Amid Explosion of Novel Agents, Chemo Could Still Have Curative Role in Urothelial Carcinoma

Dean Bajorin, MD

Even with 1 FDA approval of an immunotherapeutic agent in urothelial carcinoma—and more expected in the coming months—chemotherapy regimens will continue to play a pivotal part in the treatment of patients with this disease.

Dean Bajorin, MD, professor of Medicine, Memorial Sloan Kettering Cancer Center, discussed the evolving role of cytoxic therapies in bladder cancer in a lecture during the 2016 OncLive State of the Science Summit on Genitourinary Cancers.

“We do know that this is still a curable disease, and that chemotherapy is the mainstay of therapy,” Bajorin says. “Cisplatin is critically important with regard to that type of long-term survival. That has not been replaced with some of the newer drugs that we’re all excited about.”

OncLive: What were the highlights of your presentation at this meeting?

In an interview, he discusses the ongoing studies exploring new chemotherapy approaches in these patients and how the cytotoxic treatments could still ultimately be replaced with immuno-oncology agents.Bajorin: Historically, bladder cancer has been treated with chemotherapy in metastatic and muscle-invasive disease. In the metastatic setting, there are 2 standards we know of in terms of chemotherapy. For the patients who are somewhat fit, in good physical condition, and have good renal function, cisplatin-based therapy is the standard of care. There are 2 available: 1 is the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen and the other is the gemcitabine and cisplatin regimen. Both are considered interchangeable with regard to first-line therapy.

Then, there is the patient population that is frailer. This is a disease that happens in the older patient; their kidney function can be compromised and cisplatin is not possible in many of those patients. Therefore, carboplatin-based therapy has been the mainstay of therapy. There have been randomized trials of carboplatin plus gemcitabine showing it as the best tolerated therapy and, in some patients, it can have a substantial benefit.

The sobering aspect of the carboplatin-based studies is that the median survival is still quote poor. We really need to work on that group as well in terms of innovative therapy. The other aspect is that, even in the patients who have stage II or III muscle-invasive disease, the likelihood of death is still extremely high.

What are we seeing in terms of newer data?

All of us know the use of chemotherapy before or after surgery should be a strong consideration. Chemotherapy combined with surgery can, in part, be a survival advantage. Some of the innovations we are seeing are to give chemotherapy in a short period of time at 6 to 8 weeks. Data show that it can still result in a proven benefit, in terms of down-staging a tumor and affecting long-term survival.Some of the newer data that we are looking at now is trying to identify which patients are likely to respond to chemotherapy. It is trying to identify mutations in DNA damage-repair genes that really confer a high degree of sensitivity to this chemotherapy.

In fact, some data from our center looking at DNA damage-repair genes show that patients who get chemotherapy can have an extraordinary response to chemotherapy. When we do surgery, we actually find very little in the way of the tumor and, sometimes, no tumor at all. Now, there is a movement to identify the patients who have exquisite sensitivity to chemotherapy. You might be able to cure them with just 12 weeks of chemotherapy alone and not have to do surgery. Those studies are ongoing.

The second set of data focuses on the newer drugs. However, the fact of the matter is, immunotherapy still only works in a subset of patients. We really need to identify new drugs and approaches in these patients—and that’s where we get into targeted therapy. There are several targets that are quite viable in this patient population.

The first we are seeing is the FGFR3 mutation, and there are several drugs active in this space. Studies show that up to one-third of patients’ disease is resistant to chemotherapy. Then, they receive a targeted agent, and they can have a major response to just an oral targeted drug. Those studies are ongoing and we are looking forward to how they play out over time.

What we do know is that those patients have also been sequenced simultaneously; this disease has a high degree of co-mutation rate. This means that the tumors don’t have 1 mutation; they have multiple that make it difficult to determine which ones are actually the functional mutations we can target. Other mutations that we are looking at are those active in other diseases, such as in breast cancer or lung cancer. Those can be targeted with oral tyrosine kinase inhibitors (TKIs), too. Those studies are also ongoing. Hopefully, within the next year or so, we will be able to identify 1 or more of these targets to be pertinent to this population and possibly treat patients with TKI therapy moving forward.

What factors are currently considered when selecting therapies?

It is an exciting time period; we have new drugs other than the immunotherapy drugs. We have dissected the biology a little bit better to identify sensitivity to new drugs. On 1 end of the spectrum, we might be able to cure early-stage disease with chemotherapy. On the other end, we might be able to identify those patients who would respond to targeted drugs and immunotherapy drugs.In terms of early-stage patients, it is clear that chemotherapy is the standard of care prior to surgery. Many of those patients, however, are not candidates for the standard cisplatin-based therapy. We really need improvements in those patients. The patients with poor performance status and poor renal function will get surgery alone or radiation therapy alone. There will be efforts there to look at immunotherapy targets.

In the patients who can tolerate cisplatin, there are efforts underway to identify targets that might be sensitive or may confer sensitivity to chemotherapy. There is even a study underway looking at gene signatures to identify whether the tumor might be more sensitive to the MVAC regimen or the gemcitabine/cisplatin regimen. That study is ongoing and we will have information within 1 to 2 years.

Does immunotherapy have the potential to be the new standard of care?

We can identify signatures or mutations to pick out the right patients who require sequencing to identify which ones will benefit. However, with immunotherapy, we don’t have good signatures. We hear a lot about PD-L1 expression, but it really is not a good marker. In terms of targeted therapy, the biomarkers are better. However, we have not systemically studied the co-mutation rate to identify mechanisms of resistance.At the present time, the standard is chemotherapy alone, but this is going to change extraordinarily rapidly. If we take a look at the studies that have been designed, they are trying to test whether immunotherapy as first-line therapy in patients not treated with chemotherapy may be the approach.

What are the most important takeaways for community oncologists?

There are multiple trials comparing immunotherapy, immunotherapy plus chemotherapy, and now immunotherapy as single agents and in combination. These trials are accruing rapidly. Over the next 1 to 2 years, we could see a wholesale replacement of chemotherapy with immunotherapy as first-line therapy in selected populations of patients. That will happen in the patients who have been pretreated with chemotherapy—as seen with the atezolizumab (Tecentriq) approval. Pembrolizumab (Keytruda) now is being discussed in comparison with chemotherapy. Also for first-line treatment, studies are looking at immunotherapy plus chemotherapy in both cisplatin-tolerant and intolerant patient populations.It is a revolution. For the community oncologist, you will have new drugs available to you immediately for patients whose diseases progressed, despite prior chemotherapy. Very shortly, [they will have them] in the first-line setting, provided these studies prove to be beneficial.

Secondly, we will be looking at a whole new set of toxicities we have to learn how to manage. Instead of nausea, vomiting, and renal insufficiency, we will be looking at autoimmune effects.

Third, we are reaching the era in which patients—when they walk through the door—are going to need next-generation sequencing to identify whether they have targets amenable to intervention with TKIs for example—or mismatch-repair genes or DNA damage-repair genes—and exploit those with regard to chemotherapy. We won’t see a one-size-fits-all approach, which is what we have now. We will really be discriminating with regard to the tumor and each individual patient. Hopefully, in a short period of time, we will be identifying those who will be best off with immunotherapy versus those who we might choose targeted therapy.