Defining Disease Progression in Renal Cell Carcinoma

Transcript:Robert A. Figlin, MD: Let’s turn our attention, Nizar, to we know that we sequence our drugs. We know that we have potent drugs that produce significant qualitative and quantitative benefits for patients. But one of the challenges is that a clinical trial that defined disease progression may not be the same as clinical disease progression that we see in our practice. RECIST criteria are helpful, but certainly are not consistent with what’s happening clinically with the patient, because oftentimes that’s radiographic progression without any change in their clinical situation. So one of the things that we’ve not done a very good job of is really talking about when we should decide to switch therapies based upon progression. So help us understand in your practice: what constitutes progression? When do you use radiologic and imaging, clinical, and what is your decision making when it comes to switching from a treatment to a second-line treatment?

Nizar M. Tannir, MD, FACP: Bob, this is an excellent question, and I think you put it succinctly. We do not have a good system to assess benefit or response to therapy. And obviously the most important, most relevant primary endpoint for any clinical trial, especially in oncology, is overall survival. But when we do not have agents that can achieve that primary endpoint of overall survival, we rely on progression-free survival—but that’s a slippery slope. Because, again, it’s arbitrary.

We went through two iterations of RECIST version 1; 1.0 and 1.1, and we’re not satisfied. So I look at this question of progression in two different crystals, if you want. One would be if a patient is on a clinical trial. Unfortunately, we are bound by the clinical trial protocol, especially if it’s an industry-sponsored trial, to follow the response criteria, which is RECIST version 1.1. So, for that patient, if that patient meets the criteria of progressive disease—a new lesion or there has been an increase of more than 20% in the sum of the longest diameters of the selected target lesions, which is the criteria—then that patient has, by definition, progressive disease. And according to the trial provisions, one will need to change therapy or take them off protocol.

But in practice actually, if I’m treating a patient off-protocol, I don’t really apply this. And I know we all have different ways of treating our patients off-protocol than on protocol. So, if a patient is clinically benefitting from the treatment and has slight growth—even if that growth is 21% or 25% but the patient is benefitting, there are no new lesions, the patient is not symptomatic from their cancer and they’re tolerating the treatment very well—I think it’s reasonable to continue with that therapy beyond that arbitrary 20% growth.

Now, obviously, symptomatic progression or clinical progression when the patient is having symptoms from the cancer, regardless of whether the radiographic changes are there or not, that patient needs to have different therapy. If somebody has bone metastasis and they’re continuing to have pain and the pain is due to the metastasis, not to an osteoporotic fracture, for example, or if the patient is having night sweats, fever, chills, what we call constitutional symptoms, those patients, even if they do not have that 20% growth, are not responding to therapy and need a change.

So I, obviously now with the immune checkpoint inhibitors, which I’m sure we’re going to be discussing, this field is now taking on a new level of challenges, where progression by RECIST is no longer accepted as [an indication that] one needs to change. Because we know about pseudo-progression with the immune checkpoint inhibitors, and so many patients initially had progressive disease by radiographic images but felt much better compared to baseline before they started their therapy. And those patients rightly should continue therapy if they have benefitted symptomatically, clinically. And then surely in some of these patients, we’ve seen the radiographic improvement lagging behind the clinical improvement, the symptomatic improvement. And, therefore, we’re going to need a new system to evaluate patients and evaluate the response to therapy and that sort of endpoint that we call progression-free survival in light of what we know now about the way these immune checkpoint inhibitors work and how the T-cell infiltration of the tumors can initially cause an increase in the size of the metastatic lesions.

Transcript Edited for Clarity