Drs. Shoag, Zhu on Whether ICI Combinations Lead to Durable Survival Benefit in Metastatic UC

Jonathan E. Shoag, MD, Department of Urology, Case Western Reserve University School of Medicine, and Alec Zhu, MD, Department of Urology, Weill Cornell Medicine, describe their recent analysis on the published data supporting ICI use in patients with metastatic urothelial carcinoma who are ineligible for cisplatin-based chemotherapy, and comment on whether this data is indicative of long-term survival benefit.

Can you detail the clinical trial data that has led to ICI use in patients with mUC who are ineligible for cisplatin-based chemotherapy? Have ICIs shown to boost durable responses in mUC?

Dr. Zhu: That is something that we wanted to tackle with our study. Checkpoint inhibitors have transformed the overall landscape of cancer care in the past decade or so. Particularly in cancers like melanoma and lung cancer, you see a lot of patients who are able to survive for a lot longer with the use of ICIs. They’ve been incorporated now into bladder cancer.

In the first-line setting, KEYNOTE-052 demonstrated that pembrolizumab was able to generate a response rate in a good portion of patients. Subsequently, KEYNOTE-361, a randomized trial of pembrolizumab versus chemotherapy, did not show an overall survival or progression-free survival benefit while KEYNOTE-052 demonstrated a response rate in patients ineligible for cisplatin. This eventually led to the FDA approval of pembrolizumab as a first-line treatment in patients who are unable to get platinum therapies.

Some medications have been approved in the salvage setting as well. KEYNOTE-045 showed that pembrolizumab provides an overall survival benefit in patients in the salvage setting. Similarly, nivolumab and avelumab showed a response in these patients treated in the salvage setting, which eventually led to their approvals as ICI therapies for metastatic bladder cancer.

I think the strongest evidence that we have for ICI use in bladder cancer probably comes from the JAVELIN Bladder 100 trial, which looked at avelumab in a first-line maintenance setting. This is essentially patients who got chemotherapy and did not progress. These patients were either put on avelumab as maintenance or just standard of care. The trial showed an overall survival and progression-free survival benefit for those patients.

Essentially, we now have ICIs that are FDA approved in the first-line maintenance setting as well as the salvage setting.

What were the study inclusion criteria for your analysis?

Dr. Zhu: We first looked at trials that were inclusive of ICIs in the metastatic bladder cancer setting. But, we really wanted to hone in on the durable survival that these are able to provide. We restricted it to trials that had FDA approval or had ongoing FDA approval. The FDA initially had accelerated approvals, but these eventually were withdrawn because later studies demonstrated that these medications didn’t actually provide survival benefit.

Dr. Shoag: To give a little bit more background, this study was based on a subset of patients that respond to these drugs. We have seen increases in median overall survival. But, immunotherapy has this halo around it in many cancers, among them urothelial cancers, in terms of the impact it’s had on survival, but also how we view the therapy as being distinct from our existing cytotoxic chemotherapies. There’s this idea that we see long tails in the survival curve and long-term durable responses.

We wanted to address this question: is that something that we see in the clinical trial data? It’s hard to look at because trials are done for a certain period of time, and then they end. They’re obviously powered to look at median overall survival or median progression-free survival. We don’t necessarily have the complete interval. But, we said in these trials that we included, are there patients who have lived for very long periods of time? Do we have data to suggest that there is this long tail of the survival curve? That was the impetus for the study in the first place.

We landed on: can we look at the number at risk, because their follow-up had ended for a variety of reasons, or they progressed, or they died of their disease? That would be the reason for that number at risk to fall over time.

That was really the impetus for our study was to see if this immunotherapy halo warranted.

The number of patients “at risk” declined over time in each trial, and no patients with continued follow-up were alive or progression-free at 48 months. What do these findings mean in terms of durable survival benefit for patients?

Dr. Shoag: Anecdotally, we’ve all seen in our clinics some patients who have these long-term durable responses. It’s not to say that that doesn’t happen. But, in these seminal trials of immune checkpoint inhibitors, we don’t see that. We don’t have data for patients having very long-term durable responses for urothelial cancer. That’s not to say they don’t exist. This trend could be a reflection of the duration of follow-up, not necessarily that everyone has progressed or died of their disease. But, we don’t see evidence for that in clinical trials, unlike other cancers, where we very clearly see evidence of these long-term durable responses and long tails of the survival curves, like in melanoma or kidney cancer.

This is a little sobering with regard to a lot of the enthusiasm around immunotherapy, which is okay. It doesn’t mean it’s not effective and that we shouldn’t use these drugs or that they shouldn’t have been approved. But, I think it reflects that median overall survival increases don’t necessarily translate into durable long-term survival. That distinction is important.

How are your conclusions on durable survival benefit for these patients limited?

Dr. Zhu: Our study does have its limitations. We rely on published clinical trial data and we see that sharp drop in the number at risk as you go through each of these trials. That’s a reflection of maybe the limitations of the medications themselves and what they can provide for patients at this time. The other major limitation is that the follow-up time is limited. We might not be able to capture any more of these patients who are benefiting. As Dr. Shoag said, anecdotally in the clinic, and a lot of medical oncologists may attest to this, we all have patients who are on these medications for a long time. Unfortunately, because we rely on only clinical trial data, we’re not necessarily capturing that within our analysis.

In your opinions, what are the future treatment approaches that have the most potential to improve outcomes in mUC?

Dr. Shoag: One of the things that prompted our work is that there tends to be these hype cycles with any new cancer therapy. With immunotherapy, there’s this idea that it is fundamentally different than everything else we’ve had before. This is the direction that the field’s going in; there’s a consolidation of research and resources around this one therapeutic idea.

One of the things that drove us to make these statements, particularly for urothelial cancer, is that if you look at the data objectively, immunotherapy actually doesn’t look that different from any other therapy. It’s obviously an improvement. But in terms of the actual patient benefit, it’s not dramatically different from other drugs. If you look at the response rates, if you look at the duration of response, there are, again, certainly improvements. But, the idea that these are very fundamentally different in terms of how patients will respond is maybe a little bit flawed.

With the focus on this class of drugs exclusively, everyone hopes that there’ll be improvements that lead to long-term durable responses and a higher percentage of patients responding, but I don’t know that that’s going to be the case based on the existent data. There are antibody-drug conjugates and other modalities that are actively being explored that may ultimately have more of an impact.

Dr. Zhu: Dr. Shoag gave a great summary. There’s a lot of interest in some of the new medications, like antibody-drug conjugates, either alone or in combination with ICIs. A lot of work is also being done on predictive biomarkers to hone in on those patients that are going to benefit. Genomics with a predictive biomarker could be very revealing and could definitely open doors for a lot of patients who would benefit even more from ICIs. It’s very exciting. I’m looking forward to seeing where we end up in the next couple of years.