Systemic Therapies in Advanced Bladder Cancer - Noah Hahn

December 20, 2021

In this 2021 LUGPA MCE presentation, Noah Hahn presents Systemic Therapies in Advanced Bladder Cancer. He reviews the current data and experiences with immune checkpoint inhibitor therapies, (ICI) targeted therapies, and antibody-drug conjugate (ADC) therapies.

Biographies:

Noah M. Hahn, MD, Professor of Oncology and Urology, Department of Oncology and Urology, Johns Hopkins University School of Medicine, Deputy Director, Johns Hopkins Greenberg Bladder Cancer Institute at the Johns Hopkins School of Medicine, Baltimore, MD. 


Read the Full Video Transcript

Noah Hahn: So we're going to cover systemic therapies here. My disclosures are still the same. I think I'm going to cover about a drug a minute here, so we're going to see if we can get through this. This is just a quick schematic, again, in the advanced disease setting, just to kind of let folks know about how much has really happened in a short amount of time. I'm not going to go through each of these, but we are talking about immune checkpoint inhibitor therapies, targeted therapies, and now more recently in the last year and a half, antibody-drug conjugate therapies. Just to remind everybody, pre-2016, not that long ago, this is what our systemic therapy landscape looked like. It was literally something we could put on two lines. We had platinum and platinum, and then we had gemcitabine with it and then a little bit of some taxanes versus best supportive care in the advanced setting after platinum progression.

If we look at it today, this is what it looks like today. And again, this diagram has changed so many times. I feel like I change it about every three months. But highlighted in green are the immune checkpoint inhibitors,  in red are the targeted therapies. [inaudible 00:01:13] talk about, erdafitinib. And then in sort of pink/lavender are the antibody-drug conjugates, and they are in the disease settings for which they have FDA approval. The ones that are underlined are ones that have approval in randomized phase three settings. So I'm going to go through this somewhat in the order of the actual approvals.

So let's start first with the second-line setting, post-platinum because this is where these agents first came in. And I'm just going to go through this real quick for the checkpoint inhibitors. I will not go through every single slide, but again, similar to what I showed you on the genomic side, very similar results for each of these agents in terms of response rates, 15, 20%, survivals, somewhere around about 10 months on average. There are some differences between the trials and the populations that went into it. And importantly, thinking about perioperative settings and even moving into a non-muscle-invasive disease, the rates of grade three, four adverse events, about 10%, 10, 15%, depending on the agent that you are looking at. And again, these were all in the post-platinum metastatic setting. So all five of these agents were approved under an accelerated approval process based on this response rate and relative safety profile in the advanced disease setting.

So the next set of approvals with these agents is that they moved up. They moved up to the frontline metastatic urothelial cancer population, and in particular, atezolizumab and pembrolizumab were the two agents approved in this particular setting. This was based on two trials that were essentially phase two, single-arm studies. Outlined in the table on the left, the IMvigor210 and then the KEYNOTE-052 trial, a little bit different size of the trials, 119 and 370 patients, but similar response rates, 23% with atezo, 29% with pembro. Survivals approaching a year, a little bit longer, in a similar side effect profile. But what got people excited about this was this so-called tail of the curve phenomenon, where for the first time we were seeing patients who were on these studies who were free of disease two years, three years out, which we had not seen before. Begs the question about whether or not some of these patients may have potentially been cured, or if they are not cured, they were put into a state where their quality of life was very good and they were going about their lives for a much longer period than before.

Well, we talked about metastatic disease, so second line post-platinum, then frontline chemo-naive. The next thing that came up was kind of jumping a little bit ahead past the muscle-invasive altogether, and pembrolizumab took the leap to move into BCG-unresponsive, non-muscle-invasive disease in the CIS patient population in particular. This was based on the results of the KEYNOTE-057 study that are summarized here. Again, I think this audience is familiar with this, with the non-muscle-invasive setting.

It's often been referred to that this was a single, not a home run type of approval. It was active, there's no surprise there. We saw that in metastatic disease.  The CR rate was 41%. In patients who had a response, the duration was a little bit over a year. But as Michael had pointed out, if you look at everyone that came into the study and you look at one year, only about 18% of these patients were actually still in response if you take the whole study population. The actual rates of adverse events were really no different than what we had seen in the advanced disease setting. So this was the first systemic agent that made its way from metastatic disease and was approved in non-muscle-invasive disease.

Well, as we had all of that going on in the post-platinum frontline and other trials accruing, I think a little bit to the surprise of a lot of us medical oncologists, we saw another checkpoint make its way through, avelumab, in the maintenance setting, in the frontline setting. So this was a design, shown on this next slide, this was called the JAVELIN trial. And these were metastatic patients who were treated with chemotherapy first, and they were required to have responding or stable disease to then enter into this JAVELIN maintenance study. And in the JAVELIN maintenance study, they were randomized very simply, one-to-one to avelumab PD-L1 targeting therapy versus best supportive care, which really in this situation is observed, at the time that this trial was conducted. The primary endpoint of this trial was overall survival.

And this sort of flew under the radar as they were running it, but it got all of our attention when they then came to ASCO last summer with overall survival data. So this was a really, really clear benefit that these patients lived longer, who got maintenance avelumab compared to those who got best supportive care. And when you say best supportive care in this, what you are really talking about here is sequential therapy. So these patients generally would go on to get checkpoint at progression, and it really seemed like a consistent advantage to maintenance therapy. And so this actually became a level one recommendation from NCCN guidelines in the metastatic setting for patients who had chemotherapy first and were responding or had stable disease.

Well, while those metastatic trials were going on, many of these companies had moved into muscle-invasive disease, and I think many of the LUGPA audiences participated in these trials. One of the natural questions was for high-risk patients after cystectomy or nephroureterectomy with high-risk disease, could we benefit them by giving them a checkpoint inhibitor versus the standard of care, which was really observation. Nivolumab is the first agent to actually get FDA approval in this adjuvant setting. This was a result of the CheckMate 274 study. This was a randomized phase three trial, which was double-blinded. Again, high-risk patients, post cystectomy or nephroureterectomy were randomized simply to nivolumab versus placebo. And the primary endpoint in this particular trial was a disease-free survival endpoint with overall survival as a secondary endpoint.

This data was presented at GU ASCO earlier this year, published in the New England Journal, and resulted in FDA approval over the summer. So this again was a positive trial. It met the primary endpoint. There was a clear disease-free survival advantage shown on the curves on the left favoring nivolumab, which is the upper set of curves. The median improvement in disease-free survival was really pretty astounding, almost doubling it. They show a benefit in the PD-L1 positive, but this is actually positive across the whole population. The overall survival data is not mature yet. So we are eagerly waiting for that, but this agent was FDA approved for these high-risk, post cystectomy, nephroureterectomy patients.

So kind of coming full circle as we kind of bounce to these diseases going late first, then moving to early and then somewhere in the middle in the perioperative setting.  While all of that was going on, we recognized that while the checkpoint inhibitors were nice and we did see patients with durable responses, the truth is the majority of patients were progressing on these. So there was a huge unmet need for agents that were active after checkpoint inhibitor therapy. And I put third line, these are kind of moving in terms of what we call third line, second line, but enfortumab vedotin and sacituzumab govitecan are two antibody-drug conjugates that are now FDA approved in advanced bladder cancer. These are different agents. enfortumab vedotin has an antibody that is targeting nectin-4. This is expressed in about 95% of all urothelial carcinomas. The nice thing about that is you do not need to have a biomarker selection for these patients. It's linked to an MMAE cytotoxic cargo. This is a tubulin inhibitor.

Sacituzumab govitecan is very different. It uses a trop-2 antibody, so a different target on the surface of the cells. Again, this is expressed in the majority of urothelial cancers, and you don't need to biomarker select for it. Its payload is different though. Its payload is SN-38. This is a topoisomerase inhibitor, which is essentially the precursor to the drug irinotecan that is used in common practice for advanced colon cancer.

The data shown here is for the EV-301 trial. So this is the trial of enfortumab versus chemotherapy. This is the randomized trial that was done versus second-line chemotherapy. The chemotherapies were standard across the world, and in the United States [inaudible 00:10:46] it generally was taxane therapy. And this was one-to-one randomization. Again, presented at GU ASCO earlier this year, and published this summer. What this showed was level one evidence that enfortumab improves overall survival compared to second-line chemotherapy in advanced bladder cancer patients. So this resulted in a permanent FDA approval for this agent in that particular setting.

It is important to understand some toxicities when we think about early-stage disease. These are not toxicity-free agents. Enfortumab has a rash. It also has neuropathy and also very rare, significant diabetes onset in patients. In general, this is better tolerated than traditional cytotoxic chemotherapy, but many of these patients do need to come off of therapy that are responding after long-term exposure. Sacituzumab, on the other hand, was studied in the TROPHY-U-01 study. This was actually more of a single-arm, rapid approval type of a design that looked at single-agent sacituzumab in post-platinum, post-chemotherapy patients with a primary outcome of response rate, and with secondary outcomes looking at overall survival and tolerability.  Again, this was last year presented for the first time and then published this year and approved within the last 12 months.

This is an active agent. About 30% of patients respond. It does have significant toxicity though, in terms of myelosuppression, neutropenia. For a fair amount of patients, we routinely give growth factor support with Neulasta for these patients. And unlike enfortumab, one of its rate-limiting toxicities is actually GI symptoms, diarrhea. They often need fluids and a lot of TLC as they are going through therapy.

And then lastly, I'll talk... Again, I think I mentioned this in the previous discussion in the second-line setting. The erdafitinib data for FGFR story. I don't want to dwell on too much. We presented this earlier, but about a 40% response rate in patients with FGFR-activating mutations in the metastatic setting. These also have unique side effects with FGFR inhibitors, including hyperphosphatemia that is typically managed pretty easily with phosphate binders. But they can get a fair amount of skin issues, fingernail changes, dry nails, splitting that can... It can be a quality of life issue. And so I think as we think about earlier stage disease, it's going to be important to really look at these toxicity profiles and whether patients can stay on these drugs or will put up with these side effects, I think is a question that needs to be answered.

So I think in summary, the systemic landscape continues to evolve very, very rapidly. I think I showed you, I think, four or five drugs that were presented in the last 12 months, published, and approved. There are multiple different agents that have different mechanisms of action. That is pretty exciting because that may allow us different combinations that can push the bar a little bit further. They are approved in different FDA indications, and I think importantly, their toxicity profiles are different. I think all of this places an increased demand for expertise, training, and clinical infrastructure in all of our practices in the community, oncology, urology, as well as academic settings in order to give these agents in the best fashion and also minimize the side effects.
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