Sharma Stresses Importance of Refining Immunotherapy in GU Cancers

Padmanee Sharma, MD, PhD

Immunotherapy has demonstrated encouraging data in some genitourinary (GU) cancers, but there is still much work left to make it a “pillar” of cancer treatment in this space, said Padmanee Sharma, MD, PhD.

For example, more effective biomarkers predictive of patient response to immunotherapy can be developed. Better education of community oncologists in how to treat immune-related adverse events (irAEs) is also necessary, added Sharma, a professor of Immunology in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center.

Updated data from the open-label, single-arm CheckMate-275 trial indicate that immunotherapy continues to play a role in urothelial carcinoma. After a median follow-up of 2 years, nivolumab (Opdivo) continued to show durable efficacy in patients with advanced platinum-resistant disease. Median progression-free and overall survival (OS) were 1.9 months and 8.6 months, respectively. The OS benefit was observed across all levels of PD-L1 expression, according to data presented at the 2018 AACR Annual Meeting.

The 1- and 2-year OS rates were 40.3% and 29.4%, respectively. The overall response rate was 20.4% for all treated patients (n = 270). Of the responders (n = 55), 54.5% had a duration of response ≥1 year. Common treatment-related adverse events (AEs) included fatigue (18.1%), diarrhea (12.2%), and pruritus (11.5%).

OncLive: What is the state of immunotherapy in GU cancers?

In an interview with OncLive, Sharma shared insight on the current state of immunotherapy in the treatment of patients with GU cancers.Sharma: [Immunotherapy] should be one of the major arms of treatment that you can use. The next step is how to make it better. Immunotherapy has been FDA approved for other tumor types like melanoma, head and neck cancer, lung cancer, bladder cancer, and kidney cancer. We need it to work in multiple tumor types in terms of GU cancers. Right now, it's not working in prostate cancer, pancreatic cancer, ovarian cancer, and some others.

What is the biggest takeaway message about the ongoing immunotherapy research in GU cancer?

You provided a safety and efficacy update to CheckMate-275 at the 2018 AACR Annual Meeting. Can you shed light on that?

Could single-agent immunotherapy be superior to combinations in urothelial carcinoma?

What is the most important message from these updates?

What are some things to look out for when treating patients with PD-1/PD-L1 inhibitors?

How do we improve on this with combination therapy? What are some rational combinations? Next, what do we look for in patient samples to tell us if this treatment will work? These are some important questions. There are multiple immune checkpoints beyond PD-1, PD-L1, and CTLA-4. We have not explored all of them yet. They are very dynamic in their expression because the immune response is a dynamic thing and it changes over time. Therefore, we need to look at the dynamic expression in these targets, and then make decisions about how to use them in a therapeutic strategy. The data still show that after following patients for a longer period of time, we still see the survival benefit we initially reported, as well as the tolerability. There is a great safety profile. The new part that we're adding is biomarker data to show that there may not be a single biomarker to help predict response; it might be composite biomarkers. We're looking at this data set to see if we can find a more effective biomarker. Combination therapies will likely become superior to monotherapy. The question is, “Which combinations will be the most effective?” Everybody knows that anti—PD-1/PD-L1 agents are FDA approved in urothelial carcinoma. Now, we need to know if we can combine that with a CTLA-4 inhibitor or different agent. Perhaps it could be chemotherapy? We'll have to wait and see what results we get. Immunotherapy should be the primary pillar in the treatment of patients with metastatic cancers. Even though you may not have a lot of experience with it yet because it is a new treatment paradigm, there is a lot of information out there about how to properly utilize it. Managing toxicities is also important to understand. It worries community oncologists and we need to make sure we educate them. When you're using anti—PD-1/PD-L1 agents, you need to think about the irAEs. Even though we're generating an immune response against the cancer, we're generating a response that could attack normal cells, too. You need to consider inflammatory conditions, such as colitis and dermatitis. Changes in hormone levels can occur, too. If we're at least aware of these possibilities and check for them frequently, then we can treat these events at an earlier stage before they become debilitating for patients.

We're just at the tip of the iceberg with immunotherapy as a whole. We have a lot of work left to do. As a community, we can certainly get there. There are even bigger things on the horizon that we can accomplish.

Sharma P, Baron A, Necchi A, et al. Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: efficacy and safety update and association between biomarkers and overall survival in CheckMate 275. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT178.