Maintenance Pembrolizumab Extends PFS in Metastatic Urothelial Cancer

Matthew Galsky, MD

Switch maintenance treatment with pembrolizumab (Keytruda) improved progression-free survival (PFS) in patients with metastatic urothelial cancer who have stable disease following frontline platinum-based chemotherapy, according to results of a randomized phase II study that were presented at the 2019 ASCO Annual Meeting.

In the phase II HCRN GU14-182 study, patients who had stable disease following ≤8 cycles of platinum-based chemotherapy were randomized to receive a median 6 to 8 cycles of either pembrolizumab or placebo for approximately 3 years.

Results showed that the overall response rate (ORR) in patients who received the PD-1 inhibitor (n = 55) was 22% compared with 12% for those who received placebo as maintenance (n = 22). In the pembrolizumab arm, this included a 9% complete response (CR) rate.

Moreover, the median PFS favored the pembrolizumab arm at 5.4 months (95% CI, 3.6-9.2) versus 3.2 months (95% CI, 2.8-5.5) for those on placebo (HR, 0.64; 95% CI, 0.41-0.98; P = .038).

“The place for a switch maintenance approach in the treatment [of patients with] metastatic urothelial cancer is really going to be defined by definitive studies, which are enrolled in what will likely read out in the next 12 to 18 months,” said Galsky, who looked ahead to the role of this treatment approach.

In an interview with OncLive, Galsky, the director of Genitourinary Medical Oncology at The Tisch Cancer Institute at Mount Sinai, discussed using switch maintenance pembrolizumab for metastatic urothelial cancer.

OncLive: Could you discuss this study of maintenance pembrolizumab after first-line chemotherapy in patients with metastatic urothelial cancer?

Galsky: Standard treatment for metastatic urothelial cancer is platinum-based chemotherapy. Treatments generally continue for approximately 6 to 8 cycles and is then discontinued, given concerns for increasing toxicity in the setting of diminishing benefit. Unfortunately, a vast majority of patients progressed despite first-line chemotherapy, and most do so within a relatively short period of time.

Because of those considerations, the switch maintenance approach has been explored in just a handful of studies in metastatic urothelial cancer. This concept is using a potentially non—cross-resistant treatment immediately upon discontinuation of first-line chemotherapy, ideally a treatment that also has nonoverlapping toxicities, as well. There are both scientific and pragmatic reasons for considering a switch maintenance approach with immune checkpoint blockade. Initial chemotherapy could potentially induce immunogenic cell death or cause depletion of immunosuppressive subsets, thereby enhancing the effects of subsequent immune checkpoint blockade.

This approach could also potentially be beneficial, largely for practical reasons. We know that about only one-third of patients who start first-line chemotherapy for metastatic urothelial cancer are able to go on subsequent lines of treatment. Therefore, if we move treatment early on in the course of the disease, perhaps we can benefit patients by just ensuring they gain access or exposure to potentially active, non—cross-resistant treatments.

That’s what was tested in the study. It's a randomized, double-blind, phase II study. Patients received up to 8 cycles of first-line platinum-based chemotherapy, and then were randomized 1:1 to receive pembrolizumab versus placebo. Treatment was to be continued for up to 24 months in the absence of disease progression. Randomization was stratified by lymph nodal metastatic disease and response to first-line chemotherapy. The primary endpoint was progression free survival (PFS), and the trial did show significant improvement in PFS with switch maintenance pembrolizumab compared with placebo.

Could you expand on the clinical activity seen with pembrolizumab in this trial?

The response rate was reported or analyzed as a secondary endpoint of the study. It's important to remember that in a maintenance study, patients can enter the study having had a CR to first-line chemotherapy. There are some different schools of thought in terms of whether or not those patients should get a switch maintenance approach. One could argue they do have the most to gain by a switch maintenance approach, in terms of moving the bar, in trying to cause a real durable complete response in this group of patients.

On the other hand, if chemotherapy has done a really good job, one might say those patients should be offered a treatment-free interval. The numbers will be small, but ultimately, we will be able to look at the subset of patients who had a CR going into the study, and were randomized to pembrolizumab versus placebo. One of the reasons for mentioning that, though, is patients who are in a CR when entering the study have to be taken out of our objective response analysis because there's nothing to measure in terms of the response assessment.

Were there any new safety findings with pembrolizumab in this population?

This is one of the cleaner data sets to look at the adverse event (AEs) profile of immune checkpoint blockade. Not unexpectedly, there are side effects associated with immune checkpoint blockade that one would expect similar to what has been reported in other studies. Interestingly, though, a lot of the grade 1/2 AEs, such as diarrhea and elevated liver transaminases, which are often immediately ascribed to the checkpoint blockade in a single-arm study, were actually encountered on the placebo arm. This reinforces the safety profile of these drugs and reminds us that there are AEs that are associated or attributed to drugs sometimes that might be associated with the underlying disease. These randomized data sets really help us sort this out.

What future does the combination approach of pembrolizumab and chemotherapy have?

The first-line randomized phase III studies in urothelial cancer that are integrating the immune checkpoint blockade with chemotherapy all involve a maintenance strategy with immune checkpoint blockade continued after chemotherapy. It's a little bit of a different question because in that situation, patients have already received immunotherapy upfront. They might be responding to that, might be responding to chemotherapy, or they might be responding to the combination. This study helps contextualize what the maintenance portion might be adding to those regimens, but it's not exactly the same. It's not exactly an “apples to apples” comparison.

People are starting to think about combinations in maintenance approaches. It’s important to step back and think about what we're trying to achieve in this setting. One of the potential benefits of immune checkpoint blockade as a switch maintenance strategy—as opposed to some of the other things that have been explored in this situation, which are non—cross-resistant chemotherapies—is that you're hoping to allow patients to have their responses maintained or improved. However, at the same time, give them a break from the toxicities of chemotherapy. The more we add in terms of AE burden in that setting, we start to diminish what we're trying to achieve, so it will be a balance.

The randomized phase III studies are testing a few different concepts. One concept is: should we give chemotherapy plus immunotherapy right from the start for the treatment of patients with metastatic disease? Or, should we double the immunotherapy regimens? Should we do what we did in this study? Should we give a switch maintenance therapy? Based on the readout of all of those studies, which are anticipated in the not-too-distant future, we will likely see a change in treatment and really refine the role of this switch maintenance approach.

What biomarkers were identified in this study, if any?

The biomarker work for this study is ongoing. PD-L1 expression was assessed centrally. All of those data are being analyzed. We have integrated the secondary endpoint, PFS, in the PD-L1 high subpopulation. That's probably one of the more important biomarker analyses, although there are biomarker analyses that will be done as part of this trial that were predefined.

In addition to those more conventional biomarkers, we did look at smoking in this study as well. Smoking has been previously linked to an increased likelihood of response to immune checkpoint blockade, perhaps as a surrogate for mutational burden or perhaps as a surrogate for mutational signatures.

However, the results have been inconsistent, partly based on the way the data have been ascertained. Therefore, we used a standardized instrument, we [asked questions on tobacco use] from the National Health Interview Survey, we quantified smoking, and we defined smoking as patients who smoked greater than 100 cigarettes in their lifetime. About 70% of patients on both treatment arms were ever smokers; about 10% to 15% of patients were still smoking at the time of enrollment. Perhaps not surprisingly, based on the sample size of the study, there was no significant statistical interaction between smoking and treatment arm on PFS. However, you do see that patients who were randomized to placebo who were ever smokers had the worst outcomes. Whether or not there's something there, it still needs to be better understood. It's certainly not an obvious correlation.

Galsky MD, Pal SK, Mortazavi A, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182. J Clin Oncol. 2019;37(suppl; abstr 4504). meetinglibrary.asco.org/record/171841/abstract.