Sam Chang: Hi, I'm Sam Chang. I'm a urologic surgeon at Vanderbilt in Nashville, Tennessee, and we are quite fortunate to have Dr. Matt Galsky. Matt's a Professor of Oncology at the Icahn School of Medicine at Mount Sinai and obviously one of the world's experts in dealing with advanced urothelial carcinoma. And so we've asked Matt actually to talk about an abstract that was presented at GU ASCO 2023, looking at the long-term results of IMvigor130. So Matt, tell us the key findings.

Matt Galsky: So IMvigor130 randomized phase III study, really trying to address what was the most relevant question in first line metastatic urothelial cancer at the time, which is should we give platinum-based chemotherapy like we've been giving for decades? Should we give single agent immune checkpoint blockade with atezolizumab? Or should we give the combination? And so this trial uses a somewhat complicated hierarchical statistical analysis plan. So the first analysis was progression-free survival between chemo plus atezo versus chemo. And that actually met its primary endpoint. There was a significant improvement in progression-free survival with the combination. Now the effect size is rather modest, but it did reach that endpoint and so that allowed then overall survival to be tested. Overall survival for that comparison has now been tested in several interim analyses and now the final analysis. And so the final analysis shows a hazard ratio of 0.85 favoring chemo plus atezo versus chemo, but with an upper bound of the confidence interval at one.

Sam Chang: Crossing, oh, at one. Okay.

Matt Galsky: But because of the hierarchical analysis plan, the pre-specified threshold for significance in terms of the P-value is much more stringent than 0.05.

Sam Chang: Okay.

Matt Galsky: So it just barely misses the pre-specified threshold. So I think this can be interpreted in several ways, but ultimately the trial did not meet its endpoint by the strict definition of the analysis plan.

Sam Chang: But looking at the hazards ratio and it hitting right at one, there seemed to be, in terms of overall survival, at least a slight benefit to the combination of atezo plus chemotherapy. In terms of, so as people try to take that all in, because we obviously very statistically stringent criteria, as you said, clearly we're integrating IO with chemotherapy. What about the side effect profile? Was there a significant difference? Were there a lot more immune toxicities associated with it or in the end not much difference?

Matt Galsky: So there wasn't much difference. It was basically what you would expect by adding those two drugs, two classes of drugs, there were not synergistic toxicities. Certainly there's more toxicities when you combine two different classes but not magnified by the combination.

Sam Chang: So Matt, I always like to put people in the hot seat here. So where do we go with this? Where are the medical oncologists going to go with this in terms of, okay, we seem to see a bit of a benefit, what do you think is going to happen?

Matt Galsky: So I think this is where we need to balance over interpreting subsets in taking a deep dive into the data versus just passing over a large randomized phase three international study and moving on to the next best thing. What I mean by that is that these studies were the first generation of metastatic urothelial cancer studies to pool patients treated with cisplatin and carboplatin. So the control arm could be either cis or carbo. The treatment arm could be either cis or carbo.

If you look at the forest plots, the effect size when you combine cisplatin based chemotherapy with atezo is much larger than when you combine carbo. And so that's a key focus of the ASCO GU analysis and it gets even more complicated, which I think unfortunately makes it even harder for folks to wrap their heads around. So there's an interaction with PD-L1 status.

Sam Chang: All right.

Matt Galsky: If you have high PD-L1 expression and you get cis, you do really well. If you get cis and atezo, you do super well. So I think this provides us with some immunological hypotheses and some clinical hypotheses that now could be tested. Should we be giving cisplatin based chemotherapy plus immune checkpoint blockade only to patients with high PD-L1 expression and that's really something that needs to be followed up on.

Sam Chang: So in looking back at this, that could be obviously evaluated, at least in retrospect. Looking at tumor mutational burden could be looked at.

Matt Galsky: Yep.

Sam Chang: Was just thinking about things were in terms of circulating tumor cells, in terms of other biomarkers, the repository I'm sure is there for that. And so is that the next step with this data?

Matt Galsky: So in following up that observation in this data has been presented in preliminary form at ESMO and the manuscript has been submitted. We did single cell RNA-seq, a peripheral blood mononuclear cells pre-treatment and on-treatment from a large cohort of patients treated with cis versus carbo plus or minus atezo. And you can actually see that different immune modulation in the peripheral blood cellular transcriptional profiles in those different treatment arms reinforcing what we're seeing clinically.

Sam Chang: So we're getting closer and closer, at least to some extent, to precision oncology for our advanced bladder cancer patients. In looking at this data and this combination, let's go beyond combination. Where do you think the next steps are going to be in terms of evaluation of the best therapies for patients that have metastatic or advanced disease?

Matt Galsky: So I think we've known for a long time that a very small subset of patients treated with cisplatin based chemotherapy with metastatic disease have durable treatment-free, disease-free survival. We haven't characterized those patients very well because most of our studies have a fixed follow-up period and then you don't keep collecting data at 5, 6, 10 years. So I don't think we've done enough to fully understand what makes the treatments that we have work so well in that small subset of patients and then try and extend that knowledge to additional patients. And I think now the technologies are there to do that and we shouldn't completely pass over these old drugs chasing new drugs until we understand why they work so well in some cases.

Sam Chang: For a subset of population, for sure. And I think that from the side of those that treat these patients, you hope for that home run because there're going to be patients that have that and then ultimately just as you said, to be able to identify those patients a priori and then to be able to maximize their therapy and avoid perhaps toxic therapy that necessarily may not actually help them as much.

Matt Galsky: If I could add one plug in that regard. So another abstract at this meeting presented by Jonathan Anchor, a fellow at Mount Sinai, explored the combination of cisplatin based chemotherapy plus CTLA-4 blockade in a trial that we did starting in 2010.

Sam Chang: So more than a decade ago?

Matt Galsky: More than a decade ago. In there we do have 10 plus year follow up data and there are four patients out of 36 patients enrolled on that study who are free of disease, who are not on treatment. And so we did whole exome sequence-

Sam Chang: With metastatic disease?

Matt Galsky: With metastatic disease.

Sam Chang: So, more than 10%, four out of 36. Okay. Yeah.

Matt Galsky: So what the IPI adds to that, what the CTLA-4 adds to that, I think one could argue, but we did hawk some sequencing of those primary tumors, identified the neoantigens that might be present in those tumors. And then we checked in the peripheral blood after that sequence of treatments if patients developed T-cell reactive immunity to those neoantigens.

Sam Chang: To those specific antigens. Yes.

Matt Galsky: We only found it in the patients with durable disease-free treatment-free survivals. So perhaps there is an immunologic basis for the durable disease control that we see with cisplatin and certainly that needs to be chased then.

Sam Chang: Yeah, I think your point about being able to actually study more on those medicines that we've had for a while that we know have some benefit for those patients, I think really bears great importance and I look forward to future work and future research. And Matt, as always, every conversation with you people come back with much more knowledge. So we really appreciate you spending some time with us at UroToday.

Matt Galsky: Thank you.