Transcript:Thomas Powles, MBBS, MRCP MD: Bladder cancer is often known as urothelial cancer because it’s not just involving the bladder. But I’m going to call it bladder cancer for the purposes of this video. Bladder cancers have evolved a lot in the last 3 or 4 years. The field was stuck with chemotherapy that was largely, or has been largely, ineffective in terms of long-term durable remissions. It’s effective at controlling the disease in the short term, but the cancer returns and the chemotherapy follows the law of diminishing returns, which means if you challenge with the same drugs a second time, they won’t respond. This means the overall survival of patients with metastatic disease was only about 12 months.

Things stayed the same for maybe 40 years, and then 3 or 4 years ago, a series of new checkpoint inhibitors—the first of which in bladder cancer was atezolizumab, which is a PD-L1 inhibitor—show significant activity. And in fact, it showed response rates going up to the region of 45% to 50% in individuals who overexpressed PD-L1 biomarker. From there, there was a debate about whether the biomarker was important or not. In fact, that debate is ongoing, and as time goes by, the biomarker seems to become less and less relevant. And what we’re beginning to see is both the PD-L1-positive and the PD-L1-negative populations responding to these drugs.

Atezolizumab was developed first, but very close behind was pembrolizumab. And then subsequent to that, 3 other drugs—which I’ll talk about in a second—have been developed. I’m going to focus on the first 2 to start with. Atezolizumab and pembrolizumab went through phase I trials. Both showed response rates in the region of somewhere between 20% and 30%, depending on your PD-L1 status. And essentially what happened from there was atezolizumab went through a large phase II study of 300 patients, which is called IMvigor 210. This trial showed efficacy for PD-L1-positive patients, again with response rates in the region of 25%, but also response rates in the PD-L1-negative patients of about 10% or 11%. And when you pull those together in individuals who’d previously failed chemotherapy, that looks better than chemotherapy. What we discovered was the drugs were tolerated, and really importantly, if you responded, you had long-term durable responses. And that’s really attractive for patients because the option of toxic chemotherapy, short-term goals, or the potential for long-term durable well-tolerated responses with immune therapy is attractive. For that reason, it was FDA approved. And that actually was probably FDA approved more than a year ago now.

Pembrolizumab went down a slightly different route. It went down straight into a randomized phase III trial from the phase I. And that phase III trial showed a hazard ratio of 0.73 for all-comers, which is beating chemotherapy in the second-line space. That’s important. In fact, that’s probably the first randomized phase III-positive bladder cancer trial for 30 to 40 years, displacing chemotherapy and bringing a new class of drugs in. There was, again, enrichment for the biomarker, but also uncertainty around the biomarker. For that reason, pembrolizumab was also recently approved in that space.

Both drugs have trials in the untreated metastatic disease population. So, I’ve been talking about platinum-refractory disease, I can now talk about metastatic disease previously untreated. And both drugs have shown significant activity in that population as well in those individuals who are not fit enough for standard cisplatin-based chemotherapy. Those both are now FDA approved in the United States where individuals who are not fit for cisplatin-based chemotherapy can get immune checkpoint inhibitors instead. And again, these drugs had response rates in the 20% or 30% region. You can enrich pembrolizumab off a bit with a biomarker, but there’s uncertainty around that biomarker. But there is this hope of long-term durable remissions. And for that reason, these 2 drugs really have become established in this field.

Following close behind that are 3 newer drugs. And those 3 newer drugs—avelumab, nivolumab, and durvalumab—actually have been used in other tumors, too, but are behind in bladder cancer. Nivolumab has similar activity to the other 2 agents in the phase II trials. Nivolumab has quite a robust phase II study in that setting. All 3 now have FDA approval. And then for the other 2, avelumab also has a phase I and a phase II trial and durvalumab has a large phase I/II trial.

So, when you pull this together, we currently have 5 immune checkpoint inhibitors. They’re FDA approved in bladder cancer. They’re showing similar efficacies in unselected patients in cisplatin-refractory disease. There are randomized data for 1 of the drugs with pembrolizumab, and there’s also front-line and second-line approval.

There has been a huge change. We’ve got some challenges in the future. We need to do better. We’re only probably helping really—long-term durable remission—1 in 5 patients. We need to do better than that. So, immune combinations, immune-tolerated combinations, and immune chemotherapy combinations reports are the first challenge.

Second, let’s bring the drugs early in the disease setting. Treating patients once they fail chemotherapy with a life expectancy of 4, 5, 6, 7, or 8 months is much harder. If we bring the drugs earlier, we’ll probably get longer benefits, in my opinion. And then the third piece is let’s try to find which patients respond to therapy by using the biomarker, or, in my opinion, moving on from immunohistochemistry biomarkers into second-generation biomarkers, gene expression biomarkers, and mutational burden T cell clonality—a huge area of work going on in that space.

It’s a really exciting time in bladder cancer. There are dynamic changes, and the last piece of this jigsaw puzzle is we now have 4 or 5 massive randomized phase III frontline trials seeking therapy; we have 2 or 3 adjuvant studies to improve outcomes after surgery, and also some work in neuromuscular-related disease. So, there is a series of new chapters that will be explored.

Transcript Edited for Clarity