Urothelial Cancer: Progression After First-Line Therapy

Arlene O. Siefker-Radtke, MD:When we consider the frontline treatment of metastatic bladder cancer, most patients and their physicians are choosing to proceed with a chemotherapy regimen. That being said, giving cisplatin can be difficult in this elderly and frail patient population, and the alternative of gemcitabine-carboplatin arguably has toxicity as well, with the potential for inferior outcomes as compared with cisplatin-based therapy. Once patients fail this treatment, the standard has been to proceed with an immune checkpoint inhibitor. With the recent approval of erdafitinib, there’s now an indication forFGFR3mutation testing and considering erdafitinib as a potential alternative in patients with anFGFR3-altered tumor. However, that occurs in a small percentage of patients—approximately 15% to 20%.

So the majority of patients will receive a second-line treatment strategy using a checkpoint inhibitor. These checkpoint inhibitors in the second line, while promising and exciting, have been limited in their long-term impact. The response rate is typically 15% to 20% in the second-line setting, and when we look long term, less than half of those remain in response 2 years later.

For the frontline treatment of metastatic urothelial cancer, there are currently 2 immune checkpoint inhibitors approved. One is atezolizumab, and the second is pembrolizumab. They each target PD-L1 [programmed death-ligand 1] and PD-1 [programmed cell death protein 1], specifically. These agents had much excitement associated with their initial response rates, with an estimate of approximately 20% to 25% of patients achieving a response in the frontline setting.

There were several limitations, though, in the treatment of these patients, with PD-L1—low tumors having a low response rate—as low as the single digits—and also in patients with high-volume disease. Patients with visceral metastases, especially with liver metastases, have typically had a very poor response rate with checkpoint inhibition. And some have argued there may be select groups of patients who require treatment other than an immune checkpoint inhibitor based upon the location or disease burden of their cancer.

When you look at PD-L1 expression, the PD-L1—high tumors are typically limited to approximately 30% of our bladder cancer patients. There are typically 2 methods of determining PD-L1 expression. One uses PD-L1 expression on the tumor cell. The other uses a combined score looking at PD-L1 expression both on the tumor cell and on the immune infiltrate to try to predict which patients have this high level of PD-L1 expression.

But since the majority of patients are actually PD-L1 low, and also given the disease burden that’s encountered in frontline metastatic patients, there clearly is an unmet need for patients who cannot tolerate the typical platinum-based therapies.

Transcript edited for clarity.