Powles Navigates Rapidly Evolving Frontline Paradigm in Urothelial Carcinoma

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.

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

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.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.

What does the future look like? That is the second part that we need to talk about. Clearly, monotherapy is going to help some patients, but it’s not going to change the world for everyone. Will chemotherapy come in? Will immunotherapy combinations come in? Or, will targeted combinations come in? The first trial to read out is likely to be an immune combination study with tremelimumab and durvalumab (Imfinzi). When that reads out, it will change things because that will be the first time we actually get these randomized data. Irrespective of its positive or negative result, it will at least clear up this issue that is outstanding at the moment.

Will the chemotherapy combinations mirror what has happened in lung cancer, or will they lag behind? We do not know the answer to that, but common sense dictates that it will be behind, because chemotherapy is about 10% more active in bladder cancer, and immunotherapy appears 10% less active. I hope they are hugely positive. Perhaps I am just a cautious person, but we should not make any assumptions at this point.

In the targeted group, we have trials ongoing in different parts of the world looking at FGFR inhibitors plus checkpoint inhibitors. We have trials with PARP inhibitors plus checkpoint inhibitors. FGFR looks like a good target. Enfortumab vedotin, which is an antibody-drug conjugate that is a bispecific with Nectin-4 as the target, looks active in platinum-refractory disease.

What is in the works with biomarker validation for immunotherapy in bladder cancer?

While we have had a huge initial wave of optimism, it has been damped a little recently. The biomarker-positive change is an example of that. We are definitely helping some patients, but how to we help more? There are 3 things we need to do in bladder cancer—we need to pick the patients better, we are going to need combinations, and we need to figure out what we are doing in the muscle-invasive bladder cancer space.The biomarkers story is 2-staged, the stage being the first- and second-generations of biomarkers. The first generation of biomarkers in urothelial cancer have been extremely confusing. The inconsistency, even within single-drug programs, is that the biomarkers are working in the second-line setting and not the first-line setting. This needs to be addressed.

Before we move on and let these biomarkers go, we have an obligation to find out what we are doing there. We can do that with a frontline trial. We will be able to clarify this issue over the next year or 2. Just when a game of chess appears incredibly complicated, it can be very much simplified by 1 or 2 simple moves. These trials reading out will be a part of that—we will know a lot more about frontline biomarkers. So, let’s not throw away PD-L1 yet.

What is your advice to community oncologists who must navigate through this time in bladder cancer?

One year ago, we all said that the second generation of biomarkers would supersede the first generation—I no longer believe that to be the case. I do believe that TMB, and some specific signatures like epithelial-mesenchymal transition and TGF-β1, may herald sensitivity and resistance, and may facilitate the building of a biomarker platform, where we can be increasingly confident that we are selecting the right patients the right patients for the right treatment at the right time.In frontline bladder cancer, at the moment, there is a lot of uncertainty, and that means that the decisions are more difficult than they have been for some time. I am currently in a position where I am advising patients who are biomarker-positive to consider immunotherapy. The patients who I would consider for immunotherapy are those patients who I feel could have the opportunity to sequence with chemotherapy after the immunotherapy if it did not work—so, patients with relatively unaggressive disease. We know that patients with rapidly progressing liver metastases do not do well, and I suspect that includes some biomarker-positive patients. But, patients with a few lung metastases and slowly progressing disease, a trial period of immunotherapy to see if it will work is attractive. This is a cautious approach currently, but that may change in the next 6 months when the randomized trials come out and we can confidently say what is safe and unsafe.

The caveat to that is that patients are coming to us asking for immunotherapy. Everyone wants the chance of a long-term durable remission. Until we know the detail of that in the frontline setting, we should probably be erring on the side of caution.