A roundtable discussion, moderated by Monty Pal, MD, of the City of Hope, focused on updates in renal cell carcinoma (RCC), including treatment in both the frontline and adjuvant settings. Dr. Pal was joined by a panel that included Daniel George, MD; Brad McGregor, MD; and Cristina Suárez Rodríguez, MD.
In the next segment of the roundtable series, the panel considers how to treat in the adjuvant setting following prior IO/IO or IO/TKI treatment.
Dr. Pal: I’m going to shift gears to another controversial topic. We’ve all probably had some discussions around adjuvant therapy over this past year or 2. Let’s just assume for sake of discussion that adjuvant therapy is the standard with pembrolizumab or immuno-oncology (IO) for high-risk patients. We’re starting to see these patients now who have adjuvant therapy with pembrolizumab and actually progress beyond that. I wanted to have a first-line discussion, but now in the post-adjuvant setting, if you will, let’s envision a patient first, Brad, who has maybe T3 grade 4 disease, goes on to adjuvant pembrolizumab, and progresses at the 2-year mark following adjuvant therapy. How would you consider that patient’s frontline approach?
Dr. McGregor: This is really an area we are hoping we know what we’re doing because we don’t have any great data to guide therapy. I think overall we say, if you have gotten immunotherapy for a year and had a year disease-free interval, that would imply that maybe immunotherapy is actually doing something and maybe just didn’t have enough. Actually, for patients who have over a 6-month treatment-free interval, I would imagine that they’re treatment-naïve and go about that approach, and some of the trials support that. In the ongoing trial, if it’s been over 6 months in the adjuvant setting, you could enroll. In that situation, over a year, I’m inclined to think about an immunotherapy-based approach. Which one? IO/IO, IO/tyrosine kinase inhibitor (TKI).
Dr. Pal: What do you think, Dan?
Dr. George: A couple questions. Would you consider that patient favorable risk or intermediate risk? Because they had a year-plus of therapy. Because that pembrolizumab sticks around a while, and now they’re progressing relatively shortly after discontinuing the pembrolizumab exposure. We don’t know that natural history and what that is. I think you could treat them either way is the bottom line. But they’re most likely going to be low volume because we’ve been following these patients, and their disease is going to be relatively low volume. I think of it as a favorable-risk setting. You could watch them if it’s really low volume and slow; if it’s multiple sites, I think you could start therapy, and if it’s a single site of disease, I think you could think about a single site of local treatment at least 1 time. That’s the way I would think about that patient population and managing them based on the volume of disease, the number of sites, and whether or not I think of them as intermediate or favorable.
Dr. McGregor: But you wouldn’t consider this to be an IO failure given that it’s been over a year? I think that’s the key.
Dr. George: I don’t actually think there are any IO failures. I’m not trying to be controversial here. But mechanistically, IO therapy isn’t targeting the cancer. The cancer is not becoming resistant to IO. It’s just that our immune system is not recognizing it; it needs something else.
To me, I think of IO therapy as contextual. Sometimes 2 IOs, 1 complimenting the other is the right context. Sometimes adding a TKI and having that response and that effect on immune cells is the right context. Sometimes that might be after radiation or after surgery and there’s an inflammatory recovery response and that’s the right context. Whatever setting, it’s different. To me, even these refractory settings, these rechallenges, they’re contextual. As long as you’re changing the context, I think it’s reasonable to consider IO in that setting.
Dr. Pal: I’ll push you a little bit further there, Dan. This patient, again, progressed on pembrolizumab. We won’t call them an IO failure given your stance there.
Dr. George: Previously treated.
Dr. Pal: Previously treated. There you go. What’s the dogma going to be in the future for a patient like this? Are we going to approach them with IO/IO on rechallenge or TKI/IO? Because it really is a matter of perspective. You can just say they’re an IO responder or maybe they need that booster from a TKI.
Dr. George: I think this is where we’re going to need some data. It’s going to be hard to write those trials because there’s such variation in adjuvant use and the timing of recurrence and all this stuff. I think it’s going to come from real-world experiences doing prospective collection of patients with metastatic disease or these adjuvant settings. Having an adjuvant registry to be able to see what are the ultimate outcomes of these patients and what happens when we retreat? That will be the real value of doing that kind of work.
Dr. Pal: Cristina, tell us your perspective, and how might you treat this patient.
Dr. Suarez: For me, something that makes sense is 6 months, like you mentioned. The immunotherapy experts put the time point in 12 weeks, which, for me, is a little bit short to consider a patient refractory or not to immunotherapy in the adjuvant or metastatic setting. For me, it’s still 6 months; like other tumors and the patient progresses after 6 months, I don’t know what to do. If the patient progresses after 1 year, I could consider immunotherapy-naïve and be in the first line situation again. I would have the same doubts about that patients in the first line because at the end of the day, the immunotherapy did something if the patient was without disease for 1 year.
When you want to consider resistant to immunotherapy, I very much like your comment. You are not targeting the tumor. So resistant to what? I don’t know if we will be able to extrapolate data from the TiNivo or CONTACT-03 trials to the adjuvant setting or not because it’s a different situation. The microenvironment is different when you are not metastatic.
Dr. Pal: Fair enough. A scenario for you, Brad, it’s tougher still, or maybe not. Let’s say this is a patient that actually progresses while on adjuvant pembrolizumab. What should we do there? We’ve all participated in the studies; we’re seeing these patients. What do you think? The patient is on adjuvant pembrolizumab and starts having tumor growth. What are you going to treat them with?
Dr. McGregor: I think that is a tougher question. I think that gets the same question in the metastatic center. Do we continue the IO? In this situation, you’re growing while on a checkpoint inhibitor. I would say I maybe could extrapolate more from TiNivo-2 or CONTACT-03 to that situation, although it’s unclear. I don’t think there’s a right answer. You could add a TKI to the pembrolizumab and continue that and hope that maybe there’s some rescue of the immunotherapy.
Dr. Pal: What are you doing right now? If you saw this patient in clinic, what are you going to offer them?
Dr. McGregor: I have done both. I’ve added TKI to pembrolizumab, and I’ve switched to cabozantinib.
Dr. Pal: You can do anything. Got it. Fair enough. It’s reasonable. There are many, many options for a patient.
Dr. McGregor: It’s really driven by the patient. There are patients who can drive that discussion. There are some patients who hold on to hope of that immunotherapy. Other patients are like, “This isn’t working. I don’t want get IV anymore. I’ll do a pill.”
Dr. Suarez: It’s clear for me that the patient needs a TKI. I don’t know in monotherapy or in combinations, but if you see the data from Titan trial using ipilimumab in this setting, it’s not going to be a good strategy. The only thing I think we all agree is that the patient needs a TKI, then in combination or not, who knows?
Dr. George: I think some of it depends on how they’re tolerating it. If they’re doing beautifully on that and they’re comfortable, and I could just add the TKI, it’s tempting to do that.
Dr. Suarez: But you would add the TKI, or you would change the IO as well?
Dr. George: Again, if they’re tolerating it well, I’m less likely to change it. Then if they don’t respond or there’s resistance or progression, then I’m kind of making a bigger wholesale change. But for the patient that has low volume, asymptomatic disease that I’m picking up on scans and tolerating the pembrolizumab well, maybe I’m adding because I don’t necessarily see that as resistance. I see it as I haven’t engaged the IO therapy yet.
Dr. Suarez: Adding the TKI to IO makes lots of sense, because they are synergistic, and you are changing the environment. Maybe you can push the effect of the IO when you are introducing the TKI. Maybe the immunotherapy can work better with the TKI.
Dr. McGregor: To Dan’s point, sometimes they’ll have oligoprogression on adjuvant IO, so I’ll do SBRT [stereotactic body radiotherapy] or something at that site and hope that we get some other effect there. When there wasn’t IO, you think about surgery in that situation—radiation. I still have that same mindset. I’m like, let’s do local control to this single 1 or 2 sites and they would just continue the IO.
Dr. Suarez: I do a lot of that.
Dr. Pal: We could probably keep talking about this for another 3 hours. This is a great topic.