McDermott Shares Insight on Immunotherapy in RCC

David McDermott, MD

Immunotherapy has made an incredible impact on the treatment of patients with metastatic renal cell carcinoma (RCC), and is now beginning to make waves in other settings of the disease.

However, though drugs such as nivolumab (Opdivo) have proven their worth as both a single agent and in combination, immunotherapy is not ideal for every patient with RCC, according to David F. McDermott, MD.

“We need to do a much better job of identifying predictive biomarkers—not just looking at immunohistochemistry, but RNA sequencing, and whole-exome sequencing,” said McDermott, director of the Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center.

McDermott chaired the Immunotherapy of Genitourinary Cancer session during the 2017 SUO Annual Meeting, which covered data on both single-agent immune checkpoint blockade and combination immunotherapy in RCC.

OncLive: Can you please provide an overview of your talk?

Combinations have been very successful in the metastatic setting. Could you comment on some of these combinations?

In an interview with OncLive during the meeting, McDermott shared some of the successes with immunotherapy in RCC and gave his insight on the future treatment of these patients.McDermott: There are a lot of new interesting data in both kidney cancer and bladder cancer for immune-based therapies. We have established that single-agent immune checkpoint blockade with either PD-1/PD-L1 is active in both diseases, and now people are looking at other questions, such as, “How can you overcome resistance to treatment by adding new agents in?” For example, does CTLA-4 in addition to PD-1 add benefit? Does blocking VEGF in addition to blocking PD-1/PD-L1 add benefit? Importantly, how can we figure out which patients should get which combination? This is because most combinations add adverse events and costs, so it is up to us to try to identify who should get which new combination therapy ahead of time.The newest and probably most exciting data come from the CheckMate-214 study, which looked at the combination of PD-1 blockade with nivolumab, and CTLA-4 blockade with ipilimumab (Yervoy), which is FDA approved in melanoma. However, this trial established its role in kidney cancer, particularly in the intermediate- and poor-risk population of patients based on clinical criteria. In that subgroup, patients who received the combination did better in terms of response, had a longer progression-free survival (PFS), and significantly longer overall survival. There was a higher complete response rate at approximately 9%, which is very exciting.

What are your thoughts on nivolumab as a single agent in RCC?

The toxicity is an issue; obviously, with combinations, it can be an issue. There were more treatment-related deaths on the CTLA-4/PD-1 combination of ipilimumab plus nivolumab, but there were actually fewer grade 3/4 toxicities. Approximately 60% of the patients who received this combination required steroids. Therefore, you must educate your team and your patients about managing these side effects. They can be managed, but they pose a challenge. The efficacy data are very exciting. We haven't seen anything like this for frontline treatment and we are looking forward to its potential FDA approval in early 2018.As you know, it is FDA approved for patients who have failed VEGF-targeted therapy in the second-line setting. We have long advocated to try to move it up to the frontline setting because it has a preferable therapeutic index and it has a pretty good toxicity profile for most patients with less than 10% having to come off for toxicity.

[Additionally] there is a small group of patients who get durable responses with treatment, sometimes even after the treatment stops. That percentage is low—it might only be 5% or 10%—but it would be exciting and important to move it up to the frontline setting for those patients so they might be able to skip some of the more toxic treatments. However, to do that, we need to do a much better job of identifying predictive biomarkers—not just looking at immunohistochemistry, but RNA sequencing and whole-exome sequencing, as well.

What is the outlook on immunotherapy as a standard of care in RCC?

We are getting a glimpse that perhaps when you combine several aspects of the tumor into a model, that you could better predict who can receive single-agent therapy. It is not only important to bring the treatment into the frontline setting, but now we are going to the adjuvant setting. There, it is even more important that the right patients are getting the right treatment because most of those patients are already cured by surgery. Hopefully, we can extend what we are learning in the metastatic setting into earlier disease to identify the patients who should get this treatment. Immunotherapy is already a standard of care for those who fail on a VEGF TKI. With CheckMate-214, it almost certainly will be FDA approved in the frontline setting. Whether that indication will be for the intermediate- and poor-risk groups or for the all comers, we must wait and see—but it will be standard of care in 2018, no doubt.

Are there any novel agents or combinations that are looking particularly interesting?

Even if it is standard of care, it still won't benefit every patient, and there are some patients who may get more benefit with VEGF strategies. That is one other aspect that came out of CheckMate-214: patients with good-risk clinical features did very well with sunitinib. Therefore, there may be some patients who can start on single-agent VEGF inhibitor, others that could start with single agent PD-1 blockade, and others who might benefit from the combination. Hopefully, that is the future that we are going to see, but we are not there yet. The next big thing in kidney cancer is the combination of VEGF blockade and PD-1/PD-L1 blockade. There are probably 5 or 6 large randomized trials looking at various combinations. The early data from phase I trials, which are admittedly small sample sizes while patient selection is interesting, show that there are high response rates and longer PFS than you'd expect with either strategy alone.

What should clinicians understand about immunotherapy in RCC?

Is there anything else that you would like to add?

Hopefully, as we get into 2018 and 2019, we will start seeing the results of these randomized trials. If they are positive, we could see the fusion of the 2 effective strategies for kidney cancer in the first-line setting. Perhaps there will be 5 or 6 versions of combinations, which will make things messy—so we will have to sort it out—but that'll probably be the next big thing for metastatic patients. First, immunotherapy is important. However, it should be rationally applied to patients who are most likely going to benefit. There are patients who get a tremendous benefit, and there are others who get none. We should identify those patients, and probably not be treating every patient [with immunotherapy]. That goes for both bladder and kidney cancer. While there are some patients who need combinations, single agents still do work for some patients and we should stick with those and look at proper sequencing. Some patients are going to need more than one strategy. However, it is an exciting time with a lot of new data.There are a series of adjuvant immunotherapy trials that are up and enrolling. If you have a patient who has just had surgery and is interested in immunotherapy, there are at least 2 trials open; one is with atezolizumab (Tecentriq) and one is with pembrolizumab (Keytruda).

As for options before surgery, there is a very interesting trial looking at nivolumab before surgery and then after surgery. Therefore, there are choices for patients with stage III disease and, hopefully, people will be open to those trials and consider their patients for them.