Initial Therapy for Advanced Renal Cell Carcinoma - Episode 10

Sequencing Therapies After Progression of RCC


Eric A. Jonasch, MD: When a patient is on frontline therapy, whether it’s monotherapy or combination therapy, we really need to make some decisions about when the best time is to move on to another agent or combination of agents. My practical guidelines here would really say that if you observe relatively slow growth of existing lesions and the patient is asymptomatic and you don’t see really any threat from any of these lesions in the immediate horizon, they can continue on this regimen. If you have 15% or 20% increase in tumor diameter but the patient is doing very well, I think they can continue on this regimen.

But if you see that an individual then starts developing new sites of metastatic disease or starts to develop symptoms, or you’re really seeing a decline in their overall physical state, then I would say it’s time to move on to another regimen.

Elizabeth R. Plimack, MD: One of my favorite things about treating patients with kidney cancer is that they often do well with multiple, different lines of therapy. I think in the past it used to be a paradigm where patients got only 1 or 2 cracks at treatment and then you were lucky if you got them to a third. I think what we’re seeing now in this era of very effective therapy is that patients are living much longer, they’re living better, and they’re also seeing multiple lines of therapy. The problem is the frontline setting is moving so quickly, and we don’t know how to adjust our second-line approach based on that. We can’t do the trials fast enough.

Right now, the paradigm I use is what we know and what we don’t know. What we know is that sequential VEGF inhibition can have benefit. We’ve proven that in multiple trials before the immunotherapy era. What we don’t know is whether sequential, pure immunotherapies can work. Some of these data are coming out, and I don’t think we’re going to see as much efficacy in second-line immunotherapy after a patient has progressed on their first-line immunotherapy. For now, in my practice, I lean heavily on the VEGF inhibitors after frontline therapy if a patient has progressed. Again, which 1 I select depends on what’s available, what trials are available, and what the data are that day, but also how they did on their prior therapy, both in terms of how they tolerated it and how well it worked on their cancer.

Eric A. Jonasch, MD: One of the questions we frequently get asked is whether there’s some mechanistic rationale based on the MOA [mechanism of action] of agents in terms of sequencing. I think that’s really somewhat challenging because of the fact that we have I/O [immuno-oncology] MOA, so we’re modulating the tumor microenvironment by enabling effector T cells; or we’re modulating the angiogenic features of the tumor, and we’re basically doing some vascular remodeling.

What’s pretty evident is that when you start with an I/O agent and then patients start progressing and you move on to a TKI [tyrosine kinase inhibitor], we have anecdotal data that are published as well as small phase II studies that have been published demonstrating that you get a remarkable response to TKI therapy after I/O therapy, in a subset of individuals. It’s almost as though the microenvironment has been preconditioned by the I/O therapy, which then results in a more robust response to TKI therapy.

Starting, for example, with axitinib plus pembrolizumab, where you’ve got a very focused VEGF receptor blocking agent together with I/O therapy. Whether then moving on to a more complex and more sophisticated VEGF TKI, like cabozantinib or lenvatinib, is going to enable and rescue some resistance with the additional targets that are blocked, really is a question that’s going to be answered with some studies that are going to be coming out in the next year or 2.

Elizabeth R. Plimack, MD: I often hear kidney cancer referred to as a crowded space. There are a lot of agents in kidney cancer, and we love that. We love having options for patients. But we still haven’t cured the disease, we still don’t have all the answers, and we still really are leaning on 3 different mechanisms of action: VEGF inhibition, MTOR inhibition, and immunotherapy. I think it’s really important that we continue drug development in this disease, that we find new agents targeting new aspects of the cancer, and that we test them alone and in combination.

To that end, we really need the courageous patients in our clinics to enroll in clinical trials to test these new therapies. All the developments we’ve made have been through the courage of generations of patients with kidney cancer before who have taken a chance and enrolled on a trial. Many of those patients actually benefited from their participation in the trial. But certainly, as a community, we all benefited from their participation, so we’re grateful to them and we want to continue to move forward and find new treatments until we have a cure.

Transcript Edited for Clarity