Latest Progress in Treating Urothelial Carcinoma

In this interview we discuss the latest clinical news in urothelial carcinoma, what we’ve learned about the biology of these tumors, and how treatment of this disease has evolved.

Ahead of the American Society of Clinical Oncology (ASCO) 2017 Genitourinary Cancers Symposium, held February 16–18 in Orlando, Florida, we are speaking with Matthew I. Milowsky, MD, who is the section chief of genitourinary oncology and the co-director of the urologic oncology program at the UNC Lineberger Comprehensive Cancer Center in North Carolina. Dr. Milowsky will give a talk at this years meeting providing an overview of the research and clinical progress in urothelial cancer over the last year.

Cancer Network: First, how would you characterize the clinical news in urothelial carcinoma in the last year or so?

Dr. Milowsky: It’s really been an extraordinary year. After almost 3 decades of little advancement in the field, particularly as related to patients with metastatic disease, the integration of immune checkpoint inhibitors in the management of patients with advanced bladder cancer has really become a theme over the past year and has led to significant improvements in outcomes for patients.

Cancer Network: Can you talk about some of the details of the trials of these agents and also how you see them being used to treat these tumor types?

Dr. Milowsky: There have been many trials that have been conducted over the past year and many are planned. Some of the prominent trials are related to several agents. There was the IMvigor 210 study using the anti–PD-L1 agent atezolizumab, with two cohorts of patients, and the CheckMate 275 study utilizing the anti-PD1 agent nivolumab. Those studies have led to US Food and Drug Administration approval of both atezolizumab and nivolumab in patients with metastatic urothelial cancer who have progressed after platinum-based chemotherapy. There is another study (Keynote 45) using the anti-PD1 agent pembrolizumab, which is the first randomized study that has demonstrated a survival benefit for patients in the post-platinum space, as compared to chemotherapy.

There have been other agents as well. An anti–PD-L1 agent, durvalumab, has also demonstrated some exciting results in patients who were previously treated. There is also some interesting data in patients who are unfit for platinum-based chemotherapy, specifically two studies. One being the IMvigor 210 cohort 1 with atezolizumab, and Keynote 52 with pembrolizumab, demonstrating very promising results in patients who historically have had very poor outcomes with standard chemotherapy.

Cancer Network: What have we learned about the biology of urothelial tumors that could potentially be applied to better strategies for treatment or maybe that are already being applied?

Dr. Milowsky: So we’ve learned quite a bit about the biology of urothelial tumors previously with The Cancer Genome Atlas experience, demonstrating that there are many potential targets for novel therapeutics in urothelial cancer based on genetic alterations that occur within the tumor, and many of those targeted therapeutics are being investigated in the context of clinical trials. There is also rationale for why urothelial cancer appears to be an excellent place to use immune-based therapy. There is a very high mutational burden, going along with other diseases like lung cancer and melanoma that have also demonstrated promising activity with immune checkpoint inhibition.

There are specific subtypes of urothelial cancers that may lend themselves to responding better to immune checkpoint inhibitors. There are RNA subtypes that are similar to the hallmarks of some of the RNA subtypes in breast cancer, specifically the luminal and basal subtypes. And there have also been observations related to DNA damage response gene alterations that appear to confer sensitivity to cisplatin-based chemotherapy, which has been the cornerstone for the management of patients with urothelial cancer over the past several decades. Now we may actually be able to use this type of genetic information to understand who is more or less likely to respond to cisplatin-based chemotherapy.

Cancer Network: Lastly, what in your mind are the big questions to address in the next few years?

Dr. Milowsky: So, it is extraordinarily exciting, as I started out saying, and I think certainly the immune-oncology space is going to hopefully continue to explode over the next several years. I think we will need to understand more about how to sequence these agents, where best to use them, how to combine them with chemotherapy or targeted therapy. Combinations of immune checkpoint inhibitors-a study, CheckMate 32, was presented by Dr. Padmanee Sharma at the Society for Immunotherapy of Cancer (SITC) 2016 meeting that combined nivolumab and the anti-CTLA-4 agent ipilimumab-those sorts of studies are going to be very exciting.

There are also new immuno-oncology agents that are likely to offer benefit in this disease based on some of the previous things that I mentioned about why urothelial cancer may be particularly susceptible to immune-based therapies. This is really unprecedented in terms of the progress that has been made in such a short period of time in the management of patients with a disease that, again, had very little in the way of progress for close to 3 decades.

Cancer Network: Thank you so much for joining us today, Dr. Milowsky.

Dr. Milowsky: It’s a pleasure.