrea Necchi, Medical Oncologist at the National Cancer Institute in Milan, Italy.

Thank you so much for being here to speak with me today.

Andrea Necchi: Pleasure.

Alicia Morgans: So, you have done some really exciting and provocative work in the neoadjuvant setting for muscle invasive bladder cancer, and I'd love to hear you summarize where you've been and where you think we're going with this part of the field.

Andrea Necchi: Yeah, we started two years ago investigating and challenging the neoadjuvant space in the patient with muscle invasive bladder cancer. First of all, there is an issue in the way we currently manage patients because I'm working together very closely with the urologist in the same department, and this, of course, is an advantage when developing ideas, when developing trials in these patients. 

And, the second point is the evolution which is ongoing in advanced disease with advent of immunotherapy, and the revolutionary wave of immunotherapy, of course, as a natural evolution will touch patients with early disease, not metastatic disease. 

So, it has been somehow easy to develop ideas in the neoadjuvant pre-operative space with the administration of neoadjuvant chemotherapy courses before radical surgery. There have been some other examples in solid tumor oncology in small cell lung cancer or melanoma or glioblastoma providing pretty much the same model that was borrowed in the PURE-01 study. Short courses of two courses, one to three courses of neoadjuvant immunotherapy just followed by surgery, inoperable disease. 

The exciting news is that we may achieve clinical immediate responses and, according to very early data, probably we may obtain some advantage also at long-term in terms of survival. But, of course, the follow-up of any of these trials is still too short.

The point here in bladder cancer is that we have theoretically and actually a recommendation suggesting the use the cisplatin-based chemotherapy in these patients. So, we challenge the existence of these guidelines by providing the inclusion of all-comers in our trials in the PURE-01 study which was a trial for all-comers regardless of cisplatin eligibility. 

Of course, this is an issue because many patients accrued in the PURE-01 study potentially may have had some guidelines and some possibility to receive the standard of care. But, the problem in Italy as well as worldwide is that the adherence to the standard of care is very poor. It is in between 15 to 25%. Is going up but it still suboptimal, and this is the reason why, from an ethical standpoint, from the practical standpoint, the vast majority of these patients actually move straight forward to radical surgery instead of receiving any systemic therapy pre-operatively.

Alicia Morgans: So, even the cisplatin-eligible patients would proceed directly to cystectomy, in general. Only 15 to 25-

Andrea Necchi: Yeah, the majority of these patients, yes.

Alicia Morgans: Okay, thank you.

Andrea Necchi: The second point that has to do with the patient perspective rather than physician perspective. Bladder cancer patient association, the newborn Italian bladder cancer patient association, was inspiring in that. Is that patients are asking for something new that may change the quality of life and may change the entire management of their disease since the beginning. So, they are usually very happy to receive something that is not chemotherapy in this context, despite their being informed very, very carefully, that there is a standard of care that provides survival advantage. But there are a lot of limitations potentially with the use of chemotherapy and, they are very happy to receive something new. And I would say that my experience of almost 100 patients treated so far in the last two years in this trial, that the overall feedback that I received from the patients is very, very high in terms of quality of life, in terms of the overall satisfaction of these patients regardless of the final success or the final response that they have achieved. But the impression is very good and this is, of course, a very good achievement for these patients.

Of course, one of the major point is to look at the future, more data coming with the combinations and of course, as I have outlined in my talk this morning, most have to do with the selection of patients because we started with all-comers but probably, of course, the natural evolution will be to focus on the special patients, molecularly-selected patients. So, the issue here is how can we select wisely patients that are more likely to respond to immunotherapy as well as to any other therapy that has been proposed this way.

In our study we put a lot of information, a lot of research and investment in trying to understand more on the biology and the underline biology of their disease together with foundation medicine scientist, we sequenced all patients before and after treatment within the trial, and we are setting up collaboration with the academic groups worldwide like in Chicago, like Dana Farber, like in Amsterdam, or in Moffitt in Tampa. In order to be able to better delineate the phenotype and the genomics underlying responses to pembrolizumab. 

What we know so far is that patients with a higher TMB, tumor mutational burden, and a high PD-L1 expression are very likely to respond completely to pembrolizumab, to only three cycles of pembrolizumab. These patients, as a next step, may be the ideal candidate to strategies that are basically aimed to spare their bladder without any radical local therapy. I mean, any surgery or any radiation onto their bladder. This may be a major achievement. The next major achievement that is asked by the patients. The possibility to provide a maintenance systemic therapy only instead of any surgical or radiation therapy approach in their primary tumor may be a good achievement. 

This strategy is being pursued, for example, by Makowski in the United States with an evolving immunotherapy trial which is aimed to achieve the strategy in patients who are harboring the gene alteration in the QR specimen, and we are targeting the same strategy in the immunotherapy context alone with single adjuvant immunotherapy in patients who have very high TMB and very high PD-L1 status.

Alicia Morgans: Absolutely. Well, can you walk us back just a touch and remind everyone what the results were. So, in PURE-01, you had patients that could have been, as you mentioned, all-comers. It was a neoadjuvant setting, ultimately planned for cystectomy. So, you could get an understanding from most of these patients what the path CR rate would be, and patients received pembrolizumab. So, what did you see in all-comers? What did you see in the sub-groups? How tolerable was it?

Andrea Necchi: In the PURE-01 study ... and the first data readout was published in JCO a few months ago ... the rate of pathological complete responses in the first 50 patients treated is 42%. Probably, may be inflated by the fact that the numbers are still small. There is inherent bias related to the small numbers, of course, but the first data, of course, promising.

And the second point is there is the clear signal towards an enrichment in pathologic complete responses in PD-L1 positive patients. You may achieve as many as, more than 55% of pathologic complete responses in PD-L1–positive patients. Interestingly, the same trend has been observed in another, very similar, study conducted in Europe; another academic study led by Tom Powles the ABACUS study, with atezolizumab, whereby 29% of pathologic complete responses have been obtained in all-comers and then these responses rise up to 40% in the population of PD-L1–positive patients.

We have no data, or at least, we have very limited data in terms of progression for survival over survival. We presented at this meeting the very early data readout in comparing the event-free survival, the early event-free survival achieved with pembrolizumab with a retrospective course of chemotherapy-treated or radical cystectomy only patients, and we observed very impressive signals that were relative to the overall population with a suggested improvement in the event-free survival in pembrolizumab treated patients, first.

And the second point is that the same advantage in terms of event-free survival is being observed also in patients who are apparently non-responding to pembrolizumab. Meaning, patients who have a very high risk disease radical cystectomy pT3, pT4 or pM-plus. They may still achieve some survival benefit in long-term. 

This issue may challenge everything that we are discussing today and we have discussed today at the meeting, that is speculating around the issue of pathologic complete response and the notion that pathologic complete response may be associated with survival improvement in the immunotherapy context. It may be not so in the next few months when we will have the mature data from the first trials. This may be an additional potentially practice impacting finding because the possibility to change the survival in these patients only with short courses of pre-operative immunotherapy may be quite intriguing.

Alicia Morgans: I would definitely say so. So, if you had to choose, though, which patients would be those that you would focus on for potentially a completely bladder-sparing approach ... so, no surgery, no radiation ... assuming that we could feel confident in the clinical complete response that would be driving that decision, who would those patients be?

Andrea Necchi: In our trial, we are developing first a pre-therapy tool, nomogram, that incorporates a biomarker, TMB, and PD-L1 expression, together with clinical stage in order to predict the pathologic response. And then, at the end of the treatment, before potential surgery or any other treatment strategy, we are implementing the development of new radiological tools to assess, or to corroborate, or to anticipate the need for re-TUR in these patients. And we are pushing forward our research towards the use of multiparametric MRI of the bladder which is a completely new field where we have very limited data so far. But, the model that we are developing may allow us to predict the pathologic complete response in a substantial proportion of patient.

Of course, data may still warrant validation and, of course, an extended validation of all the data is ongoing, but the possibility to have a non-invasive reassessment of the response also potentially sparing their re-TUR in these patients may be another achievement within clinical research.

Alicia Morgans: I completely agree, and I so appreciate you sharing your perspectives and expertise on this. You are really, as you said, challenging the way that we're thinking to move the ball forward in a way that I don't know many of us realized we were ready for.

Andrea Necchi: Yeah.

Alicia Morgans: So, I really appreciate that.

Andrea Necchi: I totally agree with the issue of the limitation of ... the fact that we are not ready to develop the large scale at least, these models. Francesco Montorsi usually says that we are losing the train of clinical research in terms of how we are organized in our department because today is time to change the way we manage since the beginning bladder cancer patients and there is ... It's clearly the time to work together, possibly in the same department, multi-disciplinary department. Medical oncologist, as I am, urologist, radiation oncologist in order to share the strategy within the same department and to develop clinical research together with pharma company or other form of support in the same environment together with the patients.

Alicia Morgans: That multi-disciplinary collaborative approach is, I think, the way that we're going to crack this larger problem, and I appreciate your time and sharing your insights and the progress that we've already made and where we need to go. So, thank you so much.

Andrea Necchi: It was a pleasure. Thank you too.