Immunotherapy Combinations Poised to Shift Standard of Care in RCC

Hans J. Hammers, MD, PhD

Immunotherapy combinations continue to demonstrate improved response rates for patients with renal cell carcinoma (RCC). Frontline therapy with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 32% compared with standard sunitinib (Sutent) for patients with metastatic disease, according to data from the CheckMate-214 study.

Median overall survival (OS) was not reached with the combination versus 32.9 months with sunitinib. In intermediate- and poor-risk patients with RCC, there was a 37% reduction in the risk of death. Moreover, progression-free survival (PFS) in the intermediate- and poor-risk group was 11.6 months with the combination compared with 8.4 months with sunitinib. Across the full study, the overall response rates were 39% and 32% with nivolumab/ipilimumab versus sunitinib, respectively.

“This combination is expected to become the standard of care as early as the first quarter of 2018,” explained Hans Hammers, MD, PhD.

OncLive: Please provide an overview of your presentation at this meeting.

In an interview with OncLive at the 35th Annual Chemotherapy Foundation Symposium, Hammers, who is co-leader of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center, discussed the game-changing combination of nivolumab and ipilimumab and highlighted other combinations that have potential in the treatment of patients with RCC.Hammers: I discussed immunotherapy combinations. It is an exciting time because it is expected that immunotherapy combinations are going to supplant first-line tyrosine kinase inhibitor (TKI) therapy. We have had sunitinib for more than a decade. Just recently, one of the pivotal trials was positive and beat sunitinib in response rate and OS. The PFS in the intermediate- and poor-risk population was 75% in all patients with kidney cancer.

The combination that was investigated was nivolumab plus ipilimumab. However, there is a race to the first-line setting, as many other combinations are being explored, such as combinations with VEGF inhibitors and PD-1/PD-L1 inhibitors.

With these new agents and a shift in the standard of care, what advice can you give to community oncologists to navigate these new treatments?

In my talk, I concluded with thoughts about how to look at these trials and what some interesting aspects are that we should look at when we try to interpret the data sets.For community oncologists, particularly those who have not treated patients with melanoma, they will be introduced to ipilimumab (Yervoy). There is an important distinction between the combination in kidney cancer and melanoma. Melanoma has the higher dose of ipilimumab and kidney cancer has the lower dose of ipilimumab. Anyone who has previously used ipilimumab in the context of melanoma will be relieved to see that the side effect profile is clearly better regarding hepatitis.

Can you discuss the severity of the adverse events that physicians should be mindful of?

Nonetheless, it is a dual immune checkpoint inhibition therapy. Around 50% to 60% of patients require immune suppression for all immune side effects. However, they can be treated well with established guidelines. Nonetheless, physicians who are treating patients with kidney cancer with this combination will need to watch them closely. We will all become experts at managing immune side effects, but early reporting is key. Patient education is going to be important in reporting side effects early. We are well poised to guide patients through that therapy.I ask my patients to tell me what they should be concerned about. They should say pneumonitis, hepatitis, colitis, and the respective symptoms. There is a plethora of other rare side effects, but those are the 3 that I say cause most of the needs for the use of steroids and are more threatening than some of the other adverse effects. Once you spend time with these adverse effects, most patients know what to call for and what to report.

It is important to see it as teamwork. I often engage the spouse, particularly with male patients. Women are much better at reporting side effects and getting the spouse to call. Creating a sense of community encourages patients to report adverse effects early, which is key. You do not want to wait until you have a grade 3/4 toxicity. You want to treat some of the side effects when they are grade 2.

Can you discuss the next line of therapy for patients who progress on the combination?

In the end, it is a matter of experience. There are well-established treatment guidelines for some of these adverse effects. Most of these patients do well with steroids. The need to add additional immune-suppressive agents is around 4%. Many patients do well with steroids from 4 to 6 weeks.Other PD-1/PD-L1 inhibitors will likely work in that space if a patient progresses on nivolumab and ipilimumab. The mechanisms of action are too similar. In that case, we are back to our work forces that we have been employing for the last 10 to 11 years, which are the TKIs and the VEGF pathway inhibitors. We have a wide spectrum of agents to choose from. For example, we know that using axitinib (Inlyta) in this particular space is safe. It is also one of the TKIs that is well combinable with other immunotherapies.

If a patient has some intermediate- or poor-risk features as well as a large tumor burden, then perhaps one should go with cabozantinib (Cabometyx), which is one of the more broadly acting TKIs. The art of oncology is choosing some new agents but, essentially, it is back to VEGF TKIs.

What are the next steps with treatments and where do you hope to be in the next 5 to 10 years with this landscape?

Hopefully, the patients can do well on these agents and participate in clinical trials—or look forward to other immunotherapy combinations that are coming up in the future. Quite frankly, we are trying to make sense and to develop a rational approach for the different agents that are coming into clinical development. The class of checkpoint inhibitors is expanding. We need to revisit the role of vaccination therapy with combinations of immune checkpoints in kidney cancer that can be mutation based. That will be a large wave of clinical trials and studies. There is lots of work to be done. We are all looking forward to other classes that are in development.

There is a phase III clinical trial that is investigating the frontline combination of epacadostat and pembrolizumab (Keytruda) versus sunitinib. There are several agents that are being tested in pivotal trials or in earlier development trials that we can hopefully get access to in the future.

Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5.