Evaluating Safety Profiles of Upfront Regimens for mRCC

Daniel J. George, MD: Before we move on from this frontline setting, though in the interest of being fair and balanced, it’s important for us to recognize the limitations of these regimens in terms of their tolerance. They’re different. The reality is that we have difference in not just the adverse effects but in the mechanism of those adverse effects as well, from things like diarrhea and liver function test abnormalities to the chronicity of these adverse effects with TKIs versus with IO therapies, as well as how we manage it with steroids versus other supportive cares and now beyond steroids. The world of immune modulatory symptom management has gotten incredibly complex and requires multidisciplinary teams, as Rana mentioned early on.

Rana, do you want to talk to us a bit about adverse effects?

Rana R. McKay, MD: Sure.

Daniel J. George, MD: Take on the IO/IO combination, the IO/TKI combinations, and TKIs alone. How do you size that up, and what are you looking for? Then, when do you pull the trigger on these multidisciplinary teams?

Rana R. McKay, MD: It’s important to understand the nature of the toxicity profiles that we see with the VEGF targeting agent or IO/VEGF therapy versus IO/IO. With VEGF-targeted therapy, the toxicity tends to be dose-dependent: it’s predictable, it’s chronic, and it’s sometimes on-target and sometimes off-target effects of therapy. When we look at the IO regimens, specifically the PD-L1 targeted therapies, they’re not dose-dependent, and they’re not necessarily predicable. With ipilimumab, we know that the toxicity can be dose-dependent, but it is also not predicable. It’s hard to know who’s going to get toxicity with IO/IO. We don’t necessarily have a biomarker to say we should be barring somebody who has an existing autoimmune disease; we don’t have a biomarker to say you’re going to get it or that you’re not going to get it. I have no idea who is going to be in the one-third category to whom I’m going to end up needing to give steroids or the small population of patients who end up getting infliximab or TNF-alpha condition. One of the biggest things is communication with the patient around the toxicity, and especially the IO/IO toxicity because of the somewhat unpredictable onset.

With that being said, when we look at the toxicity profile curves from Checkmate-214, most of the severe grade 3/4 adverse events did seem to come on within the first 6 months or so of therapy. Once the ipilimumab was removed, discontinued, or stopped, and they remained on PD-L1 inhibition alone, then the degree of severe toxicity did come down; whereas, when we look at the IO/VEGF, there’s that chronicity of toxicity that we continue to see from the chronic ongoing TKI. The other confounder with IO/VEGF is that there’s a lot of overlapping toxicity, particularly with the diarrhea and the hepatitis, that you’re asking, “Which one is it?” You don’t want to call everything immune-mediated right away because that has significant implications for rechallenging, steroids, and tapering.

The beauty of axitinib is that it’s got a short half-life; you can quickly stop it. You can try to tease out, “Did the diarrhea get a bit better? Did their LFTs get a bit better? Okay, maybe it’s the axitinib. Let me ride this out and maybe redose them at a lower dose or something like that.” It requires a lot more nuance and a lot more checking to see what it is, whereas, with the IO/IO, unless somebody’s got some concurrent ongoing comorbidity or something, you can point to the IO/IO agent, the nivolumab/ipilimumab.

The biggest thing is communication with the patient and, honestly, the communication to the nursing staff, as well, because they are the people who are at the first lines. When a patient calls and says, “I’m having a little bit of diarrhea,” well, how much is a little bit? What’s your baseline? We have huge education sessions with our nursing team, our LVN [licensed vocational nursing] team; the people who are the front lines, who triage calls, and who triage symptoms. We instruct the patient, for anything that you’re not sure on, you can call us, and we’ll walk you through it, or we’ll triage for you. Don’t do the triage yourself. It’s about educating the entire care team.

When there are significant grade 3 or 4 adverse events, there may be delaying the initiation of steroids or dragging your feet around it. Where I’ve gotten burned has been where I’ve just thought, “Should I, or should I not?” If there’s a high index of suspicion, and the patient’s not doing well, start them on steroids. Historically, we used to do a full-fledged diagnostic work-up to get a biopsy to prove that it’s immune-mediated, but we don’t necessarily have to go through that if the patient is sick and there’s a high index of suspicion. Just start, and if there’s no improvement, then add the infliximab.

Daniel J. George, MD: That’s great advice. I’m curious: we’re all at academic centers, and we at academic centers have specialists and subspecialists in these areas of GI, or dermatology, or cardiology or what have you, who help us when we get into these complicated cases and whatnot.

How do you advise folks in the community, Neeraj? You’re up there in Utah, and you have a lot of community doctors in relatively rural areas. How do you advise them on how to manage that and when to send the patient to a tertiary center for help with this or when to bring in their local specialist who can help them recognize that this is something more serious with this rash, or something more serious with this pulmonary situation? How do you advise folks there?

Neeraj Agarwal, MD: First of all, my experience is that my community colleagues are smart clinicians who are able to manage patients with a hundred different kind of cancers. That’s the first impression I have of my community oncology colleagues. To start off, I wouldn’t say advise; I would say for patients with metastatic kidney cancer, I may have used ipilimumab/nivolumab just recently, but many of my colleagues are using this for melanoma for many more years. By far, VEGF/TKI plus PD-1 access inhibitor combos are more popular with the community practices as opposed to ipilimumab/nivolumab, which is the preferred regimen, at least in our practice, in academic institutions. This has to do with the unpredictability of the colitis part with ipilimumab.

The single most important factor that drives the uptake of VEGF/TKI plus PD-1 combos versus ipilimumab/nivolumab in academic cancer centers is that we have more support: supportive oncology clinics, triage lines, nurse practitioners, and fellows. These are usually not available in community practices, especially, and as you said, Dan, in the Intermountain West area. Many practitioners are all by themselves and 300 miles out, so if somebody is getting ipilimumab, I tell them to have a low threshold for starting steroids versus somebody who is receiving axitinib plus pembrolizumab, for example.

Daniel J. George, MD: That’s great advice, and Rana said this, as well: we’d rather be safe than sorry.

Transcript Edited for Clarity