Efficacy and Safety of Pembrolizumab for Metastatic Urothelial Carcinoma

5-Year Follow-Up Data From KEYNOTE-045 and KEYNOTE-052

Peter O’Donnell, MD, University of Chicago, IL, shared key outcomes and insights from an analysis of the KEYNOTE-045 and KEYNOTE-052 trials, showing pembrolizumab yields durable response among patients with metastatic urothelial carcinoma after extended follow-up.

The KEYNOTE-045 trial compared pembrolizumab with taxane-like chemotherapy for patients with refractory, metastatic urothelial carcinoma, while KEYNOTE-052 looked at frontline pembrolizumab for cisplatin-ineligible patients with metastatic urothelial carcinoma.

Dr O’Donnell also addressed the debate of immunotherapy retreatment, noting that data from this study suggests patients who have a recurrence or progression of disease after stopping immunotherapy may have a response to retreatment with pembrolizumab.

Transcript:

Hi, I'm Dr. Peter O'Donnell at the University of Chicago. I'm a genitourinary medical oncologist. And I'm happy to be talking today about the recent publication on efficacy and safety of pembrolizumab in metastatic urothelial cancer results from the combined KEYNOTE-045 and KEYNOTE-052 studies, after up to 5 years of follow up, and this was published in Annals of Oncology. These 2 studies looked at the utility of pembrolizumab, which is a mainstay therapy now in metastatic urothelial cancer. And these were 2 of the pivotal trials that really led to the indications for this drug.

As you remember, KEYNOTE-045 was the phase 3 study that looked at pembrolizumab against taxane-like chemotherapy in the refractory setting for metastatic urothelial cancer. Patients were randomized in that study to receiving pembrolizumab or receiving treating-physician-choice of paclitaxel, docetaxel, or in Europe, vinflunine. And of course, the study was positive, showing a prolonged overall survival for pembrolizumab.

Now, this follow up specifically looks at the long-term outcomes of that subset of patients that was randomized to pembrolizumab in that study, and we'll talk about the results in a minute. The article now also combines that long-term follow up on pembrolizumab-treated patients in the refractory setting with the long-term outcomes for pembrolizumab-treated patients in the frontline setting. And specifically, from KEYNOTE-052, those patients were all cisplatin-ineligible, previously untreated with metastatic urothelial cancer, and they all received pembrolizumab upfront in this single-arm study. And again, the advantage of this most recent analysis is that we have now this long-term follow-up data on those pembrolizumab treated patients.

To highlight some of the key results from this combined dataset, we're looking at now nearly 700 patients combined, when you think about the pembrolizumab, pembrolizumab treated patients from both studies. Really, the key outcome is that there clearly are portions of patients who respond to pembrolizumab and do so quite durably. And these data sets now examine patients out to the five-year mark and in some cases even beyond. And we're able to really see what the long-term responses are to those patients. For example, in KEYNOTE-045, the duration of response among those patients who've responded to pembrolizumab approaches 30 months. Another way to think about it is at that 3-year mark, that 36-month follow-up mark, nearly half of the responding patients are still remaining in response. A tremendous example of the durability of immunotherapy that we all know and really is the upside of that treatment.

For the KEYNOTE-052 study, we have again that long-term follow up. And here it's informative to see the overall survival data for the overall cohort, which was 11 months. But in that group that has high PD-L1 status, in this study the benefit was even greater now, over 18 months for the overall survival. And again, if we think about the group that's going to respond, and it's a subset that responds, we see that those who respond tend to remain in response for very long portions of time.

In KEYNOTE-052, the overall population, regardless of PD-L1 status, among responders, have a median duration of response of over 33 months. Another way to look at it here, if we think about the 4-year time point or even the 5-year time point in this study, we can see that it approaches 60% of patients with high PD-L1 status that still remain in response. Even for all comers, it's nearly 40% of all of those patients, regardless of PD-L1 status, remain in a response if they initially respond at the four-year mark in this study. Long-term data really showing the durability of pembrolizumab as a treatment.

I'll highlight one last key result that was really interesting from this study and can really help us when we think about treating patients. And that is the idea of re-treatment with immunotherapy. We all know that there's a debate about how long patients might be treated for with immunotherapy when they're responding. Some oncologists if a patient goes into a complete response, will stop the immunotherapy at that point. Others follow the 2-year mark, like many of these trials were designed, where patients who have complete response, partial response, or even stable disease at the 2-year mark would be discontinued from pembrolizumab. What if those patients then have recurrence of disease or progression of disease after the immunotherapy is held?

We have some data from this study that could inform us that re-treatment with pembrolizumab may be useful. While there were very small numbers of patients falling into this category from both studies, in both of those studies about half of the patients who received a second course of pembrolizumab after previously stopping pembrolizumab responded again. And many of those patients responded quite durably with median durations of treatments anywhere from six to 11 months in these two studies.

This is one of the first looks that we've gotten at this idea of, could we retreat a patient with immunotherapy who was previously on immunotherapy and had an excellent response, and then we stopped that immunotherapy by treating physician choice, could we retreat that patient with pembrolizumab? And these data would suggest that the outcomes might be quite favorable to doing so.

This is really great long-term follow-up data on pembrolizumab. It really, in my view, cements the role of pembrolizumab as 1 of the possible treatment options that we have for this disease. In that frontline space where there's been a lot of debate about what to do in that cisplatin-ineligible population and treatments that are coming down the line, pembrolizumab is the only non-chemotherapy right now that we have sitting here in January of 2023 to use in that select group of patients that might benefit from receiving immunotherapy alone. The FDA has retained that indication for pembrolizumab as the only immunotherapy in that space and these data speak to that. They also speak to the durability of pembrolizumab when used in the refractory setting.

Thanks for your time today.

Source:

Balar AV, Castellano De, Grivas P, et al. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: Results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. Published online: December 6, 2022. doi:10.1016/j.annonc.2022.11.012