Dr. Plimack on Whether Hypomethylating Agents Induce Immune Activation in aUC Resistant to ICI

Elizabeth Plimack, MD, MS, Deputy Director, Fox Chase Cancer Center, comments on whether the results of her phase 2 study were conclusive about using a hypomethylating agent to induce immune activation in patients with metastatic UC who are unresponsive to ICIs, as well as a preview of research to come.

Were your results conclusive about using a hypomethylating agent to induce immune activation in patients with metastatic UC who are unresponsive to ICIs?

Dr. Plimack: Unfortunately, we did not have any patients achieve a RECIST or measurable response to treatment, and that’s what we were going for. When we knew by about the 18th or 21st patient that we weren’t seeing enough responses to justify continuing in the study, we closed enrollment to this study. However, we did have some interesting findings clinically, one is that about 4 or 5 patients had prolonged stable disease, meaning that on treatment, their cancer stayed put for a number of months. Those patients were considered to be the best performers in this study.

Then, we had a number of patients who unfortunately had very rapid growth of their disease, more rapid than we would expect. We’re investigating them to understand better the concept that’s been described in the literature of “hyperprogression,” meaning when we give a cancer treatment, perhaps it has unintended consequence of spurring cancer growth. If that’s the case, we want to understand the mechanism.

The correlative studies really dug down to look at the two hypotheses that we used as the basis for this study. One is that we would undo exhaustion in T-cells. We would reinvigorate these T-cells. Unfortunately, we did not see that when we studied the circulating immune system in the patients on study who were generous enough to donate biopsy tissue specimens as well as peripheral blood for our research. The other was that we would induce endogenous retrovirus activity within the tumor, and unfortunately, we didn’t see that either.

I think we learned a lot from this study. We’re very grateful for the patients who courageously volunteered for this. We did conduct this at a time where there were way fewer good options for patients with urothelial cancer. And the legacy of this group of patients who volunteered for this study will live on as we seek to understand markers of hyperprogression better. Work is ongoing in that area.

What are your next steps for research and analysis in this patient population?

Dr. Plimack: There’s limited enthusiasm to pursue hypomethylation in urothelial cancer and in solid tumors in general based on the collective literature. But we learn from every study we do. In this study, the unintended consequence was some hyperprogression. For those patients, we are deeply studying their tissue, their blood, and their immune system to see if there’s any clue we can identify early that might indicate a patient is susceptible to this. Obviously, we’re not going to pursue the guadecitabine combination, but we think understanding the biological underpinnings of this hyperprogression phenomenon could help us identify patients who should not get immune checkpoint inhibitors in the frontline for instance, as hyperprogression was seen in some subsets of those patients as well.

Now, the label’s been restricted. For the most part, we aren’t using single agent checkpoint in those populations, and that may solve the problem clinically, but we always like to understand the “why” behind what we’re observing. I think further research stemming from samples donated as part of this study will help us understand that.

View Dr. Plimack’s previous comments on Hypomethylating Agent Plus Anti-PD-L1 for mUC After Disease Progression.