Petros Grivas: Hello. I’m Dr. Petros Grivas. I’m a medical oncologist at Seattle Cancer Care Alliance and Associate Professor of Medicine at the University of Washington and Associate Member of the Fred Hutchinson Cancer Research Center. I’m really thrilled and honored today to host Dr. Guru Sonpavde, who’s the director of the Bladder Cancer Program at Dana Farber Cancer Institute at Harvard. Dr. Sonpavde, welcome.

Guru Sonpavde: Thank you.

Petros Grivas: It’s great to have you here, and there’s so much going on in the field of bladder cancer. You have done so much work yourself. So, to start us off, I would like to pick your brain about the ongoing efforts in the new adjuvant space to create more treatments. We all know that cisplatin-based combination chemotherapy is the standard of care, but many patients may not be able to receive cisplatin because they’re not fit enough. And some others may not respond. So, in that effort, could you comment a little bit on your own trial in progress that you have an abstract here, regarding a randomization design in the neoadjuvant setting?

Guru Sonpavde: Thank you, Petros. So, as you rightly said, about half the patients are not eligible for cisplatin-based neoadjuvant chemotherapy because of renal dysfunction or poor performance status or comorbidities. So in patients who are cisplatin eligible, we have historically given them cisplatin-based combinations. As you know, the level one evidence is with MVAC chemotherapy, but we have used gemcitabine cisplatin or GC in the community a lot. So going forward we want to improve upon that in the cisplatin-based treatment population. So what’s going on is, obviously with the emergence of PD-1 PD-L1 inhibitors, it makes sense to combine the immunotherapy agents or PD-1 PD-L1 inhibitors with the cisplatin-based chemotherapy.

So that’s what’s going on in that space. In the trial that we are presenting as a trial in progress poster is the one that’s a phase three trial that’s going to look at gemcitabine cisplatin, GC standard arm. There are three arms.

The second arm is GC nivolumab. The third arm is still somewhat up in the air because there is a lead-in phase to establish the safety of combining an IDO1 inhibitor in addition to GC plus nivolumab. So it’s a quadruplet: two immunotherapy agents and the standard GC chemotherapy. So, assuming that the lead-in phase establishes the safety of that combination of the double IDO and double chemo, there will be a three-arm trial. If the safety is not established, it might end up being a two-arm trial. So, we’ll wait and see.

Petros Grivas: That’s very interesting. And this trial is, from what I hear, is already being launched?

Guru Sonpavde: Yes.

Petros Grivas: And the third arm is going to depend on the feasibility and safety of the IDO1 contribution–

Guru Sonpavde: Right.

Petros Grivas: … in the backbone of chemotherapy and anti-PD1.

Guru Sonpavde: Right.

Petros Grivas: Very exciting study and that will also give a lot of answers regarding the combination strategy in the neoadjuvant setting, chemoimmunotherapy combination.

Guru Sonpavde: Right.

Petros Grivas: And also will give a plethora of tissue and blood for correlative studies.

Guru Sonpavde: That’s right. Exactly right. So there will be a lot of opportunities for correlative studies. Of course, in this study, both the experimental arms are being compared with the standard arm. And the two experimental arms are not formally being compared with each other. But there will be some analysis to look at that also.

Petros Grivas: That’s exciting. And I think in the context of many other clinical trials in that new adjuvant setting, we’re going to have huge data sets that we can try to align biomarker discovery and validation. For example, we’re working on a clinical trial with nivolumab by itself, monotherapy, or in combination with lirilumab, which activating natural killer cells, NK cells, which opened in a few sites in the U.S. and also in the neoadjuvant setting. So we have an opportunity to evaluate biomarkers and, of course, other clinical trials with other checkpoint inhibitors.

There’s also a trial with nivolumab, and I think a nectar compounds in cisplatin unfit patients. And also trials with other checkpoint inhibition molecules. So I think it will be amazing to see these trials coming along in the next few years.

Guru Sonpavde: That’s right. As you rightly said in the cisplatin-ineligible population, in the neoadjuvant space, the trend has been to look at immunotherapy alone or the combination of immunotherapy. So basically chemotherapy-free approach. But that still needs to be teased out and whether there should still be some role for chemotherapy in that space. Probably does need to be teased out at some point.

Petros Grivas: It’s a great question. And there’s a huge debate in the field whether in patients who are not eligible for cisplatin, should immunotherapy alone do the job, or should it be any combination?

And this question is still open up in the air. Because without the context of clinical trials, we do not use carboplatin in the neoadjuvant setting. It’s either cisplatin or clinical trial or straight to cystectomy or chemoradiation as bladder preservation approach.

Guru Sonpavde: Right. So as you know, the POUT trial was a phase three trial that looked at adjuvant gemcitabine platinum chemotherapy in the upper tract urothelial carcinoma space. And that trial was positive. It was stopped early because of the disease free survival benefit. That trial did allow gemcitabine carboplatin. About a third of patients received carboplatin gemcitabine. And if you look at the sub-analysis, the gem-carboplatin, the benefit was up in the air a little bit because the hazard ratios were reasonable. 0.63 range. But the confidence interval is crossed one. So you can argue either way. Some people would say there is some benefit, but not as much as cisplatin. Others would say it’s not worthwhile doing carboplatin.

Petros Grivas: And it’s interesting because we have this debate all the time, and in these situations, we tried to put patients in clinical trials to answer the questions more definitively, as you said. POUT trial has been a very important phase three trial in the upper tract, urothelial cancers, adjuvant space. And also there are many trials with checkpoint inhibitors for patients who had cystectomy or nephrectomy. A trial with pembrolizumab called AMBASSADOR. By Dr. Apolo and colleagues, atezolizumab and nivolumab. All three of them have adjuvant trials.

Guru Sonpavde: That’s right. So we will have to wait and see what the results of those trials are. So those trials are of course allowing new adjuvant chemotherapy in patients who have muscle-invasive disease post neoadjuvant chemo. But they also allow patients who are cisplatin-ineligible that went straight to cystectomy and have extravascular or lymph node positive disease.

So those trials will give us hopefully some data confirming the benefit of these drugs, hopefully. So we’ll wait and see.

Petros Grivas: I fully agree with you. It’s a very exciting landscape and continuously evolving. Moving into the metastatic disease setting, you have done significant work there as well. So I would like to pick your brain regarding patients who are cisplatin-ineligible, unfit for cisplatin, and they’re chemotherapy-naive for advanced disease. In this particular situation, we have now options like chemotherapy, carboplatin, gemcitabine. We have checkpoint inhibitors, atezolizumab or pembrolizumab, but for the subset of patients who are pretty low and high, or if they’re chemotherapy unfit, even for carboplatin. So, of course, we always want to do clinical trials in this setting. But in the absence of a clinical trial, some patients may get chemo or immunotherapy. Can you comment on the other abstracts that you’re working with your group and your colleagues in Dana Farber Cancer Institute? It’s a collaboration across different institutions with Dr. Way and others regarding the optimal sequence of chemotherapy and immunotherapy in that setting.

Guru Sonpavde: Good question. So we looked at this to look at the sequencing issue of carboplatin-based chemotherapy and a PD-1 PD-L1 inhibitor. So carbo followed by PD-1 PDL-1 or PDL-1 followed by carbo. And the reason we picked Cisplatin ineligible patients was that this sequence would be difficult to compare in the cisplatin eligible population because that population does not get a PD-1 alone first line. So that’s why we had to pick a cisplatin-ineligible population so that both those sequences would be done in some patients, and we could compare the outcomes. And this was done in an era before we used to do PD-L1 testing routinely because now the change in the label and the fact that the PD-1 PD-L1 inhibitors are inferior to carboplatin-based chemotherapy in PD-L1 low patients. That data came out sometime in the middle of last year.

So this study had collected the data somewhat before that time point, so we did not collect PD-L1 status. Obviously, it would be interesting to look at the differential survivals based on the PD-L1 status. But basically what we found is, in unselected patients, both sequences lead to similar survival. There were some differences. There was a longer gap between end of first-line and start of second-line in patients who start with carboplatin. Whereas with PD-1 inhibitors, there was less of an interval between the last PD-1 inhibitor dose and the carboplatin-based chemotherapy.

That might be more a practice pattern because chemo you do about six cycles and stop. Whereas with PD-1 inhibitors, you tend to keep going. So that might be just an artifact of that. But overall it was reassuring to see that in unselected patients, both sequences might be reasonable. There did not seem like there was one clearly superior.

Petros Grivas: I think it’s very interesting data and to one of the very unique data sets in this particular subset, or setting of patients. And of course, clinical trials will answer the questions more definitively. But give us some insight that patients who end up getting both therapies, the sequence might not have huge differences in the overall survival endpoint.

Guru Sonpavde: Yes, it’s possible. Again with the caveat that we now know that in PD-L1 low patients, you should not be starting with a PD-1 PD-L1 inhibitor. So we kind of know that from the ongoing phase three trials which are still not reported. So one of the ways to think about it is, in PD-L1 high probably you had to start with carboplatin-based chemotherapy. So this is reassuring. But in the PD-L1 low patients, it’s up in the air.

So, I mean, PD-L1 high patients are up in the air. We don’t quite know what would be better upfront PD-1 or the carboplatin-based chemotherapy. There might be a certain cutoff of PD-L1 expression where the PD-1 inhibitor is better than carboplatin to start as first-line therapy and a different cutoff where carboplatin-based chemotherapy might be better. So we need to tease this out.

Petros Grivas: I agree with you. I think we are learning continuously, and the PD-L1 expression label change came afterward in the context of this cohort. So it’s hard to tease out this particular detail. Talking about this significant clinical need, there are multiple clinical trials that are trying to answer the question. The Phase III trials like the KEYNOTE-361, IMvigor130, the DANUBE trial, CheckMate901. There’s [inaudible 00:11:11] maintenance trials, one with pembroluzimab, the other with avelumab, and of course some smaller trials.

And you are involved with the clinical trial with a vaccine in combination with atezolizumab, this CV301 vaccine. What’s your opinion about the vaccine strategy in combination with tech one inhibition, and how do you view that strategy in urothelial cancer?

Guru Sonpavde: I think it’s an interesting strategy, with the theory being that the vaccine makes the tumor more immunogenic. And it’s somewhat antigen targeted therapy, more specific immunotherapy and the CV301 vaccine that you mentioned is a pox virus-based vaccine which targets a couple of different antigens. CEA-MUC-1. It’s also an off the shelf vaccine, so it’s not a customized vaccine, which a customized vaccine has pros and cons. The pro being it’s customized, and the con being it takes a very long time to manufacture. While the CV301 is an off the shelf product.

So, it’s an interesting strategy. We are looking at that in patients who are PD-1 inhibitor naive in the post platinum space as second line, but also in the first line space in cisplatin-ineligible patients. And that is regardless of PD-L1 status. So both PD-L1 low and high patients are being enrolled with the theory that even PD-L1 low patients might benefit. Because the vaccine is on board to make these tumors more immunogenic and potentially more responsive to the atezolizumab.

Petros Grivas: I think it’s an interesting strategy, and as you said when you have the combination regimen PD-L1 inhibitor plus a vaccine, that relative value of a PD-L1 expression is unknown. And I think that’s why the regulatory agency may allow these combination trials regardless of PD-L1 expression because we don’t know what is the value of that particular biomarker in the context of the combination regimen.

Talking about you know, different biomarkers of course, and we have, you know in this ASCO multiple interesting data sets. And the biomarkers can be cumin intestinal burden, can be PD-L1 can be gene expression profiling, can be delineated mutations. And all of these biomarkers need to be prospectively validated in the clinical trials, which is I think a very important point that has to be made in clinical trials in urothelial cancer. How can we align this bio market development across studies, which is a very hard thing to do?

Having said that, another significant aspect of it, especially talking about mutations, is the issue of not only somatic mutations but also germline mutations. And germline mutations are important. We know from the field of prostate cancer, breast, ovarian, and other cancers that are important for the patient, but also for the broader family because germline mutations have inheritable component and might inform cascade testing and screening prevention for other family members.

You have done work in the field of germline mutations in urothelial cancer. You have the poster at ASCO. Can you talk a little bit about that?

Guru Sonpavde: Yeah, so basically what we looked at is patients in the Invitae data set. Invitae is a company that does germline testing. They have a panel which is analytically validated for bonafide germline pathogenic or likely pathogenic germline mutations. So we looked at the data set, and we looked at patients who had bladder cancer. Now they could have had bladder cancer plus minus other cancers. So it turned out we had around a thousand patients, 1038 that were evaluable. And about a third of them had only bladder cancer. Two-thirds of them had bladder cancer plus at least one other cancer.

Petros Grivas: Okay.

Guru Sonpavde: And regarding family history, not everyone had a family history. Many of them, the majority did have, but some of them did not have a family history. So it was somewhat… It’s not an unselected population, because these patients underwent genetic germline testing. Because there was some suspicion that there might be a germline variant involved, because the patient was either young or had one more cancer in addition to bladder cancer or had a family history.

So anyway, with that caveat, what we found is that in, it’s a big data set, 1038 patients, around 29% of patients had some germline variant. But when you look-

Petros Grivas: Wow. That’s a big number.

Guru Sonpavde: That’s a big number. However, we are not sure about the relevance specifically with a link with the relation to bladder cancer. What we know is out of those, 18% seems pathogenic or likely pathogenic. Then what we did was, we really had confidence mostly in the DNA damage repair genes because the problem was not everybody underwent testing for that same panel. There were different panels. With time the panel evolved. So then we zoned down on DNA damage repair variance because that was somewhat the common theme among all the panels testing. 

Petros Grivas: Sure.

Guru Sonpavde: So we looked at the panel of the DNA damage repair genes. So when you look at that, around 11% of patients had a pathogenic or likely pathogenic DNA damage repair gene.

Petros Grivas: Wow.

Guru Sonpavde: Again, remember this is not unselected, patients. This is patients selected for some other suspicion. So next, our goal really is to look at in the unselected patients without a family history or particularly young, is there any increased prevalence of germline alterations in this disease?

Petros Grivas: Interesting. So I think the prevalence and incidence of germline mutations overall urothelial cancer seems to be much higher than expected or much higher than we knew. And it sounds from what you’re telling me, that the majority of those mutations may be in the DNA damage responses family. Of course, not only there, maybe other mutations too.

Guru Sonpavde: That’s correct.

Petros Grivas: And the question is whether there can be a way, a tool, to screen families for urothelial cancer down the road, but also can we potentially target them therapeutically. I mean, in patients who have already urothelial cancer, targeting those DNA repair gene mutations, if they’re functionally relevant, if they have the functional impact, in the protein, right?

Guru Sonpavde: That’s true. And the issue of bladder cancer is a little more complicated than just looking at germline variants that lead to bladder cancer. There can be germline variants that lead to a disruption of the metabolism of toxins. And so that can also lead to bladder cancer by just increased accumulation of toxins. So there’s other ways that these germline variants may need to be looked at. There could be some other unknown germline variant. So there’s really a lot of work that needs to be done.

Are these variants increasing the progression of non-muscle invasive disease to invasive disease? This is somewhat like what we see in prostate cancer where metastatic prostate cancer, there is an enrichment of these germline DNA damage repair alterations in these patients. And these genes seem to promote the progression to metastatic disease. So do we have a similar phenomenon occurring in bladder? So I think this needs to be teased out.

Petros Grivas: I agree with you, and there is a huge opportunity to generate more knowledge. With that, I would like to thank you for your time for being here and sharing your knowledge with us. I look forward to talking with you again in the near future. Thank you for coming.

Guru Sonpavde: Thank you.

Petros Grivas: And thank you for the audience for staying with us today.