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Petros Grivas: Hello. I'm Petros Grivas. I'm a Medical Oncologist at Seattle Cancer Care Alliance. And I'm an Associate Professor at the University of Washington/Fred Hutchinson. I'm very excited today to host Dr. Dimitrios Makrakis, one of our mentees at the University of Washington. Dr. Makrakis finished his medical school in Greece and came to Seattle to work with us in research in urothelial cancer, working on database work, retrospective data, and statistical design. So we are very excited to have you.  Thank you, Demetrius, for joining me today.

Dimitrios Makrakis: Well, thank you for having me. It's a great opportunity.

Petros Grivas: So Dimitrios, you are presenting a poster here at ASCO GU 2022, which I think is very interesting. And you are actually looking specifically at the potential association between the time of prior therapy, associated with the response and outcomes with a checkpoint inhibitor in patients receiving checkpoint inhibitor, a single agent in metastatic urothelial cancer. Can you tell us a little bit more about the design of the study, the rationale, the hypothesis, and the findings?

Dimitrios Makrakis: Yes, of course. So we decided to look at patients that have received first-line platinum-based chemotherapy and subsequently second-line immune checkpoint inhibitors. We wanted to see if the time from the initiation of platinum-based chemotherapy to the initiation of second-line checkpoint inhibitors can be associated with response to immunotherapy. We used this time in the trial as a surrogate for platinum resistance, because it is known that sensitivity to platinum is associated with also sensitivity to checkpoint inhibitors. To study this association, we identified 268 patients, and we did two analyses. And the primary analysis we divided, we did [inaudible] the exposure into progression to second-line within six months and after six months. And in our secondary analysis, we broke this down to change to second-line immunotherapy within three months, between three months to six months, and after six months from the initiation of first-line platinum-based chemotherapy.  What we found was that the time point of six months did not give us any results.

So there was no significant difference in either survival, so progression-free survival or overall survival between patients within six months or after six months. And also there was no difference in response rates between the two groups. However, in the three group analyses, the patients that had changed to therapy within three months actually did worse. They had a significantly worse overall survival and a significantly worse progression-free survival as well. And of note, these were OS, median OS or five months, and a PFS of only three months. So these patients, live significantly less than the rest of the patients. And we think this is a very interesting finding because it potentially identifies a subgroup of patients that do not do well on platinum, do not do well on immune checkpoint inhibitors, and live significantly less than the others.

Petros Grivas: Thank you, Dimitrios. That's a great summary. And if I can comment on this, we are always struggling in the clinic, right? How we treat patients where these platinum-resistant patients, right, have a primary progression on platinum-based chemotherapy. And these patients do, as you said, poorly across different subsequent lines of therapy. So progression early on, on platinum-based chemo, these primary refractory patients have a negative prognostic value, as an estimation. And the question is how do we treat those patients?

So I think it's important to keep the data you are presenting in mind because single-agent checkpoint inhibition does not appear to reverse that resistance. And maybe there is potentially some overlap in the resistance between platinum-based chemo and checkpoint inhibition. So we need probably other agents, right? Maybe combination trials. And we are having some data here at ASCU GU with the combination of sacituzumab govitecan and pembrolizumab that we are going to present in this population of patients. And of course, we have other antibody-drug conjugates, enfortumab vedotin, and we have erdafitinib, an FGFR inhibitor.  Any comments about, how do you think, for example, the [inaudible] metastasis might impact response to checkpoint inhibition, I know you are working on a different study looking at that as well.

Dimitrios Makrakis: Yes, we are looking into this as well. There is a lot of data indicating that patients with metastatic heavy disease, do not respond well to checkpoint inhibitors as well. We still don't know why this happens, but it's definitely an interesting marker. If you have a patient that has heavy metastatic disease, for example, liver metastasis is well known to be associated with worse outcomes in checkpoint inhibitors, then you have some indicators that the patient may not do well on checkpoint inhibitors.

And with new agents coming up, what you say is really great. For now, we still have a fixed sequence in our agents, most of the time we start with platinum, we move to checkpoint inhibitors, then we move to the newer agents, enfortumab, sacituzumab, but who knows in the future, we may change this sequence. And we may be able to use this early data with every patient and decide which drug we are going to move on to next. For example, if you have a patient with a lot of negative prognostic factors for checkpoint inhibitors, you may skip that and go to the next available agent. And this is probably the direction we are heading towards right now.

Petros Grivas: And that's an important point because it is very hard to make a distinction between a prognostic factor, which means, it can impact outcome regardless of therapies versus a predictive biomarker, which can, in theory, predict benefit to individual therapy. And we're doing okay with prognostic factors, but not that well with predictive biomarkers and your study is retrospective. So it looks more like a prognostic factor, but we have to do a better job as a scientific community with predictive biomarkers to help select the right treatment for the right patient. And to your point, and we are looking into that, is the site of the liver metastasis or bone metastasis or the location of the metastasis. Does this impact the treatment selection for second-line therapy for metastatic urothelial cancer, especially for those referred to platinum, should we go to an antibody-drug conjugate or target therapy or checkpoint inhibition in the absence of randomized trials?

So I think it's important data to keep in mind. I think indirectly, it can help the discussions about decision-making in the clinic and also help us interpret the results of clinical trials and help us in the design of trials with eligibility certification in different criteria. So very interesting work. And maybe the last question for you, in the last couple of minutes, as you see overall, these are the basics you have formed, how do you envision, the collaboration happening in already 26 centers, right, in that study, how do you see the future of this database that you have built going forward?

Dimitrios Makrakis: So this is an amazing collaboration. We have 25 or so centers from across the US, but also from Europe and lots of wonderful colleagues contributing to this database, we would like to expand to include genetics. And we always look to add more patients. We also look to start collecting real-world data on [inaudible] maintenance, which is another important part of bladder cancer care these days. So I'm looking forward to expanding, including more information on genetics, and avelumab, and conducting more studies in the future.

Petros Grivas: That sounds great. And just for the audience, to recap this is a multi-institutional retrospective database with 26 centers so far and we are collecting data on patients who received checkpoint inhibitors for metastatic urothelial cancer, that was the database data pool to help with the poster you are presenting here. And the future directions of this database are to look at different questions, prognostic biomarker questions, switch maintenance avelumab real-world data, and whether genomic biomarkers may have an association with different treatment responses. So all these important questions will hopefully be answered in this huge multi-institutional effort. So thanks for the great work you're doing and for working with our team, and thanks for joining us here today.

Dimitrios Makrakis: Thank you too. It was a great conversation.