Dr. Elizabeth Plimack on a Hypomethylating Agent Plus Anti-PD-L1 for mUC After Disease Progression

Elizabeth Plimack, MD, MS, Deputy Director, Fox Chase Cancer Center, provides an overview of a recent phase 2 trial of guadecitabine plus atezolizumab in metastatic urothelial carcinoma progressing after initial immune checkpoint inhibitor therapy.

How have treatment options evolved in recent years for patients with metastatic urothelial carcinoma who are unresponsive to initial ICIs?

Dr. Plimack: The study we’re about to discuss was designed in 2017. But the field has changed dramatically since then, all for the better with more options available for patients with urothelial cancer that spread or is metastatic.

In 2017, the standard of care was either frontline chemotherapy or immune checkpoint inhibitor. Now, we’ve switched to where standard of care is chemotherapy followed by maintenance immunotherapy or salvage immunotherapy. We also have novel agents that have been approved since 2017: enfortumab vedotin and sacituzumab govitecan, as well as erdafitinib for patients with FGFR alterations who fit the criteria for that drug.

Recently, as of March 2023, the FDA approved on an accelerated basis the first line use of enfortumab vedotin with pembrolizumab for patient’s ineligible for platinum-based chemotherapy. That changes the field for us yet again.

Why was guadecitabine plus atezolizumab chosen as an investigative arm for these patients?

Dr. Plimack: Going back to 2017 when the standard of care incorporated an immune checkpoint inhibitor, it was disappointing when a patient’s disease grew through immunotherapy, either initially from the get-go refractory disease or resistance that developed during the course of treatment after an initial response. It’s that group of patients for which there really is still an unmet need. It was more unmet in 2017 than it is today.

The concept behind this study was developed with colleagues, the Van Andel Institute, and Coriell Institute, and the trial was done with colleagues at Hopkins and USC. The idea was that guadecitabine, which is a hypomethylating agent used mostly in hematologic malignancies and not used clinically in any solid tumors, would do two things: reinvigorate exhausted T-cells to enhance the immune response to checkpoint inhibitor, and induce endogenous retroviral activity that would make these tumors more immunogenic.

So, our thought and premise was twofold, that guadecitabine would do this, and that it would do this in a group of patients who were refractory or resistant to their prior checkpoint. The idea was to then get atezolizumab, another checkpoint inhibitor (in some cases, the same checkpoint the patient had received) to work again and to get that nice immune response that some of our patients who are fortunate can enjoy.

What were the patient criteria for the phase 2 study and what were the primary and secondary outcomes?

Dr. Plimack: We were including patients who had received a prior checkpoint inhibitor, and whose disease had demonstrated growth through that initially refractory or overtime resistant disease. There were a variety of other inclusion criteria but most of those were standard. We tried to be very inclusive.

The primary endpoint of the study was responsive rate. We wanted to see these tumors shrink with treatment. Secondary endpoints were standard overall survival and progression free survival. This trial was funded by Stand Up To Cancer through their Genentech catalyst mechanism and as such had a really wide array of correlative studies built into it. In fact, the paper and clinical cancer research is really focused a lot more on what we learned from studying patient’s tissue samples on this study.

View Dr. Plimack’s continued comments on Whether Hypomethylating Agents Induce Immune Activation in aUC Resistant to ICI.