Advanced RCC: Strategies for Patient Selection in First-, Second-Line

Rana McKay, MD, University of California, San Diego, and David Braun, MD, PhD, Yale Cancer Center, share their strategy for strategy for patient selection in the clinic – including first- and second-line treatment options.

Dr. McKay: Thinking about advanced disease, what is your strategy for patient selection in the clinic? When you’ve got somebody before you in the frontline space, how do you strategize? And then, we’ll talk about what to do in the second-line space.

Dr. Braun: It’s a great question. I think I have my internal algorithm for how I approach things, with the caveat that there’s still a lot of unknowns; and a lot of this is based on a little bit of data and a lot of anecdote, and there’s certainly room for debate. But, my approach has been, first of all, there’s obviously patient-specific factors of comorbidities, their preferences, all these things have to be taken into account. But for many of the patients in front of me, I ask the question, “Is this truly a widespread, metastatic disease, or is this something that’s more of an oligometastatic picture?”

If it’s more oligometastatic picture, my first branch point is to think about locally directed therapies: surgery, radiation ablation, these sorts of things. Because if you can render a patient NED with locally directed therapies, there’s a subset of those patients who will do very well. That depends on the number of sites, but also kind of the trajectory; whether it’s rapidly grown disease or whether this is 10 years after the primary, there’s a singular recurrence that you can deal with locally directed therapies. So, that’s one branch point.

The second is whether this is clear cell or one of the variant histologies. There’s individual variants like RMC that really have a totally different treatment paradigm. My thinking does shift between something like a papillary and certainly a chromophobe compared to a clear cell, just as I think of a pure IO-based approach versus non-pure IO-based approach. But for most clear cell patients in front of me, the next thing I assess is, for lack of a better term: What is the rate of disease growth? In my mind, I’m thinking, “Is there some sort of impending visceral crisis?” Because the question I’m asking is, “Am I thinking of the long term, where I am hoping this patient, if they respond, they might have a reasonable chance of being in response 2, 3, 5 years later down the line? Or do I need a response right now? If this patient doesn’t respond in the next 6, 8, 12 weeks, is it actually going threaten their life in some way in the short-term?” That helps me to think a little bit between IO/IO-based approaches and IO/TKI-based approaches.

Again, we talk about the one outlier here, which is sarcomatoid histology, which tends to skew me more towards the IO/IO, but if it’s non-sarcomatoid standard clear cell, that’s my decision tree. If it’s something where I need to get a rapid response, I need to cytoreduce, or this patient’s really sick, I veer towards the IO/TKIs just because, when we do comparisons between trials, they almost certainly have a higher response rate, and so that’s really what I’m going for is a high response rate, low risk of primary progressive disease. If there’s a patient who, yes, it’d be great to get a response, but if they don’t respond in the next 8 or 12 weeks, it’s not going to really impact their life in a meaningful way, and I’m thinking about the long term, that’s where I tend to go for IO-based approaches.

It’s not that I think IO/TKIs don’t necessarily have durability. I just don’t think we know perfectly yet. I think with CheckMate 214, with nivo plus ipi, we have long-term data where we really see that flattening of the PFS curve, where we kind of convince ourselves that some if patients get a response, decent chance are going to be a response a few years later. I just don’t think we have that longer term data that’s as convincing for the IO/TKIs yet.

So, that’s kind of my decision tree. I’ll go metastatic or not. Is it non-clear cell or is it clear cell? Then, it branches into basically long-term durability with IO/IO, or if I need a response upfront, do I need to cytoreduce? If I want to get this person to surgery in the short term, then an IO/TKI.

Dr. McKay: I think it’s really important to understand those clinical variables, those patient variables that are really factored into clinical decision-making when we are in the setting where we lack really robust biomarkers to guide just exactly what regimen to use. For patients that are progressing after they’ve seen IO-based treatments, what’s your strategy? Do you utilize the same sort of approach, or how do you think about therapy for those individuals?

Dr. Braun: It’s an excellent question; one where I think the landscape is changing pretty rapidly. I think if this question was asked a couple months ago, there are a lot of people who would use, even after an upfront, IO-based strategy, might use an IO/TKI in a later line. There’s certainly some evidence to support that. There’s the phase II trial from Dr. Lee at Sloan Kettering, which showed pembrolizumab plus lenvatinib having pretty good response rates after first-line IO. That really provided a basis for a lot of people to think about IO/post-IO.

The thing that has changed in the last couple of months is the CONTACT-03 trial, which really tried to evaluate this in a systematic way. For patients who had received prior IO therapy, getting randomized to a TKI by itself, cabozantinib, versus TKI plus IO, cabozantinib plus atezolizumab. This systematically asks that question, “Does IO/post-IO help?” There are some caveats to this trial, of course. Atezolizumab is not an approved agent in kidney cancer, and I think we certainly know it’s a clinically active drug. We know that back from the IMmotion150 trial, but it stills not an approved drug, so there’s caveats.

But at least the top line results really don’t show any benefit for the addition of IO/post-IO. It at least gives us a little bit of pause for using that sort of strategy. Personally, my approach is to go much more conventional. Obviously, I always think of clinical trials and think of what is the next evolution and what’s possible, and not just a combination of the existing job, but novel agents as well. But, for the standard patient who’s not going to be enrolled in a clinical trial, I use a series of TKIs. Cabozantinib is what I frequently use next, though there’s a whole range of very reasonable options. That tends to be my progression through the later lines of therapy.

View their other comments on Current Biomarkers, Novel Biomarkers, and Novel Therapies With the Most Promise.