RCC Doublet Considerations: Immune-Mediated Toxicity, Duration of Treatment, and More

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt University Medical Center, focused on the spectrum of therapy for frontline renal cell carcinoma (RCC), including a comparison of monotherapy and doublet and triplet treatment options. Dr. Rini was joined by a panel that included Monty Pal, MD; Moshe Ornstein, MD; and Shuchi Gulati, MD, MSc.

In the next segment of the roundtable series, the panel discusses treatment-related toxicities and when to consider stopping treatment.

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Dr. Rini: I wanted to talk about retreatment with immune therapy after immune-mediated toxicity. Let’s say a patient has a bothersome grade 2/3 requiring steroids and pick whatever one you want. Either for ipilimumab/nivolumab or an immuno-oncology (IO)/tyrosine kinase inhibitor (TKI) regimen, what’s your threshold to then reintroduce the immune therapy? Because I think that comes up in practice. You’re like, well, it wasn’t a terrible colitis, but it was kind of bad and I needed steroids, or it was liver function test that didn’t resolve or something, and I’m not really sure when to restart. Moshe, let’s start with you.

Dr. Ornstein: For me, the pendulum has swung. When I first started seeing patients, I was very concerned if I saw an immune-related toxicity. They weren’t getting the IO again. Then I kind of shifted and was saying, we’ve got all these specialists, we know how to manage the toxicities, we want the long-term benefit of IO. Everybody should get it. It all comes down to patient selection. The 2 immune-related toxicities that I’m most concerned about, and as a general rule, don’t resume, is if it’s something neurologic or cardiac. But if we’re talking more about colitis or transaminitis or even dermatitis, I look at a few things. How severe was it upfront? How much did it impact the patient’s life? How long did it take them to return to a grade 1 with immunosuppressants? If somebody needed 4 months of relatively high doses of steroids, plus another immunosuppressant, you might not want to rechallenge that patient. But if somebody who had an AST and an ALT in the 200 to 250 range, and they were on prednisone for a week and then quickly lowered, that patient you might be more likely to say, let’s retry it. I do quote patients that it’s probably a third of patients who had an immune-related adverse event and are rechallenged with an IO agent that are going to develop either the same one or another one, and that’s the discussion with patients.

Dr. Rini: Shuchi, would you think the same approach or something different?

Dr. Gulati: I agree. I just want to add that myocarditis and neurologic side effects, I don’t rechallenge those patients with immune checkpoint inhibitors.

Dr. Rini: Myocarditis is 50% fatal, so…

Dr. Gulati: Exactly. But others, I agree with you.

Dr. Rini: How about pneumonitis?

Dr. Gulati: If it was something I managed as an outpatient, they needed a touch of steroids and then it resolved, it’s fine. But if the patient ended up in the ICU and they were intubated, I might consider not using it.

Dr. Rini: Similar to Moshe. Monty?

Dr. Pal: I’m feeling like a real wimp because I actually don’t rechallenge very much if I get to that level of needing steroids and so forth. If their liver function tests are up to the 250 to 300 range, or they recover after a week of steroids, I’m not entirely sure it’s necessarily IO-mediated in that context. Usually a real IO-mediated issue is going to take weeks and weeks of steroids for resolution. Then I really have a very, very high threshold, if at all, for restarting therapy.

Dr. Rini: You’re not restarting, but do you use scan results to decide? If somebody’s responding wildly versus stable, like truly stable, zero-zero.

Dr. Ornstein: I think if someone’s had an exceptional response, and they’ve been on therapy already for 9 to 12 months, where usually they’re going to have the depth of responses they’re likely to have, I would take that into consideration. But someone who’s still relatively early on, 3 to 6 months in, I’m not sure they had the IO benefit yet. I think it’s worth the discussion because the only way we’re going to see a long-term clinical benefit for the patient with a deep, durable response is with IO-plus. I do have the discussion with them. I lean heavily on the specialists. We have gastroenterologists that are interested in this and rheumatologist interested, and we loop them into the discussion.

Dr. Rini: Which is an advantage at a large academic center that in the community they probably don’t have—pick up the phone and call somebody who not only is a gastroenterologist but has an interest in immune-mediated toxicity. That’s a very different breed, but I agree with you.

Last topic around doublets is duration of therapy. As long as we’ve been giving immune therapy, we really have no idea what the right duration is. We’ll start with that as a premise, but Monty, when you’re giving cabozantinib/nivolumab, are you stopping the nivolumab at 2 years? What are you doing with the cabozantinib? Are you basing it on response? If somebody has to stop for toxicity, obviously let’s take that out of the equation. But they have expected but manageable toxicities.

Dr. Pal: I really leave it up to the patient. By the time I’m getting out to 2 or 3 years on IO, the patient is usually developing some bothersome arthralgias or other side effects that make them want to stop. But if they’re cruising along and if they actually feel more comfortable staying on therapy, I’ll give them the option of continuing. I will bring up discontinuation. But more often than not, I’ve found that if they’re completely unbothered by toxicity, they really would prefer to stay on in that scenario. The one difference is in the setting of a complete response (CR), then I definitely have a stronger conversation around discontinuation, maybe even earlier than 2 years.

Dr. Rini: In practice, I think we see far less CRs than those near CRs. There’s a lymph node here, and there’s lung nodules here. What do you do with those deep partial response (PR) patients?

Dr. Pal: I usually keep them going. I’ll have that conversation with the patient, but it’s disconcerting to them to see that there’s still residual disease lingering for the most part.

Dr. Rini: Well residual abnormalities. We don’t know if it’s disease.

Dr. Ornstein: Do you get any pushback from insurance companies? Because I’ve had instances where I’ve tried to continue the pembrolizumab after 2 years and the insurance will decline it.

Dr. Pal: I haven’t run into that yet, actually. Have you guys?

Dr. Gulati: No.

Dr. Rini: I’m always stopping, so I haven’t run into it, but Shuchi, what do you do duration wise?

Dr. Gulati: Other than complete responders, I’m not stopping it. I probably have a lot of patients who will get super anxious even if I mention stopping. Other than complete responders, I keep going. Maybe I haven’t been in practice long.

Dr. Ornstein: I think patients want to stop the TKI. I know we’re talking about stopping the IO as per the trials. I have the discussion at the 2-year mark and for patients with a deep PR, I lean toward stopping. I think that patient has had a 90%-plus tumor burden reduction and has been on therapy for 2 years; at that point they’re kind of done. They don’t love the idea of coming in every 4 to 6 weeks, depending on what they’re getting. They’ll start by skipping every other infusion, like not showing up.

Dr. Rini: I stop in pretty much everybody. Frankly, I don’t give them a choice. I say, “This is what the trial showed. We have level 1 evidence.” We don’t have great analysis of patients who stopped yet. There’s a little from KEYNOTE-426, hopefully we’ll have more, and I’m sure from the other studies. I just say, “Listen, the way this regimen is designed, we’re going to stop the infusions at 2 years.” I think it’s partially reflective of the geography in which I practice in. They say, “Okay, doc, great. Awesome, I don’t have to come in.”

TKI is more challenging. It’s really the one you want to stop. It’s the one causing chronic toxicity predominantly. I don’t really have a standard practice. I don’t necessarily stop it, but what I tell people is take breaks as often as you want.

Dr. Ornstein: I find that if they’ve gotten to the 2-year mark and they’re still on their TKI, they’re taking their breaks every few weeks and not telling you, or they’ve already assigned they’re taking it Monday through Thursday in their pill box along with all their other medications. They’re on some schedule where they figured out a way. I find the chronic toxicity of TKIs to be within those first 6 to 9 months. I think once a patient has figured out how to be on it beyond 1 year, they know how to handle it.

Dr. Rini: They kind of figured it out, by definition.

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Continue on to watch the next roundtable segment.