In a one-on-one conversation between Brian Rini, MD, and Elizabeth Plimack, MD, MS, they discuss updated KEYNOTE-426 and CLEAR data released at the 2023 ASCO® Annual Meeting and IO/TKI treatment options for patients with renal cell carcinoma.
Dr. Rini: We’re going to talk today about several topics; the first being updates for immunotherapy (IO)/tyrosine kinase inhibitors (TKIs) that were presented at ASCO 2023. As many people know, there’s been debate really over the last several years about the appropriate frontline doublet in kidney cancer. Ipilimumab/nivolumab is an all-immune doublet with the longest data, I think characterized by durability of response and on the positive side. Then there are 3 IO/TKI doublets that have shown to extend survival over single-agent TKI: KEYNOTE-426, which was axitinib/pembrolizumab, CheckMate 9ER, which was cabozantinib/nivolumab, and the CLEAR study, which was lenvatinib pembrolizumab. KEYNOTE-426 and CLEAR had updates at ASCO , and I think I’ll describe them, Betsy, then I’ll ask you your opinion on them.
I think in general I would say that these updates are really important because the outlook for kidney cancer patients is now measured in years, in 5-plus years, and there are patients who can have durable disease control. It’s not just short-term outcomes that we care about, it’s long-term outcomes. I think it’s very important that these 5- and 4-year updates were presented.
Axitinib/pembrolizumab, what we saw was not surprisingly preservation of response rates in progression-free survival (PFS) as all those events happened early. We saw preservation of the overall survival benefit. There’s no formal statistical testing as you get far out because all these trials met their endpoints early on with significant P values. We did see the hazard ratio rise for KEYNOTE-426 up into the 0.8 range, and I think what that reflects is that the vast majority of sunitinib monotherapy patients, patients randomized to that arm, the vast majority got salvage therapy and the vast majority got salvage immune therapy. In fact, most people got more than 1 line of subsequent therapy, and I think that that reflects the real world. That’s what happens to patients in the real world is that they tend to get multiple lines of therapy.
I think the other, probably, 2 features of that study were that I think we are seeing a flattening of the curve for PFS at about 20%. Again, this is a minimum 5-year follow up, so pretty far out for that one-fifth of patients. Also remember, in all these studies the IO component stopped at 2 years and that’s probably a whole separate discussion. Perhaps we certainly still need more follow up, but I think there is maintenance of that disease control, that immune effect if you will, now that we get out to 5 years for KEYNOTE and 4 years for CLEAR. I think the CLEAR update was largely similar. Again, it was 1 year less just the timing of the trial, but 1 year less.
My summary for these trials was that I think they reinforced current practice. I don’t think there was anything earth-shattering one way or the other. I think it’s good to see long-term data; it’s good to see data now, 2 and 3 years after stopping pembrolizumab. I don’t know that they’ll impact practice much. I think if you’re an IO/TKI user you’ll keep using it; if you’re an ipilimumab/nivolumab user it probably didn’t sway you. I don’t know what your thoughts are, Betsy.
Dr. Plimack: Sure. I agree; I do think our opinions are somewhat fixed early based on what data comes first, which is maybe good, maybe bad, I don’t know. It’s another discussion. I agree these long-term data can be thought of as sort of nuances or reinforcing what we’ve already thought. I was just encouraged, I think we need to start looking at long-term data a little differently than we look at short-term data, because we have the luxury to do that because we have people riding these curves out really far.
A couple of things to pay attention to are, when looking at duration of response, how many people respond in the first place because in order to have a durable response you have to respond. We tend to look at those curves in isolation. Looking at how clean the curves are, are we really collecting data out 5, 7, 10 years beyond? It’s hard to do in a study. A lot of companies decide not to do it. To the credit of these companies, they have decided at least to do it to 5 years, which is great. But some studies have a lot more dropout than others; some data are collected a lot more sort of assiduously than others. It matters because the cleaner the data, the more accurate it is in terms of what we’re looking at.
I agree; I think we’re continuing to see reinforcement of the short-term outcomes we saw before; the response rates, again, haven’t changed. PFS does happen early, it’s something that’s in imbalance in how it’s captured across the studies. I think the further out we get, the less relevant the comparator is to the control arm, in my opinion, than the comparator across trials, which is of course fraught. That’s because sunitinib is no longer the standard of care; it’s not something we’re doing anymore, and subsequent therapies have evolved a lot over the course of these trials.
I do hope further follow up gets us to look at a couple key things. One is landmark data for TKI/IO combinations compared to ipilimumab/nivolumab, which will always have the longest data because it started sooner. I think looking carefully at what data is actually captured versus what’s inferred in the curves is going to be important because we make treatment decisions when we meet a patient, hoping that we can predict, based on what we choose, their best long-term outcome. Looking forward with the data we have in order to make decisions at the initial presentation is one of the challenges in the field.
Dr. Rini: Let me ask, you were there for the discussion and there was some discussion around what’s in the best long-term outcome of our patients. There was, I think, much debate and discussion not only at the session but afterwards. You’d mentioned that in your comments, that of course you have to respond to be a durable responder. How do you compare regimens? This is a sort of trick question; how do you compare regimens? As you say, we’re really comparing all parts of the curve, right? It’s not just the long-term responders we care about, it’s all patients. Like you say, you’re making a treatment decision, you don’t know if the patient’s going to respond on day 1. Obviously if you did, we’d all be a lot smarter and treat patients better. Let me phrase it another way. Do you put much stock in comparing tails of the curve and saying one has a better long-term outcome?
Dr. Plimack: Yeah, so we discuss this a lot. I think the ipilimumab/nivolumab curve has a lot of dropout. I wish it didn’t. I think it flaws our understanding of how durable these responses really are, and so it’s harder; I would say I trust the TKI/IO data better, more, because it’s cleaner and the capture of these events was more fastidious. I’ll put that there.
I think short-term benefit is important. You have to respond to be a durable responder. If I have 100 patients theoretically in front of me, I’m going to want as many of them as possible, collectively, to get as most time as possible on this planet feeling well, with their family, enjoying life. It’s not just rolling the dice for the best long-term outcome, especially since we’re not totally sure or secure into what that is with ipilimumab/nivolumab. But collectively, I really feel like the IO/TKI regimens give the most patients the most number of years overall. It’s also influenced by my clinic where I have a lot of people in treatment-free survival after ceasing therapy with IO/TKI. I think that’s where anecdote kind of reinforces the lens that I use to look at that data.
Dr. Rini: Yeah, that was going to be my next question maybe to wrap this up, was about stopping IO at 2 years. I tend to do it, if I haven’t stopped already. Of course, I tend to sort of prep the discussion when they have 2 or 3 infusions left and say, hey listen, here’s how the studies were conducted. I don’t think we see curves come together afterward. I don’t think there’s any drop off of those patients after 2 years. Quite obviously they’re the best patients, they’re doing well, they made it to 2 years on therapy, etc. I tend to stop IO at 2 years. I use a lot of axitinib/pembrolizumab and lenvatinib/pembrolizumab.
Then the TKI is sort of a discussion with the patient. Most people are still on the TKI at that point. We don’t have good data about stopping the TKI or the dose or anything, but I tend to encourage very, very liberal breaks. I’ve had a couple patients just in the last month say, hey doc, I’m kind of tired of taking these pills, can I stop? I say, sure, if you’re willing, I’m willing, let’s go. Let’s stop everything and see what happens. That takes, I think, some bravery by the patient because there’s no real data. But I don’t think it’s an unreasonable approach because, again, quite obviously they have durable control at least at 2 years.
Dr. Plimack: I totally agree with that, and I do the same. I would say one of the conversations we have around that juncture is, we would love to get you to this treatment-free survival where your cancer is controlled and you don’t need any treatment, and we won’t know if you’re one of those people who has achieved that unless we try. It’s sort of asking the question, is this something we should try to do? But it’s absolutely a conversation, and again, this underscores your point to long-term data being important. We want to watch those folks and see how they do so we can inform the next set of decisions coming up the road as people hit 2 years.
Dr. Rini: I think it’s fair to say that this debate over doublets probably will continue long after we stop doing this, until maybe triplets come or something. But people are pretty grounded to their opinions and I guess it makes for…
Dr. Plimack: But there will always be the next thing, and I think as oncologists we have to at least try to be nimble and react to data and change our minds if what we previously thought is sort of upended by new therapies or new information.