Experts Call for Refined Treatment Paradigm in Urothelial Cancer

Treatments for metastatic urothelial cancer are expanding due to the number of immunotherapies available to patients and physicians, but the paradigm for patient treatment needs to be refined according to Dr. Daniel P. Petrylak.

There have been several immune checkpoint inhibitors (ICI’s) approved for the treatment of metastatic urothelial cancer. Between May 2016 and May 2017 the Food and Drug Administration approved seven immune checkpoint inhibitors in this landscape. However, the majority of them, including Tecentriq (atezolizumab), Opdivo (nivolumab), Imfinzi (durvalumab), Bavencio (avelumab) and Keytruda (pembrolizumab), are indicated in the second-line setting for patients who continue to progress after platinum-based therapy. Of the several ICI’s approved by the FDA, only Tecentriq and Keytruda are approved in the frontline setting in patients who are not eligible to receive chemotherapy.

“The question is ‘how can we start moving these drugs earlier in the course of therapy?,’” Petrylak, a professor of medicine and urology and the co-leader of the Cancer Signaling Networks at the Yale Cancer Center, said in a presentation at the 13th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies. At the conference, Petrylak presented on how the focus of research needs to shift to stocking up on frontline therapies in the urothelial cancer setting.

He discussed multiple trials looking at combination therapies of these ICI’s with chemotherapy and other ICI’s that are focused on being used as a frontline option. The two other approaches he highlighted were a switch-maintenance therapeutic approach and greater emphasis on targeted therapies.

The switch-maintenance therapeutic approach is one that allows for physicians to use a maintenance ICI after chemotherapy and continues this process as the physician deems necessary. In his presentation, Petrylak said this could maximize benefits in patients with urothelial cancer and highlighted the findings of the phase 2 HCRN GU14-182 trial that showed a delay in disease progression for patients with metastatic urothelial cancer on maintenance Keytruda after platinum-based chemotherapy. Compared with placebo, the maintenance therapy arm of the trial showed a progression free survival (the time from treatment to disease worsening or progression) benefit of 5.4 months versus 3.2 months respectively.

“There was a PFS difference that favored patients treated with pembrolizumab, suggesting that giving maintenance therapy may be better than just simply observing a patient after they’ve had a response,” Petrylak explained. He also noted a number of studies looking at combining PD-1/PD-L1 blockade with CTLA4 inhibition in the secondary setting as a way to enhance the use of ICI’s used in the frontline setting.

As targeted therapies have grown in importance with researchers having a better understanding of the genetics behind cancer biomarker testing in urothelial cancer, it is important to craft targeted treatments that maximize benefits. Especially as multiple pathways are involved in the mechanisms of the cancer including FGFR3, ERBB2, EGFR, TSC1, and TSC2. There are currently only two FDA approved targeted therapies for urothelial cancer.

“We don’t really see any one dominant pathway. We see that there are multiple pathways, but none of them are particularly dominant,” Petrylak explained. “They are all at most [found in] about 25% of our patients and this is why molecular profiling of our patients is going to be so important to selecting these patients in the future.”

A version of this article originally appeared on OncLive®, our sister publication, as, “Further Study Is Needed to Maximize Therapeutic Benefit in Urothelial Cancer”