Early Immunotherapy Data: 8 Questions With a Bladder Cancer Expert

The FDA granted the PD-L1 inhibitor Tecentriq an accelerated approval in May 2016 as a treatment for patients with locally advanced or metastatic urothelial carcinoma, following encouraging results of the phase 2 IMvigor 210 study.
BY Gina Columbus
PUBLISHED July 19, 2016
The FDA granted the PD-L1 inhibitor Tecentriq (atezolizumab) an accelerated approval in May 2016 as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC), following encouraging results of the phase 2 IMvigor 210 study. The indication is for patients whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

“It is a new paradigm,” explains Peter O’Donnell. “Now, for patients in the postchemotherapy setting, we have another standard of care in an area where there really hadn’t been a second-line standard of care for decades.”

O’Donnell, an assistant professor of Medicine at the University of Chicago Medicine, discussed these findings and more in an interview with CURE.

What should community oncologists understand about the advancements in refractory metastatic bladder cancer?

It has been decades since we have really had any new therapies in the United States for metastatic bladder cancer. The past few years have been so exciting with the onset of these immunotherapy drugs in clinical trials, and now with the approval of Tecentriq for patients with platinum-refractory metastatic disease.

Immunotherapy is going to be paradigm changing; there is no doubt about that. Any of us who have used these drugs to treat patients with urothelial cancer know that, when it works, it is dramatic. It is not subtle when these patients begin responding, even in the first few weeks that they are on the drugs.

Then, what is really remarkable is the durable response in many patients, where they are living beyond one year in the post-platinum setting, which is just unheard of for this disease. There is not only clinical benefit for patients, but also a real disease-altering type of effect.

You were very much involved with the IMvigor study. Can you shed some light on that trial and discuss the significant findings?

It is a study of over 300 patients who were all treated with prior platinum-based therapy in the metastatic setting. All patients received Tecentriq once every three weeks as part of the schedule. What is notable from it is that, not only does it seem to really move the needle from what we would expect from a survival standpoint in patients that expressed PD-L1 specifically, but it also worked in a number of patients.

It passed the primary endpoint of the study as far as response rate, and the therapy was quite tolerable. Something that we are all familiar with is that patients are clambering to try to get these immunotherapies because they are even aware that, compared with chemotherapy, these drugs are really well tolerated. There is this 15 percent rate of grade 3 and 4 adverse events, but that is really acceptable compared with other therapies that we use for metastatic cancer.

What are some of those treatment-related adverse events? How do you best manage them?

The ones that really caught attention are these immune-related adverse events, which happen in 5 percent of patients at the grade 3 and 4 levels, so those are severe ones that we really need to be concerned about. It was a small number, but still notable. I have had patients who have had these severe, immune-related adverse events — pneumonitis, hepatitis, and colitis. One patient even had a case of a myositis where she was not able to even lift her arm above her shoulder; this is very rare, but striking and debilitating to these patients.

The good news is that, when those happen, they are generally manageable — meaning we withdraw the PD-L1 drug, give the patient steroids and, usually, within days, we see resolution or regression of the immune-related adverse events. Unfortunately, in most of these patients with that severe toxicity, it means they are probably not going to get the drug again. That is the hard part because, for a lot of these patients, it is helping them.

How will the FDA approval of Tecentriq impact the treatment landscape?

The use of other cytotoxics, which many oncologists try, really was not changing the landscape. It was not really extending survival in these patients. Now, there is a well-tolerated therapy that is clearly having durable activity — at least in a subset of patients.

It is going to change how we try to evolve to this. It is going to be combining chemotherapy with immunotherapy in the frontline setting. It is going to be moving immunotherapy to the preoperative setting. It is going to be trying to combine targeted drugs with immune-based therapies. This is really going to be the exciting part of how we move forward.

What are some possible combinations with Tecentriq being studied that you are anticipating the results of?

There is a question in the community about whether immunotherapy compared with carboplatin-based therapy in the frontline setting is going to be just as good and better tolerated for patients. These patients are frail, and those who receive carboplatin have several comorbidities. The idea of a well-tolerated therapy that may be just as good is a big question for the field to answer next.

Tecentriq is just one of many immunotherapy agents that are being tried right now. Keytruda (pembrolizumab), which is approved for other cancers, has been reported in multiple abstracts at this point. Durvalumab has received breakthrough designation for urothelial cancer based on phase 1 data. These drugs are going to be coming onto the scene in the near future pending FDA approval.

Then, we have to think beyond that and consider when to use two or more immune therapies together. Certainly, we are doing this in clinical trials right now. Anecdotally, there are patients who are dying before our eyes and go on some of these immunotherapy combinations and just have dramatic response in their tumors. That is going to be a next frontier.

What are some of the biggest challenges that remain in treating this disease?

There are many. Even if these immune-based therapies are changing survival, the majority of patients are still going to die from this disease. Until we solve that, we are not done.

This biggest scientific challenge will be to better understand what we do for patients who do not have PD-L1 expression because, clearly, these therapies are not very active in those patients.

What about combining genomic markers? The Cancer Genome Atlas and other molecular characterization studies that have been done have changed the whole landscape of urothelial cancer. We are now able to learn that urothelial cancer is fragmented into multiple different subtypes of disease based on genomic markers, and so we need to capitalize on that and use genomics in the context of immunotherapy to assess how to use targeted drugs with this therapy. How could we understand which subsets of urothelial cancer are most likely to respond to immune-based therapy, and which ones should perhaps receive targeted therapy or other combinations? There is a lot left to do.

Where do you think we are in terms of biomarker development?

PD-L1 is sort of the biomarker that several individuals are wondering about right now; there are many different assays out there that experts are using. Each drug that has been in development has its own assay that is accompanying that, and there are different cut points as to what we determine as PD-L1–positive. There is a known dynamic nature in patients who are PD-L1–negative turning PD-L1–positive, and vice versa. That is a challenge. Do we biopsy the metastatic site, or, can we use archival primary tissue to determine PD-L1 status? There are many remaining questions there, as well.

Will chemotherapy continue to have a role in this disease as time goes on, or will it slowly fade out?

It will still have a role. It is undeniable that chemotherapy works in the majority of patients. There are many highly symptomatic patients who start chemotherapy, and they get better immediately. Within a week of receiving chemotherapy, symptoms will regress. Pain will immediately get better.

This is an area where I do not think we are going to ever be able to do without chemotherapy because immunotherapy can take longer to work. The response rates for immunotherapy in all-comers are probably lower than they are for chemotherapy. Therefore, for those patients who need immediate activity, cytotoxics still have a very important role. It is still the only class of agents to show the survival advantage from a primary analysis standpoint.
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