Dreicer Discusses Pivotal Trial, Excitement With Atezolizumab in mUC

Robert Dreicer, MD

If approved by the FDA for the treatment of patients with metastatic urothelial carcinoma (mUC), the PD-L1 inhibitor atezolizumab would shift the treatment landscape in the disease overnight, according to Robert Dreicer, MD.

Atezolizumab was granted a priority review by the FDA in March 2016, based on promising phase II findings from the IMvigor 210 trial, in which atezolizumab demonstrated an overall response rate of 15% in patients with locally advanced or metastatic disease. The FDA will make its approval decision by September 12, 2016.

“Basically, what you have is a therapeutic in a disease that hasn’t seen an approved drug since the mid-1990s in the United States, where you have unequivocal activity with reasonably good safety and, in those patients who respond, some of those responses are very durable,” says Dreicer. “That is a pretty compelling story in a disease that has not had any developments in therapy for 20-plus years.”

OncLive: Can you provide an overview of the IMvigor 210 study?

In an interview with OncLive, Dreicer, professor, Division of Hematology/Oncology, University of Virginia Health System, provides insight on the IMvigor 210 study and how atezolizumab will dramatically change the treatment paradigm for patients with metastatic urothelial carcinoma, who have a severe unmet need.Dreicer: This was a large phase II clinical trial with 2 cohorts. The cohort presented at the 2016 AUA Annual Meeting was “cohort 2,” which consists of platinum-refractory patients with locally advanced or metastatic disease. All patients received atezolizumab intravenously at the same dosing schedule every 3 weeks. The primary endpoint of the trial was objective response, while secondary endpoints were progression-free survival, overall survival, safety, etc.

What is the significance of the reported findings?

“Cohort 1,” which will be presented at the 2016 ASCO Annual Meeting, consisted of patients who were not fit for platinum-based therapy upfront. It’s a small number of patients, and that data are not yet in the public domain, so there is not yet much to say about it.There is unequivocal activity of an anti—PD-L1 monoclonal antibody in heavily pretreated patients with mUC. There is no question that those patients respond.

Seeing as there were responses regardless of PD-L1 expression, what does this mean for using PD-L1 as a biomarker?

Although there was more activity in patients who more heavily expressed PD-L1 in their tumors, there was still activity and responses seen in patients who did not harbor any PD-L1 expression. Therefore, there is a range of activity in those patients who responded. Many of the responses were very durable and lasted many months.The reality is that, in many solid tumors that we’re treating, we have a little bit of sudden diversity. In the findings that led to the approval of nivolumab (Opdivo) in kidney cancer, PD-L1 was not predictive of response. However, in lung cancer and urothelial carcinoma, there seems to be more activity in higher expressing PD-L1 tumors.

Atezolizumab has been granted a priority review. What impact will an FDA approval have on the treatment landscape?

I think that immunologists will be the first to tell us that we don’t really know what the appropriate assay is—whether we’re looking at tumor-infiltrating cells, stromal cells, etc. We don’t know whether or not these will change over time. The biomarker is as we describe it, based on how the trial was done, but how to use it going forward is unclear. There is a lot to learn.Given that bladder cancer is one of the last solid tumors that have a really amazingly unmet need, this will, overnight, change the management paradigm.

What toxicities are associated with atezolizumab that oncologists should be aware of?

What questions still remain with atezolizumab?

Frontline therapy with platinum-based therapy remains, but if atezolizumab is approved in this space, it basically becomes the de facto standard of care the day it is approved.Like all checkpoint inhibitors, there are a small number of immune-mediated things such as pneumonitis, colitis, etc. The incidence in this trial was really in the 1% to 2% range. The most common side effects are fatigue, gastrointestinal toxicities, low-grade nausea, and decreased appetite. The safety profile here is similar to other checkpoint inhibitors, nothing that stands out, per se.There is an enormous amount of things that we don’t know. We don’t who should be optimally treated. This drug and other checkpoint inhibitors are in trials across the disease spectrum in urothelial carcinoma—from non-muscle invasive to upfront to salvage to adjuvant—so we’re going to get much more of an understanding about where the drug fits in as things evolve. Who is the optimal patient to treat? What is the optimal duration of therapy?

There are some intriguing issues with mutational load in this disease and response, perhaps, to PD-L1 therapy. The fact is there is enough activity for me to believe that there is rationale for it to be approved. Therefore, if the FDA agrees, hopefully we’ll have new therapies come on aboard, and then we have a lot of work yet to do.

Do you envision atezolizumab being combined with other agents?

Even though one-third of patients respond—which is nice, and some of it is durable—that means two-thirds of patients are not responding. We need to figure out how we might leverage this drug with other therapies to carve into that larger group of patients who are not benefitting.There is no question that there is work ongoing in combination with chemotherapy. There will be work done in terms of combinatorial immunomodulatory therapies. Clearly, that is an important strategy, given the fact that there is a checkpoint inhibitor that’s already showing dramatic activity.

Aside from atezolizumab, what other ongoing studies are looking at immunotherapy in this space?

What have been some of the major challenges in finding effective agents for this disease?

How can we leverage that by better understanding the whole checkpoint pathway? All of those things are ongoing. I am not sure that I’m more excited with one over the other; I’m just kind of excited over the fact that there is this drug that we can begin to build on.Other anti—PD-1/PD-L1 agents are immersed in clinical trials. All of those studies are important. We will get readouts on some of them over the next year or 2, so I am very interested in that. There are next-generation checkpoint inhibitors that are sort of working their way through the phase I paradigm. How could those have an impact, and will they be more active? All of those questions remain. However, it is a pretty exciting time in this disease, as well in oncology, in general.In the 1980s and 1990s, when cisplatin was broadly introduced in the management of this disease, there was a lot of excitement. There clearly was antitumor activity and we were seeing a small number of patients cured with nodal metastases.

In the 1980s, 1990s, and the first part of the 2000s, there were a multitude of chemotherapeutics tested. Many chemotherapy drugs have some level of activity in the disease in terms of objective responses, but none of them translated into anything meaningful.

For the last 5 to 10 years, frankly, we ran out of novel agents. Unfortunately, TKIs were tested in urothelial carcinoma but did not have significant activity. We were not getting anywhere. Even diseases that were felt to be horrendous, such as melanoma, suddenly had the development of novel therapeutics—molecularly targeted therapies, immunotherapies—it was a paradigm shift in management.

That had not yet occurred in urothelial carcinoma, so that is a really long dry spell in a disease that’s already compromised, in the sense that it is an older patient population who already carry comorbidities, have a higher degree of renal insufficiency, etc. It really became a difficult group of patients to take care of. That is why the enthusiasm for this therapy is so high, given the dramatic unmet need that we have been working with.

Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909—1920.