Impact of Immune Checkpoint Inhibitors on Advanced Urothelial Carcinoma

Immune checkpoint inhibitors are becoming more common treatments for bladder cancer, with the US Food and Drug Administration (FDA) approving several drugs of this type for use in patients with advanced bladder cancer.

Shilpa Gupta, MD, director of the Genitourinary Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute and co-leader of the Cleveland Clinic Genitourinary Oncology Program, discussed the impact of immune checkpoint inhibitors on care of patients with advanced bladder cancer.

GU Oncology Now: How has the FDA approval of several immune checkpoint inhibitors changed care for patients with advanced bladder cancer?

Dr. Gupta: Prior to the approval of the first checkpoint inhibitor in 2016, we really had nothing for patients who progressed on cisplatin. There was a long void of almost 4 decades where we had nothing following cisplatin or carboplatin-based chemotherapy. Some salvage chemotherapies were used with really dismal responses. Immunotherapy has really transformed the care for our patients. It is a valid option for a good subset of patients. I’ll say about 20% to 25% of patients benefit from it, and when they do benefit, they have long-term good survival outcomes, which has really changed from the past.

However, not all the checkpoint inhibitors pan out eventually. For example, pembrolizumab is the level 1, based on level 1 evidence. It has data from the phase 3 trial showing an overall survival benefit compared with salvage chemotherapy. As far as some of the other agents, avelumab was also approved initially based on the phase 1 trial, atezolizumab was approved, nivolumab was approved. However, durvalumab and atezolizumab were withdrawn in the refractory setting, as the phase 3 trials did not show overall survival benefit. Those were supposed to serve as the confirmatory trials.

I’ll say that the approval of multiple checkpoint inhibitors has certainly added a lot of treatment options. However, as far as level 1 evidence goes, we tend to use pembrolizumab more than anything else.

GU Oncology Now: While immune checkpoint inhibitors can be better tolerated than traditional chemotherapy, response rates can be low. What challenges remain with immune checkpoint inhibitor treatments?

Dr. Gupta: That’s a very good point. The toxicity profile of immune checkpoint inhibitors is completely different from chemotherapy. Patients don’t lose hair. They don’t feel sick. They’re not throwing up. They’re not going through all those toxicities of the chemotherapy. However, because of the nature of the mechanism of action, immune therapy can cause some rare and serious side effects, which can sometimes be fatal, because the immune system is upregulated and can turn against normal cells. You can get inflammation of pretty much any organ, like pneumonitis, colitis, some serious flare-ups of autoimmune diseases. You can get neurologic toxicity, endocrinopathies, skin toxicities.

But the good news is that prompt use of steroids and a good symptom check-in with the patients can address these events. We have to be cognizant that patients tend to under report the side effects with immunotherapy, as opposed to chemotherapy, where everything is very apparent, and they are very vocal about it. So, we really need to make sure we are digging into these questions like, “Do you have severe fatigue, which is unusual?” In which case, we look for adrenal insufficiency, start steroids, and things like that.

I would say that, as the field has evolved and these treatments have become available, we have really evolved as practitioners who can manage these toxicities, and prompt referral to subspecialties is very important to make sure that these events don’t become life threatening.

GU Oncology Now: Any final thoughts?

Dr. Gupta: We have made a lot of progress in the last few years in management of advanced bladder cancer patients, and the field has really exploded with a lot of treatment options. Patients are living longer. They’re doing better. We do have lots of options to offer our patients, and a whole range of new trials that are going on to further challenge the standard-of-care chemotherapy in the frontline.