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Expert Addresses Advances and Challenges With Immunotherapy in RCC

Gina Columbus @ginacolumbusonc
Published: Monday, Jun 26, 2017

Moshe Ornstein, MD

Moshe Ornstein, MD

Immunotherapy combination regimens are likely to be the future of metastatic renal cell carcinoma (RCC) treatment, while agents such as interleukin-2 (IL-2) and nivolumab (Opdivo) monotherapy will continue to play an important role for these patients, according to Moshe Ornstein, MD, an oncology fellow at Cleveland Clinic.

In the ongoing phase III CheckMate-214 trial, for example, the PD-1 inhibitor nivolumab is being studied in combination with the CTLA-4 inhibitor ipilimumab (Yervoy) versus standard of care sunitinib (Sutent) for patients with previously untreated, advanced, or metastatic RCC (NCT02231749). Researchers are investigating response rates, progression-free survival, and overall survival.

While these novel regimens could be game changers for the field, Ornstein warns of the challenges of using immunotherapy agents in RCC, including pseudoprogression.

During the 2017 OncLive® State of the Science Summit on Genitourinary Cancers, Ornstein lectured on the obstacles physicians are facing with the use of immunotherapy for their patients with RCC. In an interview, he explained these challenges, the role of IL-2, and the future combinations that could change the RCC landscape.

OncLive: What did you discuss in your lecture on immunotherapy on kidney cancer?

Ornstein: We focused on the past, present, and the future. For the past, we talked about IL-2 and the role past immunotherapy has in 2017. For the current landscape of immunotherapy, we are really focusing on nivolumab, for which the approval was based on the phase III CheckMate-025 trial. What we tried to highlight were some of the challenges that clinicians and patients face when using nivolumab or any immunotherapy that may come down the road.

Lastly, after covering the past with IL-2 and the present with nivolumab, we focused on some of the future directions, which are combination strategies [involving] immunotherapy for metastatic RCC. 

What role are you envisioning for IL-2 going forward as more modern immunotherapies take a front seat?

The benefit of IL-2, even now in 2017—when we have plenty of targeted therapies, such as nivolumab and probably other immunotherapeutics down the road in metastatic RCC—is that, for a subset of patients, this is one of the only therapies for which we have long-term data and long-term durable complete remissions (CRs).

One of the challenges with high-dose IL-2 is patient selection. It is a fairly toxic regimen and, although it will benefit a subset of patients, there is also a reasonable mortality and morbidity rate. Although it is low, that still has to be balanced against the durable CRs. The biggest challenge in 2017 is for us to think of IL-2 in the context of the other therapies available and with patient selection. 

We did have the SELECT trial that was published in 2015, which looked to prospectively validate a scoring system to select which patients are most likely to benefit. Unfortunately, we don’t really have predictive markers. It is really up to individual physicians to decide with their patients, and to decide which patients are best suited to tolerate the toxicity.

We are generally looking at young patients with minimal comorbidities who have clear cell RCC who don’t have bone metastases or brain metastases. Although there are no formal guidelines for high-dose IL-2, those are probably the main features we look at when deciding which patients in 2017 will benefit from IL-2.

What are some challenges physicians face with immunotherapy in RCC? 

Although the element of immunotherapy, particularly checkpoint inhibitors, is really exciting for all solid tumors and even in hematologic malignancies. They do come with a handful of challenges. One challenge is the issue of pseudoprogression. Patients may appear as though they have progression on a scan, but it may be pseudoprogression, in the sense that that enlargement of the tumor, or what appears to be tumor enlargement, is only an infiltration of immune cells. If that patient was maintained on therapy, that tumor would subsequently regress in size or at least remain the same. 

What that leads to is potentially having patients who seem to be progressing but are not, and are being taken off of the immunotherapy, in this case nivolumab, prior to being able to have the optimal benefit. 

This presents a number of challenges. First, how do we measure progressive disease in this setting? If a patient has progressive disease, can we treat them beyond their progression? We do have data from the CheckMate-025 trial that there are a handful of patients who will benefit when they are treated beyond their disease progression. 

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