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Powles Navigates Rapidly Evolving Frontline Paradigm in Urothelial Carcinoma

Angelica Welch
Published: Wednesday, Dec 12, 2018

Thomas Powles, MBBS
After a wave of success with checkpoint inhibitors, the frontline setting of bladder cancer has been a space of uncertainty, according to Thomas Powles MBBS, MRCP, MD.

In May 2018, the FDA issued a drug safety notification warning against the use of frontline single-agent immune checkpoint inhibition for patients with urothelial carcinoma considered biomarker-negative, which are those with PD-L1–low expressing platinum-eligible disease. A similar warning was issued by the European Medicines Agency (EMA), both following data demonstrating lower overall survival with pembrolizumab (Keytruda) and atezolizumab (Tecentriq) compared with platinum-based chemotherapy in these patients.

Due to these developments, there is a renewed need to investigate biomarkers and combinations with chemotherapy and targeted agents.

“There are more unknowns as it stands,” said Powles. “How active are the drugs? What is the problem? How active is the biomarker-positive population? My current feeling—and not everyone agrees with me on this—is that we should only be using drugs such as atezolizumab and pembrolizumab in the biomarker-positive population, because that is the indication we have been given,” said Powles.

In an interview with OncLive, Powles, professor of genitourinary oncology, lead, Solid Tumour Research, Barts Cancer Institute, director, Barts Cancer Centre, discussed the changes to the frontline landscape of bladder cancer and where research should focus moving forward.

OncLive: How is the frontline treatment of bladder cancer changing?

Powles: The frontline treatment of bladder cancer is evolving very quickly. It is actually evolving quicker than it ever has before. The immune checkpoint inhibitors were approved in the frontline setting in patients who are ineligible for cisplatin-based therapy, which was cool. It is a big step in the right direction, because chemotherapy is not associated with long-term durable remissions. But, the immune checkpoint inhibitors seem to lose control in large groups of patients, and only seem active in maybe 1 in 8 or 1 in 5 patients. It looks as if half of the patients may be getting no benefit at all. Chemotherapy helps most patients a bit.

Recently, the EMA and FDA announced that they wanted to change the frontline labels of these checkpoint inhibitors. We do not know where the FDA and EMA's information comes from, but we know they have now restricted these labels to the biomarker-positive population. That must mean that there is a big problem with the biomarker-negative patients. That raises a number of important issues. We can assume that immune checkpoint inhibitors are not going to supersede chemotherapy in unselected patients in a randomized trial, even in the cisplatin-ineligible population. Biomarkers are going to be important in the future. If the trials are positive, they will be driven by biomarkers.

Over the last 3 or 4 years, I have been talking about biomarkers not working in bladder cancer. In the second-line setting, they look pretty unhelpful, actually. Now, we are being told that these agencies have seen data showing that [checkpoint inhibitors] are helpful. We need an explanation as to what is going on there. Giving it to biomarker-negative patients seems quite hazardous. Two agencies have gone out of their way to give us information that it is unsafe.

At the 2018 ESMO Congress, we saw a frontline renal cell carcinoma study, a frontline breast study, and a frontline head and neck study [of immune checkpoint inhibitors]. Who would have guessed 4 years ago that the breast or head and neck cancer communities would get frontline trials before bladder cancer? Something has happened in bladder cancer, and we need to know what is going on.

There is some work by Matthew Galsky, MD, of Mount Sinai Hospital, looking at the stromal signature in urothelial cancer. Although tumor mutational burden (TMB) and PD-L1 expression are high and there is T-cell infiltration, there may be inhibitory stromal signatures that might be the reason why the drugs are not as active as we thought they might be. They certainly are not as active as they are in lung cancer, where we now have immune combination therapy, chemotherapy combinations, and single-agent therapy for patients. We are lagging a little bit behind.

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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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