First-Line Pembrolizumab Just the Beginning for Novel Approaches in Bladder Cancer

Arjun Balar, MD

First-line pembrolizumab demonstrated significant antitumor activity in cisplatin-ineligible patients with metastatic urothelial cancer, according to the results of a planned interim analysis from the phase II KEYNOTE-052 trial.

The analysis included the first 100 patients enrolled in the trial. After a median follow-up of 8 months, the objective response rate in these patients was 24% (95% CI, 16.0-33.6). The median time to response was 2 months (range, 0.1-13.4).

“The activity that we’ve seen is clearly clinically meaningful, and there are durable responses that we are observing with these patients,” said lead study author Arjun Balar, MD, who presented the study results at the 2016 ESMO Congress.

OncLive: Could you provide an overview of the results you presented here at ESMO?

In an interview with OncLive, Balar, director of the Genitourinary Medical Oncology Program at NYU Langone Medical Center, discussed the significant findings from this interim analysis, as well as what that next steps may include.Balar: KEYNOTE-052 was a first-line study of pembrolizumab in cisplatin-ineligible patients with advanced urothelial cancer. Overall, the study enrolled 374 patients. However, what I presented today was the interim analysis of the first 100 patients. The key objectives of this planned interim analysis were to get a sense of what the objective response rate was in the first 100 patients, but also to develop the biomarker—the PD-L1 expression score—that would subsequently need to be validated in the remaining patients in the study.

What we found was that the objective response rate in the first 100 patients was 24%, including 6% of patients achieving a complete response. Additionally, when we looked at PD-L1 expression, what we did in this particular trial was look at something called the combined positive score (CPS). That score is calculated by looking at both the expression of PD-L1 on tumor cells and infiltrating immune cells, and take that over the total number of tumor cells in the tumor, and reflect that as a percentage.

So, based on that formula, it’s possible that the PD-L1 expression level can actually be above 100%. Using that CPS, we aimed to find a level of expression where we enriched greatly for responses but also minimized the false-negative rate.

In essence, what we found was that the PD-L1 expression CPS cut point of 10% or greater, seemed to enrich for responses really well. Of the 100 patients, 30 met that criteria of 10% or greater expression, and in that group, the objective response rate was 37%, and the complete response rate was 13%. A high proportion of patients also had stable disease.

Were there any noteworthy toxicities associated with pembrolizumab in this study?

Notably, in patients who had under-expression of PD-L1, including the absence of expression, there were also some responses there, including 18% responders in that group. So what we see is enrichment, but we do see responses in patients who have no expression or very low expression.The safety profile of pembrolizumab in the first-line setting was well tolerated. Overall, the grade 3/4 adverse event rate was 16%. We did see some notable immune-related adverse events, such as colitis, nephritis, and pneumonitis, in patients enrolled in this trial. But the overall frequency in the first 100 patients was very low, which means only 1 or 2 patients had developed each one of those toxicities.

What are the next steps following this interim analysis?

Are there any other ongoing studies in this space that you’re excited to see the results of?

What would you like the community oncologist to take away from your presentation?

What would you like to see in this space in the next 5 to 10 years?

What’s also notable is that only 5% of patients discontinued treatment due to side effects, and there were no treatment-related deaths.The next step after the preliminary data from KEYNOTE-052 is to see if the outcomes observed in the first 100 patients can be validated in the next 274 patients. This includes objective response rate, complete response rate, and the CPS high cutoff of 10%. Does that also discriminate in terms of enrichment of response in the subsequent 274 patients? But most importantly, what do the survival outcomes look like? Median survival and long-term outcomes will need to be investigated, and that is something that we eagerly await for in the remaining study population.In this disease state, we have a number of different trials investigating immuno-oncology in bladder cancer. Of particular interest are novel immune combinations, such as PD-1/PD-L1 in combination with CTLA-4, and PD-1 in combination with CSF1R inhibitors. I also hope to see combinations with PD-1 or PD-L1 and IDO inhibitors.The activity that we’ve seen with these compounds is clearly clinically meaningful, and there are durable responses that we are observing with these patients. Now, there seems to be 2 trials that show that first-line immunotherapy is certainly a viable treatment option and could represent a new standard of care for some patients who are cisplatin-ineligible with metastatic disease.I hope that we have revolutionized care for patients who are suffering from metastatic, locally advanced, or even muscle-invasive bladder cancer. I hope to see immunotherapy as a backbone upon which we develop other novel therapeutic approaches. Those certainly could be combinations. However, there could be a subset of patients who only need to receive immunotherapy, even at the moment that their diagnosis is made, and I think that’s a very promising outlook because those are the patients who could have durable, complete, or partial responses without ever needing chemotherapy.

Balar A, Bellmunt J, O’Donnell PH, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase II KEYNOTE-052 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA32.