Arjun V. Balar, MD, discusses the phase II data demonstrating the efficacy of atezolizumab as a single agent, its potential as part of combination regimens, and planned clinical trials looking at immunotherapy in patients with metastatic bladder cancer.
Arjun V. Balar, MD
The PD-L1 antibody atezolizumab is demonstrating practice-changing promise in the field of metastatic bladder cancer, both as a single agent and in combination with chemotherapy and other immunotherapy agents, explains Arjun V. Balar, MD.
In the phase II IMvigor 210 trial, second-line treatment with atezolizumab demonstrated significant clinical benefit in patients with metastatic urothelial carcinoma who had a poor prognosis after progressing following platinum-based chemotherapy.
Results of the study, which included data from 311 patients and were evaluated according to the degree of PD-L1 expression on immune cells and on all comers, showed that significant overall response rate (ORR) improvements were seen across all groups, with rates increasing with higher PD-L1 expression. ORR by RECIST 1.1 was 15% (P = .0058) in all comers, 18% (P = .0004) at the IC1/2/3 level (any PD-L1 expression), and 27% (P = .0001) in the IC2/3 subgroup with PD-L1 expression ≥5%.
The FDA granted atezolizumab a breakthrough therapy designation in 2014 for patients with metastatic urothelial carcinoma whose tumor expresses PD-L1.
Aside from the exciting phase II data, additional studies are examining the PD-L1 antibody combined with chemotherapy in localized bladder cancer, as well as in combination with bevacizumab (Avastin) as a treatment for metastatic disease.
In an interview with OncLive, Balar, an assistant professor in the Department of Medicine and coleader of the Genitourinary Cancers Program at NYU Langone Medical Center (NYULMC), discusses the phase II data demonstrating the efficacy of atezolizumab as a single agent, its potential as part of combination regimens, and planned clinical trials looking at immunotherapy in patients with metastatic bladder cancer.Balar: In the field of metastatic bladder cancer, we’re doing a number of clinical trials that are really focusing on novel targeted therapies, as well as immunotherapies—as single agents and in combination. In particular, our current focus at NYU is to look at the activity of immune checkpoint inhibitors in metastatic bladder cancer.
This first began with single-agent studies in a phase II trial with atezolizumab, which is an anti—PD-L1 antibody, which first aimed to see if this drug was active and safe in a cohort of patients who previously progressed on chemotherapy. That trial also enrolled a number of patients who are chemotherapy-naïve.
Since that time, other immune checkpoint inhibitors have also been tested in bladder cancer. These include pembrolizumab (Keytruda), which is an anti—PD-1 antibody. It has been tested in the second-line setting as well as in the first-line setting. The preliminary evidence, both from the phase I and phase II atezolizumab studies, demonstrate that the drug is very active and extremely well tolerated, leading to durable responses.One of the interests in the bladder cancer community is to see if the activity we are seeing in the second-line setting with PD-1/PD-L1 blocking antibodies are also active in the localized disease setting.
While we recognize that the therapies are very active in the second-line setting, only approximately 15% of patients are destined to respond. This means that we need to find more effective ways of finding the other 85% who are not responding to this type of therapy.
With this in mind, we at NYULMC developed a phase II trial that is going to build upon standard therapy in muscle-invasive bladder cancer. The current standard of care for muscle-invasive bladder cancer includes a surgery in which the entire bladder is removed. What we have learned, however, is that half of all patients will not be eligible for such an aggressive approach. We treat those patients with radiation therapy with low doses of radiosensitizing chemotherapy.
We have also learned that the radiation in chemotherapy can actually be immunogenic, in the sense that it may lead to release of neoantigens, T-cell priming, and an increased trafficking of T cells into the tumor, and that might actually promote the development of antitumor immunity.
With those 2 principles in mind, we developed a phase II clinical trial that is going to use standard chemotherapy and radiation, and add a PD-1 antibody to it, to see if we can make it more effective.
This is a very novel clinical trial that were leading here at NYULMC. We’re aiming to enroll about 55 patients and it is expected to open in early March 2016. We’ll be leading the trial and enrolling it at 4 other centers, including Memorial Sloan Kettering Cancer Center (MSKCC), University of Chicago Medicine, University of Michigan Health System, and University of North Carolina at Chapel Hill.From phase I and phase II clinical trial experience, we have learned that therapy with atezolizumab is very active and extremely well tolerated. For the patients who do respond, their responses are very durable. Time will tell how durable these responses are. It seems to be a very active therapy in a subset of patients.
The challenge is to determine what setting and which patients should get this type of therapy. To put things into perspective, chemotherapy is associated with a 20% to 30% grade 3/4 toxicity rate. With this class of therapy—and immune checkpoint inhibitors in general—that toxicity rate is far lower, between 10% and 15%. We know that, in this elderly patient population, a very well-tolerated treatment is highly desirable.
PD-L1 overexpression and immune-infiltrating cells seem to correlate with response. In the patients who had overexpressed PD-L1, approximately 26% responded to atezolizumab. In patients who did not overexpress PD-L1, that number was 10%. One could imagine that we could use PD-L1 staining as a biomarker for selection of patients to receive this type of therapy. However, that is challenging because patients who don’t overexpress don’t necessarily not respond. Even if you don’t overexpress the PD-L1 protein, that doesn’t mean that you won’t benefit from the therapy.
The summary of the data to date tell us that all patients in the second-line setting should probably get at least one opportunity to receive atezolizumab therapy.That data has not yet been presented. We will be presenting that data at the 2016 ASCO Annual Meeting in June. One of the main questions is, “Is there a subset of patients who never need to receive chemotherapy as their first-line therapy and, in fact, can only be treated with atezolizumab as a single agent?”
This is a very enticing idea because of how well the therapy is tolerated and the durability of responses, but we’ll need to see that data to be sure.Moving forward, we need to determine which combination strategies make the most sense. In melanoma, we have learned that blocking additional immune checkpoints, namely CTLA-4, and adding that to a PD-1/PD-L1 antibody seems to have synergistic effects. That same concept is now being tested in a variety of solid tumor malignancies, notably in bladder cancer.
There are phase I trials being led by Bristol-Myers Squibb, as well as by MedImmune and AstraZeneca, to see if we can combine those 2 types of therapies safely, and to see how much better the immune responses are in that particular setting.
Additionally, we will also be looking at therapies that block VEGF, since we have learned that VEGF is very important in maturation of immune progenitive cells. Inhibitor of VEGF can actually promote the development of dendritic cells and other immune populations that are important in anti-tumor immunity. When we combine that with a PD-1 blocking antibody, then we might see added effects between the two drugs.
It appears now that when bevacizumab, which is a VEGF inhibitor, is added to atezolizumab, the activity seems to be quite promising, at least in advanced renal cell cancers. The next question now is to see if that same combination strategy is effective in breast cancer and bladder cancer, as well.
There is another trial that NYU, along with MSKCC, will be leading. This is a phase II randomized trial of atezolizumab with or without bevacizumab in the frontline setting for patients who are chemotherapy-naïve and ineligible for cisplatin with metastatic bladder cancer. It is to test that very concept that inhibiting VEGF can block the immunosuppression that VEGF promotes.
Our goal in developing this trial is to see if the combination improves the 1-year overall survival rate as compared with atezolizumab alone. This trial is currently in development and we hope to have it open by the end of this year.