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.
OncLive: What research have you been focused on involving atezolizumab as both a single agent and in combination for patients with metastatic bladder cancer?
: 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.
What similar trials are looking at localized bladder cancer?
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.