Additional Research Required for Immunotherapy to Replace Chemo in Upfront Bladder Cancer Care

Gopa Iyer, MD

Immunotherapy may be having a moment in the changing landscape of bladder cancer, but expert Gopa Iyer, MD, advises that there is much research to be done before physicians replace chemotherapy with these agents upfront.

The PD-L1 inhibitor atezolizumab (Tecentriq) is FDA-approved for use in patients who progress on cisplatin-based chemotherapy, while clinical trials of the anti—PD-1 agents nivolumab (Opdivo) and pembrolizumab (Keytruda) are both showing promise in the second-line setting, as well. However, first-line trials are already being conducted to evaluate the efficacy of these therapies upfront.

For example, the multicenter, open-label, randomized phase III IMvigor 130 trial is investigating atezolizumab in combination with gemcitabine plus carboplatin versus the chemotherapy regimen alone in untreated patients with locally advanced or metastatic urothelial cancer and are ineligible to receive cisplatin-based therapy (NCT02807636).

OncLive: The field of bladder cancer has certainly evolved in recent months. What are your thoughts on these advances?

In a panel discussion during the 2016 OncLive State of the Science Summit on Genitourinary Cancers, Iyer, an assistant attending physician at Memorial Sloan Kettering Cancer Center, discussed the standard chemotherapy options available for patients with bladder cancer, the ongoing progress with immunotherapy, and the management of immune-related toxicities. Iyer expanded on these topics, including potential frontline therapeutic possibilities, in an interview during the event.Iyer: For the last 20 years or so, treatment has really been chemotherapy with cisplatin in combination with a number of other chemotherapy agents. While these treatments resulted in responses in a little over 50% of patients, most of these patients will relapse. When we try to give chemotherapy in the second-line setting, the responses are only about 10% to 15%.

There has been a real sea change in the last 6 to 8 months or so with the FDA approval of atezolizumab in patients with metastatic bladder cancer whose disease has already progressed on chemotherapy.

What toxicities are commonly observed?

Aside from side effects, what else should community physicians know about treating patients with these agents?

There are standard chemotherapy options available for patients, and we also need to determine when to use immunotherapy in these patients and how to deal with some of the toxicities with immunotherapy.The toxicities that most people are recognizing with immunotherapy have been the inflammatory or autoimmune toxicities that some patients are experiencing, such as pneumonitis, hepatitis, and colitis. Most of the time, the treatments for these toxicities have been to hold the drug initially and to treat with a course of steroids—such as prednisone therapy—to quiet the immune system and reduce the inflammation that is going on.One of the main advantages of immunotherapy has been, when patients do respond, a real durability of response. Although the overall response rates to immunotherapy have not been all that impressive—between 15% and 24% of patients who will have a response—studies are starting to show that probably between 70% to more than 80% of those patients are responding up to 1 year out while they’re on treatment. That really speaks to the durability of response from immunotherapy, but also the tolerability of the treatment.

However, 1 of the things we do see early on in a small percentage of patients is what looks like progression of disease on the first scan that patients have performed while they are on the treatment.

For example, after 3 treatments with atezolizumab, we will check a scan and sometimes it will show that the lesions—the metastatic sites—have grown in size. However, the patents seem to be clinically benefiting from the treatment. They are feeling better, gaining weight, and have better appetite and energy levels. What we think is happening in those cases is pseudoprogression; when we see an increase in these lesions, it is actually the immune cells starting to infiltrate the tumor and attack them. Many of these patients actually will continue on treatment despite what the imaging studies may show, as long as they’re gaining clinical benefit from treatment.

Frequently, what we will see on the second scan after another 3 treatments is that things are stating to shrink again and hopefully will continue to do so. The other thing that is important to keep in mind is recognizing the toxicities early when they do happen. With colitis, patients will often present with diarrhea as the real presenting symptom for that.

With the explosion of immunotherapy agents being studied in this field and moving through the pipeline, what do you predict for the future landscape?

With some of the other immunotherapy agents, that may not be the immediate side effect that happens early on—it can be delayed after a number of treatments. Just keeping an eye on those toxicities is essential so that we can quickly manage them and prevent long-term damage to the tissues.There are probably a few different paths that this is going to take. We are going to see FDA approvals of the monotherapies; right now, we have atezolizumab, and nivolumab will likely get approved, as well. The trials that have been completed and published thus far have been all for patients who have already progressed on chemotherapy.

What will happen is that some of the trials will shift their focus to the frontline setting, primarily in patients who can’t tolerate or are unable to get cisplatin-based chemotherapy because of their performance status or underlying renal function. It would just be too toxic for them to obtain cisplatin. Those patients are usually then on a carboplatin-based regimen, which is less effective than cisplatin and unlikely to result in long-term cures. In that setting, immunotherapy will play a huge role in the cisplatin-ineligible patients.

Will chemotherapy still have a role for these patients?

Another focus will likely be combining immunotherapies with chemotherapy. We don’t have great safety data yet on what that combination looks like in bladder cancer, so it will likely take a little bit of time but that will be another focus. If the safety, dose, and schedule are established in the metastatic setting, then we might actually move to the neoadjuvant setting when patients have muscle-invasive bladder cancer that is not yet metastatic. Those patients usually receive a course of chemotherapy followed by surgical radical cystectomy, so we might actually incorporate that therapy into that setting.For the next 5 to 10 years, I would not be surprised if chemotherapy still has a significant role. Right now, the standard of care is still cisplatin—both in the neoadjuvant and metastatic settings—and that is going to be a higher bar to replace completely with immunotherapy.

Where are we currently with biomarker development?

The other possibility that’s starting to be explored is that, when patients become resistant or stop responding to immunotherapy, are there combinations of immunotherapy agents that might be able to be used? An example is nivolumab combined with another class of agents, such as OX40 inhibitors. Whether or not combination immunotherapy may replace chemotherapy altogether I suppose is a possibility, but there is still a lot of work to be done.Biomarkers in immunotherapy are a huge topic being explored right now. What we can say from the atezolizumab studies so far is that the intensity of PD-L1 expression seems to correlate with response. Most of the responders seem to be enriched with tumors that are PD-L1—positive, but there are many issues with that because we still have seen patients have complete responses that have no PD-L1 expression at all. Clearly, it is not a “black and white” biomarker. As of now, we don’t have a predictive biomarker for immunotherapy but that is where a lot of research is taking us.

For targeted therapy, there are a lot of actionable alterations in bladder cancer; there are mutations with genes such as FGF3 or PEG3. There are a lot of agents being developed in other cancer types for similar alterations. We will need to definitely test those more in bladder cancer.

I suspect that 1 major limitation with targeted therapy in bladder cancer is that overall mutational burden is actually quite high. Therefore, it is unlikely that any single targeted therapy will work effectively in most patients with bladder cancer. It will likely require combination treatment with multiple targeted agents and then the possibility of combining targeted therapy with immunotherapy, as well.