Expert Addresses Advances and Challenges With Immunotherapy in RCC

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.

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

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.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.

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

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. 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.

What are some challenges physicians face with immunotherapy in RCC?

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.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.

Another challenge with nivolumab, and all immunotherapy, is the duration of therapy. Specifically, in metastatic RCC, we have data from the expanded phase I, phase II, and the phase III CheckMate-025 trial to suggest that there are a significant number of patients who will come off of therapy for nonprogressive disease reasons. They come off of therapy for intolerability, adverse events (AEs), or other reasons.

Despite being off of therapy, they are able to sustain a long-term response without any subsequent treatment. That produces a dilemma to figure out whether we are really treating patients appropriately, in the sense that we are treating them continuously or indefinitely. Or, is there some other algorithm we need to figure out when enough therapy is enough, particularly when we take cost effectiveness and AEs into consideration.

What are we seeing for the future of the RCC landscape, regarding immunotherapy?

The primary issues we are talking about are measuring response, deciding who to treat beyond progression, and deciding what the duration of therapy is. The future of drug development in metastatic RCC, from an immunotherapeutic perspective, really revolves around combination therapy. This can mean multiple things. It can mean combining a checkpoint inhibitor with another checkpoint inhibitor, such as ipilimumab and nivolumab. It can mean combining a checkpoint inhibitor with a VEGF-directed therapy. We certainly know some of the VEGF TKIs can lower the number of myeloid-derived suppressor cells. It can decrease the T-cell infiltration to the tumor microenvironment, creating a more immunogenic environment for the immunotherapy to work. It can also mean vaccines.

One of trials that physicians are most excited about is CheckMate-214, which is ipilimumab plus nivolumab versus sunitinib, which we will have results of relatively soon. There is also the IMmotion151 trial, which combines bevacizumab (Avastin) and atezolizumab (Tecentriq) and those are also versus sunitinib, which is the standard of care frontline therapy. Those trials, aside from being exciting combination trials in terms of checkpoint inhibitors plus checkpoint inhibitors and checkpoint inhibitors combined with VEGF-directed therapy, may also produce predictive biomarkers, particularly in the IMmotion151 trial with bevacizumab and atezolizumab.

What were the key takeaways for the community oncologists in attendance?

One of the primary endpoints is looking at progression-free survival based on PD-L1 expression. In addition to providing combination therapies that can provide clinical outcomes, the future of immunotherapy in metastatic RCC is developing drugs with predictive biomarkers and to identify which patients are likely to benefit from immunotherapy. There are a couple of takeaway messages for the community oncologists regarding immunotherapy in metastatic RCC. First and foremost, it is important to remind oncologists that there is still a role for high-dose IL-2 in the appropriate patient. Mortality, in an appropriate center and in a hospital that sees a lot of patients with metastatic RCC and treats a lot of them with high dose IL-2 is still low. Again, patient selection is critical in that setting, but there is definitely still a role for IL-2 in the appropriate patient.

It is also important to know that, although we’re very excited about giving nivolumab, we might be stopping nivolumab too early in patients who had progression early on, which may have just been pseudoprogression. It is important to keep that in mind when there is progression on scans and it looks like the patient is doing well and the labs look well. One may want to consider continuing therapy for a few more cycles and repeating scans at that point.

Also, remember that if a patient is not tolerating therapy, it doesn’t mean that the drug needs to be discontinued indefinitely. You can hold therapy for a couple of cycles, see how the patient does, and consider resuming therapy. We know that there are definitely patients who have long-term responses, despite early discontinuation of therapy.