Nanus Discusses Importance of Neoadjuvant and Adjuvant Care in RCC

David M. Nanus, MD

The inclusion of neoadjuvant and adjuvant therapy in the treatment of patients with renal cell carcinoma (RCC) may reduce the risk of recurrence after surgery, said David M. Nanus, MD. Specifically, tyrosine kinase inhibitors (TKIs) and immunotherapy are showing benefit as adjuvant treatment options for patients with high-risk disease.

After the NCCN guidelines were updated to include adjuvant sunitinib (Sutent) as an option for patients with high-risk disease, the FDA approved the agent in that setting. This approval was based on the phase III S-TRAC trial, in which adjuvant sunitinib prolonged disease-free survival by 1.2 years compared with placebo following nephrectomy in patients who were at high risk for recurrence.

Immunotherapy is demonstrating benefit in a number of other genitourinary cancers and has shown improved progression-free survival (PFS) in RCC. Nanus said that it is the most exciting advance in RCC to date, although overall survival (OS) data have yet to confirm this.

Moreover, Nanus, said that although surgery is still a vital part of the treatment of RCC, its pairing with TKIs or immunotherapy may offer a prolonged benefit for high-risk patients.

OncLive: Can you discuss the issue of neoadjuvant and adjuvant therapy in patients with kidney cancer?

In an interview with OncLive^®, Nanus, a medical oncologist at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discussed the promise of immunotherapy and the continued role of surgery in the treatment in RCC.Nanus: There have been many studies over the years, dating back 3 or 4 decades, trying to improve the outcomes for patients with renal tumors. These are generally large tumors that have invaded the vena cava that have a higher risk of relapse after surgery. Can we do anything to reduce that risk of relapse? For the longest time, we had no benefit—meaning that all of these randomized trials never showed an improvement in OS. Many of these studies are from the cooperative groups, specifically studies with sunitinib, pazopanib (Votrient), and sorafenib (Nexavar).

What treatments in RCC seem to be the most promising?

More recently, one study did show a benefit for patients in terms of PFS. These are patients with T3 and T4 kidney cancer—a very high-risk subset. This showed that there was an improvement in PFS. Meaning, the patients who went on sunitinib for about 1 year seemed to have a lower risk of progression. Although, there was no improvement in OS, so patients haven't yet seemed to live any longer. There is continued follow-up. Based on those data, the NCCN guidelines changed, making this an option for treatment. You could still do observation, or you could consider giving sunitinib adjuvant therapy. What may be most promising is immunotherapy. It could be combined in the future with a TKI—some of those studies in advanced-stage patients have showed impressive preliminary results. The use of immunotherapy has a lot of rationale and is generating a lot of excitement. There are questions in terms of when to use immunotherapy. In preclinical models, the concept of giving immunotherapy while the tumor is still there—so that their immune system actually recognizes the tumor antigens—then removing the tumor surgically and continuing immunotherapy seems to be one of the more effective strategies. There are a number of trials using that rationale.

Are there certain toxicities that physicians should be looking out for, or telling their patients to be aware of with immunotherapy agents?

In lung cancer, bladder cancer, and other tumor types, we are seeing efficacy in high-risk relapsed patients. The toxicities tend to be less. If you look at all of the TKI studies, there was, almost universally, a dose reduction because of adverse events (AEs). With immunotherapy, many patients have minimal AEs, and only some have severe AEs. That is the most exciting area, and there will be future studies of combination TKIs and immunotherapy. There is a lot of hope and optimism that we are going to improve outcomes for patients with T3, T4, and bulky T2 disease. There is more of a recognition of AEs by the community oncologist who commonly handles immunotherapies. The general internist doesn't understand it. I have had cases where patients have gone to the emergency room and don't know what's going on. They get admitted and then they reach out to me, and I say, "Oh, you have adrenal insufficiency. You have to do this and that."

More and more, oncologists are recognizing these AEs, and they are looking for them. It is mostly things like adrenal insufficiency, rashes, nephritis, hepatitis, and so forth. As oncologists—maybe more than urologists—we tend to do the same thing, which is check the blood test and examine the patient. As a community, we are getting better at it. There are a lot of publications and seminars on how to taper steroids.

What ongoing trials are you particularly interested in seeing the results of?

The oncologist should be telling their patient to reach out to them if they are feeling fatigued or with any issue. In the community, the other doctors taking care of the patients may not understand these AEs.There are a number of phase III upfront trials that will be interesting. One of the issues with combinations, such as ipilimumab (Yervoy) plus nivolumab (Opdivo), is the risk of immunologic AEs. We are seeing that some of the trials with a PD-1/PD-L1 inhibitor plus TKIs may have less toxicities and better tolerated, with just as good efficacy.

What are the key messages for community oncologists treating patients with kidney cancer?

In the adjuvant setting, there are about 3 or 4 immunotherapy trials. There are a lot of things going on, and there will probably be more than 1 drug that shows benefit and will have a new indication. I would say in the next few years, we will be using some of these agents. Hopefully, there will be an improvement in OS, not just PFS.[There are a] couple messages. The first is that the role of cytoreductive nephrectomy in patients with metastatic disease, and the concept that surgery is a big part of our care for patients with kidney cancer. Just because we have newer drugs doesn't mean we should stop doing surgery.

Secondly, there are a lot of trials, and you should refer your patients for clinical trials. There are adjuvant and neoadjuvant trials for high-risk patients. There are many early-stage patients that can just get surgery, but those more advanced T3 and T4 patients should be participating in a study. In select patients, you can have a discussion about adjuvant sunitinib therapy. It is a discussion with the patient. Some patients say they want to do everything possible. Oncologists still would like to see an OS benefit before they buy into it—myself included. However, there are select patients for whom the conversation should be had and immunotherapy should be considered.

Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375:2246-2254. doi: 10.1056/NEJMoa1611406.