Daniel J. George, MD: Second-line renal cell carcinoma is probably one of our widest selection opportunities in solid tumors. We have, if you look at our NCCN guidelines, no less than 10 different treatment options listed there, many of them based on what we call “level 1 evidence.” There were phase III study data showing a significant clinical benefit versus a standard control arm and a consensus among the panel. So, how do we select therapies? Let me walk you through what I consider to be probably the 4 most common treatment options for patients in the second-line setting and give you at least a thumbnail view of how I consider the value to each one of these.
Let’s start first with, who are the patients that we treat with second-line axitinib therapy? Axitinib is a drug that has been around for a while. It was approved back in 2011 based on a phase III study showing a statistically significant improvement in progression-free survival for axitinib compared to sorafenib, another VEGF TKI in the field. And so, that’s compelling. That’s helping us understand that these 2 drugs are not bioequivalent; one is superior to the other. There wasn’t an overall survival benefit, however, seen in that study.
Axitinib gives several differences in the field for VEGF TKI though, besides that clinical benefit that was seen. Axitinib has the shortest half-life. It is a twice-a-day medicine that allows us to have fairly good control in terms of our dosing. It comes as a 5-mg tablet that we can dose-escalate in some patients by 1 mg increments, up to 10 mg twice a day, or decrease the dose down, again by 1 mg increments, down to 4, 3, 2, even 1 mg twice a day.
I find axitinib is a drug that I like in patients, where I’m really concerned about tolerance, because I have an ability to go up and down, particularly down, in that drug. It also is the only drug that’s approved to allow us to go up. Let’s say I’ve had a patient that has been on a VEGF inhibitor and hasn’t had an increase in their blood pressurethat has been, for us, a biomarker in predicting who’s benefiting from a VEGF inhibitor. Axitinib gives me the opportunity to escalate that VEGF inhibition above and beyond what has, in the general population, been the maximum tolerated dose.
So, I like it for the dose flexibility, particularly in those patients that didn’t show that increase in blood pressure. I like it in patients that have particular toxicities like liver toxicity, to other agents, because it has the least amount of hepatotoxicity associated with it. And I like it because it gives us the ability to shut the drug off very quickly. If I have a patient that is perhaps having real difficulty with diarrhea, I can wash the drug out very quickly. But because we don’t see a survival benefit with it, for me, it’s a drug that I’m focusing on primarily in that second-line space, in patients where I’m confident we’re going to be able to get on to subsequent lines of therapy, particularly other agents that have that overall survival benefit.
Now, the next agent we can talk about is nivolumab. Nivolumab is different from the VEGF tyrosine kinase inhibitors because it’s a PD-1 inhibitor. It’s a completely different class of agent, works by primarily activating the immune system, particularly T cells, to attack the tumor, and results in about a 20% response rate in this second-line space in patients previously treated with a VEGF TKI. I like this drug not only because it has a response rate, but because it has an overall survival advantage associated with it.
What’s interesting about this drug is it’s not necessarily associated with an improvement in progression-free survival. For me, for patients that have relatively slow progression of disease, progression-free survival is less of a driving issue. I like this drug. I also like this in patients that have relatively aggressive or poor prognostic features because the drug was shown to have its survival benefits in patients that had worse prognosis. So, in patients who have poor prognostic features but maybe have a relatively modest disease progression, to me, that’s a really ideal population for nivolumab. I like it in patients that had difficulty tolerating a VEGF TKI because, again, a different mechanism, a different side effect profile.
I’m not as keen on using nivolumab in the second-line space or in patients who have a need for steroids. Steroids are one of the limiting factors on this agent, particularly high-dosed dexamethasone for brain metastasis, spinal cord metastasis, or significant pain control issues. Those are patients where we run into trouble being able to dose nivolumab when the dexamethasone is used at, say, 4-mg daily doses or higher.
So, that’s one of the limiting factors. Another would be patients who have pre-existing autoimmune conditions, where we’re worried about flare, whether that be lupus and rash or whether that be other autoimmune conditions with a GI tract, ulcerative colitis, or Crohn’s. Other situations for me, besides the brain metastasis, would be really symptomatic bone metastasis, where I’m concerned about progression resulting in complications requiring surgery, radiation, need for hospitalization, or need for steroidsso impending complications or preexisting complications also can prohibit our ability to dose the medicine effectively. Those would be the reasons for and against nivolumab.
Now there’s a new combination out there called lenvatinib/everolimus, which is an interesting combination strategy that was also studied in the second-line space and is also FDA-approved here. It’s based on relatively limited data, so we have a relatively small randomized phase II study comparing that combination to everolimus alone and demonstrating a survival benefit, response rate benefit, and progression-free survival benefit.
Our experiences with this combination are more limited, but it’s exciting to see the data because of the long overall survival and the relatively high response rate seen with it in the 30%-to-40% range. To me, this is a combination I’d consider, particularly in patients where we think the everolimus component is warrantedpatients who didn’t respond at all to a VEGF-targeted therapy, patients with known mutations associated with the mTOR pathway. Mutations in mTOR—TSC1, TSC2—these are enrichments for a response to everolimus and mTOR strategies, and even the lower dose of everolimus here could be very responsive. So, that’s another kind of selection approach for patients who tolerated VEGF-targeted therapy well and we think are robust enough to tolerate this combination. I think that’s another important factor; along with the increased efficacy, increased toxicity was seen. So, in patients who I’m worried about toxicity tolerance, this combination may not be such a good choice. Overall, because our experience is more limited, I’m focusing that strategy more on the patients with genetic susceptibility and other reasons why we think maybe an mTOR strategy makes sense.
The last agent is, of course, cabozantinib. And cabozantinib was approved specifically in this space in patients previously treated with VEGF-targeted therapies. And in that space, again, cabozantinib demonstrated clinical benefits in overall survival, progression-free survival, and in response rates. What’s nice about the cabozantinib data is that it showed benefit across all subgroups. There wasn’t necessarily one group that was less responsive than another, and that makes it easy. That makes it easy for us, knowing the genetic variation and the variance in response to primary VEGF-targeted therapies. This is an agent that can be used regardless of those issues. So, to me, it’s an agent I’m particularly interested in in patients who have tolerated VEGF-targeted therapies, but are no longer responding.
Cabozantinib is different from all the other agents in the field in its ability to inhibit MET and AXL, and those 2 targets may be really important, not just in adding to the profile, but in specific mechanisms of resistance to primary VEGF therapy. We see really high progression-free survival rates for cabozantinib in patients previously treated with either ceritinib or pazopanib, our 2 most commonly used VEGF TKIs in the frontline space.
So, in summary, I think you’ve got a choice of multiple agents out there to use. I think there’s rationale for using any of these. I think probably the agents that offer the greatest overall survival benefit in this space, as well as disease control and response, are the ones that are probably most attractiveand as well as immunotherapy—because of the change in mechanism and the opportunity to get this more perhaps durable disease control in a subset of patients.
Case Scenario 1: A 50-year old male with relapse of metastatic RCC