Harnessing the Potential of Immunotherapy, Optimal Sequencing in Advanced RCC

GU Oncology Now spoke with David Braun, MD, PhD, assistant professor of medicine and a principal investigator at the Center of Molecular and Cellular Oncology at Yale Cancer Center, regarding currently available later-line therapy options for patients with advanced renal cell carcinoma (RCC), how the therapies are sequenced, and the “buckets” of treatment options most worthy of further research.

Let’s begin with a general overview of later-line therapy for patients with advanced RCC. What are the current options?

Dr. Braun: It’s a nuanced question, and the landscape has become much more complicated in recent years because of the changes in frontline options. In the past, when frontline options were tyrosine kinase inhibitor (TKI) monotherapies like sunitinib, pazopanib, or cabozantinib, the choices were simple and straightforward. Even when we had our first immunotherapy approval in the frontline, nivolumab plus ipilimumab, the landscape and subsequent lines were relatively straightforward and consisted of TKIs (and, to a lesser extent, integration of mammalian target of rapamycin [mTOR] inhibition).

Nowadays, later-line therapy options are largely dependent on what has been given in prior lines of therapy, and so I like to think in “buckets.” What buckets of tools are available? There may be a few.

Immunotherapy is certainly an option, especially if it’s not given in the frontline, though there is some evidence that upfront immunotherapy followed by more immunotherapy may still be effective. A prospective phase 1b/2 trial out of Memorial Sloan Kettering Cancer Center (Keynote 146) of pembrolizumab plus lenvatinib included a cohort of patients who had previously received immune checkpoint inhibitor (ICI) therapy in the frontline setting. The response rates were more than 60%, which shows this approach may be a reasonable option.

There are also prospective data that indicate pure immunotherapy can be effective. Two separate retrospective studies (from Drs. Gul and Ravi) looked at patients who had previously received ICI therapy, stopped therapy due to progression or toxicity, and were then rechallenged with immunotherapy combinations. The response rates were close to 20%. Similarly, in the prospective FRACTION-RCC study, there were some responses to nivolumab plus ipilimumab in patients who received prior immunotherapy. Thus, even in those later lines, an immunotherapy rechallenge is not unreasonable.

Targeted therapy is another bucket. It mostly consists of TKIs, with a small and diminishing role for monotherapy mTOR inhibition. Patients who have a difficult time tolerating therapy with numerous TKIs and earlier-line immunotherapies may benefit from everolimus monotherapy. Cabozantinib is another option, along with axitinib, lenvatinib plus everolimus, and third-line tivozanib.

Lastly, it is worth noting the newest player on the market, belzutifan, which is not quite approved in the later-line setting. It is currently approved for patients with inherited von Hippel-Lindau disease. Early data suggest that it will be a pretty efficacious therapy, though phase 3 trial results are still pending.

Which bucket of later-line therapies or combination therapies has the most robust data for improved survival outcomes?

Dr. Braun: When it comes to progression-free survival, all of these buckets have support. Overall survival (OS) is a tougher bar, particularly in that later-line setting, because of therapeutic crossover and the high numbers of subsequent therapies patients receive. The TKIs likely have the strongest OS data, especially cabozantinib in the METEOR trial. However, it is worth noting that those data are typically from an older era, prior to the routine use of immunotherapy in the frontline, and so it is debatable how applicable the data are today.

This is also true for immunotherapy, and specifically nivolumab monotherapy (from the CheckMate 025 trial, which showed an OS benefit over everolimus in treatment-refractory clear cell RCC). These data are limited by having a comparator arm that doesn’t reflect standard-of-care treatment in the real-world setting. While OS data are promising, the treatment landscape has changed so much in recent years that the clinical setting in which the CheckMate 025 trial was conducted is not the clinical setting we see today.

In sum, these examples highlight the difficulty of relying only on OS data for prescribing therapies, particularly in later lines of therapy. While OS has historically been the gold standard, it is a longer-term outcome, and the treatment landscape is advancing at a quicker pace than the availability of these long-term data. Later-line trials that show an OS benefit are from a different treatment era.

What are the ongoing research efforts to determine optimal sequencing of these therapies?

Dr. Braun: We’re starting to see how efforts to optimally dose and sequence existing therapies, rather than only developing novel therapies, yield significant survival benefits in kidney cancer. The PDIGREE trial is a good example of this. Nivolumab plus ipilimumab is given upfront, and then cabozantinib is sequenced in multiple ways based on patient response to therapy. Nivolumab alone is continued for patients with a complete response, cabozantinib alone is given for patients with progressive disease, and the remaining patients (who have partial response or stable disease) are randomized to receive nivolumab alone (a current standard of care based on CheckMate 214) or nivolumab plus cabozantinib.

In what direction is advanced RCC treatment headed over the next 5 to 10 years? Are we likely to see improved use of available therapies through dose optimization and sequencing trials? Or will the real advancement exist in novel immunotherapies or targeted therapies? If you had to forecast, what will be the biggest game-changers?

Dr. Braun: My hope and belief is that the game-changers will come in the form of immunotherapy because we have a different paradigm for treating kidney cancer now than we did in the past. Historically, when it came to advanced disease/metastatic solid tumors, the efforts were not to cure, but rather to prolong life while minimizing detriments to quality of life. Nowadays, in advanced kidney cancer, I truly believe that immunotherapies, particularly ICIs, are yielding excellent long-term durable responses, potentially even cures, but only for a small subset of patients. The goal is to expand these results to more patients, and I believe immunotherapy will be the predominant way to grow the group of long-term survivors.

This is not to say that other types of therapies don’t have a role to play in the immediate future. TKIs are still vitally important for obtaining a response and achieving cytoreduction. However, I don’t believe these therapies will compete with the long-term responses and cures that immunotherapies will provide.

As a field, we have to be smarter about immunotherapies. We have a couple of checkpoints that are borrowed from other tumor types, but it is paramount that we continue to gain a better understanding of the immune biology of kidney cancer in order to identify disease-specific checkpoints. Can we harness therapeutic cancer vaccines and cellular therapies to form a combined immunotherapy approach that not only reinvigorates the immune system but specifically targets the kidney tumors themselves? This question should, and likely will, drive the research in the coming years.