Sznol Reflects on Immunotherapy Advances in mRCC

Mario Sznol, MD

Immunotherapy is poised to become the standard of care for patients with metastatic renal cell carcinoma (mRCC), according to Mario Sznol, MD.

In April 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC based on results from the CheckMate-214 trial. These phase III data showed that nivolumab plus ipilimumab had a superior survival benefit to sunitinib (Sutent), with the combination reducing the risk of death by 32% in the frontline setting.

In addition to dual immunotherapy combinations, Sznol said that VEGF inhibitors are another potential pair for checkpoint inhibitors. PD-1/PD-L1 inhibitors can be combined with other receptor inhibitors, including bevacizumab (Avastin), sunitinib, cabozantinib (Cabometyx), and lenvatinib (Lenvima), Sznol explained. Cytokines, NKTR-214, IDO inhibitors, and interleukin 15 (IL-15), are also under consideration for combination strategies with PD-1/PD-L1 inhibitors.

OncLive: There has been much success with immunotherapy in mRCC. Can you reflect on some of the biggest advancements in the past year?

In an interview with OncLive^®, Sznol, professor of Medicine, and co-director of the Cancer Immunology Program at Yale Cancer Center, discussed the latest developments with immunotherapy in mRCC.Sznol: There are really 2 big advances. The first was the recent study combining ipilimumab and nivolumab [in the frontline setting], which showed a survival advantage over sunitinib in patients with mRCC. This was primarily in the group with intermediate- to poor-risk patients, but the survival advantage was very significant. It probably represents a new standard of care for that subgroup of patients with RCC.

Just in the last few months, Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, presented a phase III trial comparing atezolizumab (Tecentriq) and bevacizumab with sunitinib, which also showed a PFS advantage in terms of PFS across all International Metastatic Renal Cell Carcinoma Database Consortium subgroups, but primarily in the PD-L1—positive group. We probably have a new standard of care, which is ipilimumab in combination with nivolumab in the frontline setting.

Are there any other combinations that look promising?

There are a number of VEGF inhibitors and anti—PD-1/PD-L1 agents that are coming down the road, which will represent another major advance in immunotherapy for RCC.[This includes any] PD-1/PD-L1 inhibitor with any of the VEGF [or multikinase] inhibitors. That includes bevacizumab, sunitinib, cabozantinib, and lenvatinib. There are going to be a number of combinations in phase III trials.

How do you see immunotherapy progressing in RCC over the next 5 to 10 years?

There are some other combinations that look promising. There are a number of cytokine and PD-1/PD-L1 inhibitor combinations that look really interesting, combinations with NKTR-214, IL-15, with pegylated interleukin 10—all which seem to show better response rates than you might expect. Combinations of PD-1 inhibitors with IDO inhibitors are showing response rates better than expected. We are going to see a number of these combinations in phase II trials coming out, and then phase III trials in the future. We have a lot of interesting things to do in metastatic kidney cancer at this point.It will be the standard of care. Most patients will receive a PD-1/PD-L1 inhibitor. Right now, we use ipilimumab in combination with nivolumab, but there are all of these other combinations that will involve the IDO inhibitors and cytokines, so it is hard to know how it will all shake out. My guess is that in most patients, we will be using an immunotherapy/immunotherapy combination first, and if they do not achieve a durable response, we will then be going to a VEGF inhibitor/PD-1 inhibitor combination in the second- and third-line setting.

Again, it is going to be hard to know. It may be possible that we use a number of immunotherapy/immunotherapy combinations in the first-, second-, and third-line settings. Only when they progress on all of those do we add a VEGF inhibitor. It could become the case that in the future, we might use all 3 agents together. We might use an immunotherapy agent plus an immunotherapy agent plus a VEGF inhibitor all together in the frontline setting. Those phase I and II trials are being done now.

What would you like physicians to know about the current state of immunotherapy in RCC?

The field is in flux because we have all these agents that appear to be active, and we don't know which subgroups to use them in and in what order.In the community, I'd like them to think about a clinical trial for their patients because we don't know how to use these agents optimally. If they don't have a clinical trial, they ought to consider an immunotherapy agent such as a checkpoint inhibitor for most patients.

Is there anything else you would like to highlight?

There may be small subgroups where it is appropriate to just give them a VEGF inhibitor first. For the vast majority of patients, we are going to be thinking about an immunotherapy/immunotherapy combination, or an immunotherapy plus VEGF inhibitor combination in the frontline setting. That will give us the best overall outcome in the future. But, I do want them to think about a clinical trial because if we don't do clinical trials, we are not going to sort out the mess we have now regarding these active combinations.The only other thing that physicians in the community need to know is that immunotherapy agents are active in non-clear cell cancer as well. We are always talking about clear cell carcinoma, some clear cell component, or maybe a sarcomatoid RCC, but about 25% of kidney cancers are non-clear cell carcinomas…We have a lot of anecdotal experience with papillary carcinoma and duct carcinoma showing reasonable activity with PD-1 inhibitors as a single agent and in combination. Don't exclude those patients from trials, and don't exclude them from consideration for immunotherapy agents.

Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5.