Advanced RCC: Novel Therapies and Ongoing Studies With the Most Promise

Rana McKay, MD, University of California, San Diego, and David Braun, MD, PhD, Yale Cancer Center, wrap up their discussion with comments on which novel therapies they are most excited about and believe hold the most promise in advanced RCC in the coming years.

Dr. McKay: What are novel therapies that you are most excited about, that you think kind of holds some promise and we should be on the lookout for?

Dr. Braun: I maybe group that into short term and longer term. I think in the short term, belzutifan and, more broadly, HIF-2α inhibition, is really promising. It’s really a molecularly directed therapy. Understanding the biology of kidney cancer and really high HIF-2α signaling that drives a lot of the disease itself and being able to molecularly target that is fantastic. We’ve seen in earlier studies, that it’s a very well tolerated drug. It has good clinical activity, even in later-line settings where patients have been heavily pretreated, and that it’s a combinable drug. We saw that with the combination of belzutifan and cabozantinib.

It’s now entering the realm of phase III trials. There’s belzutifan by itself against everolimus in the later-line setting. There’s belzutifan plus lenvatinib against cabozantinib at a refractory setting. There’s belzutifan as part of a pembro/len combination in the frontline setting, and even belzutifan in an adjuvant setting in combination with pembrolizumab.  It’s being explored in every potential space within clear cell RCC, and so I think the next couple of years will be really exciting to see where it fits in, what’s going to be its best place. But, I suspect it’s going to have a role in one of those settings, if not multiple. So, in the short term, that’s the most promising.

In the longer term, I still hold out a lot of hope for novel immunotherapies; and in my mind, CheckMate 214 and this idea of a checkpoint inhibition really represented an inflection point in how we treat kidney cancer. We had some early evidence from high-dose IL-2 that even metastatic disease is not just treatable, but really actually curable, or at least controllable for the long term, but only in a very small number of patients. With modern checkpoint inhibition and things like nivolumab plus ipilimumab, that number is probably increased to patients who have really long-term response; I hope it even translates into a cure. But, we need to move from proof of concept to actually having that be the majority of patients, and I just don’t think targeted therapies will ultimately get us there. I think they have tremendous value in prolonging life and making people feel better and improve their quality and quantity. But, getting to that ultimate goal of long-term control, of really cure, that’s going to require an IO-based approach. Whether that’s novel immunomodulatory drugs, new checkpoints and other cytokine-based therapies, or of the space of antigen-directed therapies, things like cell therapies, things like vaccine-based approaches. That’s going to be the next generation that’s going to hopefully not just move the needle and move the median survival, but really lead to long-term survival and cures.

Dr. McKay: It’s really exciting to see where the field is going with novel therapies. We have a series of VEGF inhibitors and a series of IO agents that are approved, but we really need some new drugs with novel mechanisms of action that can help overcome some of the resistance pathways, enhance our ability to induce deep, durable responses earlier on.

We highlighted the different kind of therapies, but  can highlight 1 or 2 ongoing clinical trials that are investigating various targeted therapies or immunotherapies that you’re looking forward to?

Dr. Braun: It’s hard to narrow it down to a couple, and I never want to exclude these. There’s a lot of things, in a good way, that are happening in kidney cancer. I’ve mentioned the belzutifan trials already, so I’ll leave those out. I’ll mention one that is more practical and one more forward-looking.

The more practical one, which I think is a really good question, is the PEDIGREE trial. It’s a straightforward design, and as a field we sort of naively think, “Well, if two drugs is better than one, three drugs are going to be better than two.” But that’s not always the case. We know if we overtreat a lot of patients, we can cause a lot of toxicity and that toxicity might not only translate into a miserable patient, but an inability to effectively receive an effective dose of the therapies, too. So, something like PEDIGREE and adaptive design that says, “You’re going to get more therapy if you need it,” is something that’s really appealing to me. I know that’s well on its way to being fully approved, and so getting those results will be helpful and informative in the short term.

The more longer-term view is the CAR-T trials. We’ve had one COBALT-RCC that’s been reported. We’ve had some initial results from the Allogene trial, these allogeneic stem cell transplants. Allogeneic CAR T-cell therapies are really exciting, and there’s a long way to go. What is the right target? How do we improve the fitness of these CAR T-cells? How do we optimize these antigen-directed therapies? But, at least they open up that space of antigen-directed therapies in kidney cancer, and once that bucket is open, there are other cell therapies. There’s vaccines. There’s a whole world that sort of emerges. The proof of concept being there that antigen-directed therapies can be used in kidney cancer is really exciting. So, those are probably the two on the short and the long term that I’d look out for.

View their other comments on Current Biomarkers, Novel Biomarkers, and Strategies for Patient Selection.