New Treatment Options Offer Hope in Bladder Cancer

Checkpoint inhibitors broke into the treatment landscape for urothelial carcinoma after three decades of minimal progress, giving a new wave hope to patients.

In May 2016, based on the phase 2 IMvigor 210 study, the FDA approved the PD-L1 inhibitor Tecentriq (atezolizumab) as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC) whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

The FDA granted an accelerated approval to the PD-1 inhibitor Opdivo (nivolumab) earlier this month as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy, based on findings from a phase 2 CheckMate-275 study.

Though not yet approved in bladder cancer, the anti—PD-1 agent Keytruda (pembrolizumab) was recently granted priority reviews by the FDA for use as a first- and second-line treatment for patients with locally advanced or metastatic urothelial cancer. The applications for frontline and second-line treatment are based on the KEYNOTE-052 and KEYNOTE-045 studies, respectively.

What trials would you say have had the most significant impact on the research of checkpoint inhibitors in urothelial cancer, and why?

In an interview with CURE, Matthew I. Milowsky, M.D., associate professor in the Department of Medicine, Division of Hematology and Oncology, at UNC-Chapel Hill, discussed advances with checkpoint inhibitors in the treatment paradigm for urothelial cancer, which he recently described in a commentary published in The Lancet Oncology.There are a series of studies that are particularly exciting. A couple are more notable than others because they have led to FDA approvals. The first is the IMvigor 210 cohort study of Tecentriq. The other is the CheckMate-275 Opdivo study, both of which have led to the approval of checkpoint inhibitors in patients with advanced bladder cancer in the post-platinum space.

There’s another study, the KEYNOTE-045 study, which is with the anti-PD-1 agent Keytruda, which is our first study to demonstrate a survival benefit in a prespecified interim analysis for which the trial was stopped. That was presented at SITC 2016 meeting by Joaquim Bellmunt, M.D., Ph.D., and colleagues. That trial was the first randomized phase 3 data versus chemotherapy that demonstrated survival benefit.

Are there any ongoing trials that you are particularly excited to see the results of?

In my opinion, those studies that focused on Tecentriq, Opdivo and Keytruda, are important studies. Keytruda is not yet approved by the FDA but likely will be in the future.We are all excited about the adjuvant trials. These are studies of patients with high-risk features post-surgery who are being treated with checkpoint inhibitors and there are several of them. There is one with Opdivo, one with Tecentriq and one that will be moving forward with Keytruda.

Then there are studies looking at maintenance of immune checkpoint inhibitors. Patients who had undergone four to six cycles of systemic chemotherapy for metastatic disease were then treated with immune checkpoint blockade. Those approaches are interesting.

What combination regimens are being explored?

We have a study here at UNC, that is looking at neoadjuvant Keytruda in combination with chemotherapy prior to radical cystectomy in patients with muscle invasive bladder cancer. In other words, moving from the metastatic advanced disease setting to earlier stages of disease. There were even studies looking in the space of non-muscle invasive bladder cancer. In my opinion it’s important to cover all spaces in the management of patients with urothelial cancer based on the promise that has been seen in the trials of patients with metastatic advanced disease.One that is most noticeable is from the CheckMate-032 study, which was presented by Padmanee Sharma, M.D., Ph.D., and that's Opdivo and Yervoy (ipilimumab), the anti—CTLA-4 agent Yervoy. That…was presented at the ASCO 2016 meeting. That study demonstrated that there was activity for that combination and will likely lead to additional combination approaches as well as novel approaches using new immuno-oncology agents in combination with checkpoint inhibitors.

What would you like to see in the next five to 10 years in this treatment landscape?

Are there any other challenges that still face checkpoint inhibitors in urothelial cancer?

There are also studies that are looking at chemotherapy as well as planned studies with targeted therapies in combination.It's already been an extraordinary time. The development of immuno-oncology in this disease has led to advancements that we haven't seen in the last three decades. Now, we need to learn more about how to best use these drugs. We need to learn what the clinical state is, how we should sequence these agents with chemotherapy or targeted therapies or among drugs within the same class. We also need to learn more about the use of PD-1 versus PD-L1 antibodies as well as the development of novel immuno-oncology drugs that also work mechanistically in a similar way in this patient population.It's quite clear from the data that has been generated that a proportion of patients respond to therapy and those responses are often quite durable. There is obviously a significant number of patients who don't respond. That is the major issue with checkpoint inhibitor therapy. The development of novel combinations and the development of biomarkers to be able to predict those patients who are going to be more or less likely to respond, is going to be critical when looking at the future treatment paradigm.