Transcript:Arjun V. Balar, MD: The treatment landscape for advanced bladder cancer has changed dramatically over the last year, and in large part, it started with the initial phase I trials of single-agent PD-L1 and PD-1 antibodies in advanced urothelial cancer. Initially, we tested these agents in patients who were platinum-refractory, which means that they had advanced bladder cancer that had progression after platinum-based chemotherapy, and then slowly what we’ve realized is that these agents are also active in the first-line setting.

To quickly summarize, we have now evidence for 5 different agents that are approved in the second-line setting. These include agents such as: avelumab, nivolumab, pembrolizumab, durvalumab, and atezolizumab, all of which are either PD-1 or PD-L1 antibodies. The summary of the evidence so far demonstrates that the response rates with these agents are in the range of 15% to 20%, but the responses are durable and treatment is well tolerated. And we now have a phase III trial, KEYNOTE-045, that compared pembrolizumab versus standard of care chemotherapy in platinum-refractory urothelial cancer demonstrating a survival benefit. This is the first ever phase III trial in a second-line metastatic bladder cancer setting to demonstrate a survival benefit against another treatment.

What we are now seeing also, is that these agents are quite active in the first-line setting as well. And we have 2 studies—IMvigor 210 cohort 1, as well as KEYNOTE-052, that tested atezolizumab and pembrolizumab, respectively, in the cisplatin-ineligible patient population. Cohort 1, which tested atezolizumab in IMvigor 210, demonstrated a response rate of 23% and a median survival of 15.9 months. We also saw 6% of patients achieve a complete response. What we saw in KEYNOTE-52 thus far, is a response rate of 29%. However, survival data to date are still immature. Both of these trials have led to the approval of both atezolizumab and pembrolizumab as first-line therapy in cisplatin-ineligible patients. This is the first ever group of drugs ever to be approved for patients who are cisplatin-ineligible with advanced bladder cancer.

And to summarize, all of these agents have redefined the way we treat this disease. In fact, survival has been impacted in the second-line setting. What it has done is laid the foundation for reshaping the way we approach this treatment for this disease, for years to come.

Atezolizumab was first approved based on accelerated approval in the second-line setting, based off results from IMvigor 210 cohort 2, which tested atezolizumab in 310 patients who are platinum-refractory. In that trial, 16% of patients have achieved an objective response and the median survival was roughly 8 months. Responses were durable and treatment was well tolerated, and on the basis of response and duration of response, the FDA-approved atezolizumab in the second-line platinum-refractory setting.

Nivolumab was tested in CheckMate-275, which was a similarly designed trial of 270 patients with advanced urothelial cancer who were platinum-refractory and who received nivolumab at 3 mg/kg every 2 weeks until disease progression. In that trial, the response rate was 19%, and similar to what was observed with the atezolizumab study, responses were durable. Coupled with the safety, the FDA also approved nivolumab as second-line treatment and accelerated approval in advanced bladder cancer.

Durvalumab was tested in a phase I trial called Study 1108. This trial was a fairly large trial that enrolled over 1000 patients and that focused on 15 different tumor types. However, there was a specific cohort dedicated to platinum-treated patients with advanced bladder cancer and it enrolled roughly 100 patients. And in this trial, we observed an objective response rate of 20%. And using the biomarker cutoff of 25% PD-L1 staining in tumor cells or immune cells, we found that these patients were enriched for responses. And roughly 31% of patients who had high levels of PD-L1 expression responded to treatment, whereas approximately 5% of patients who had low PD-L1 levels responded to treatment. On the basis of these responses and durability of responses, again, similar to what we observed of other agents in this class, the FDA granted accelerated approval for durvalumab in the second-line setting. And in this instance, patients were treated with durvalumab at 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity.

Avelumab was evaluated also in a large phase I trial called the JAVELIN study, that enrolled roughly 44 patients with advanced bladder cancer who had previously progressed on platinum-based chemotherapy, although a few patients who were treatment-naïve in the first-line setting were also enrolled. And in this particular trial, we saw roughly about 18% response rate for avelumab, and also similarly a duration of response that was similar to other agents in this class.

Patients who had high levels of PD-L1 were more likely to respond to therapy. And on the basis of the response, duration of response, and safety observed with durvalumab, the FDA granted accelerated approval for avelumab in a second-line setting in platinum-pretreated metastatic urothelial cancer.

Pembrolizumab was granted full approval by the FDA on the basis of KEYNOTE-045, which tested pembrolizumab versus standard of care chemotherapy in roughly 542 patients in the United States as well as globally. And in this particular trial what we observed was that for pembrolizumab, the response rate was 21% versus chemotherapy, which was approximately 11%. However, there was a significant benefit in terms of survival, which was a primary endpoint with a hazard ratio of 0.73.

Interestingly, patients who had PD-L1 overexpression in that particular study did not enrich for responses. And in fact, the response rate for patients who had high levels of PD-L1 was 21%, which was similar to the entire study population.

Transcript Edited for Clarity