Navigating Treatment Sequencing and Toxicity in RCC: Insights From TiNivo-2

Part three of this roundtable discussion examines the evolving role of adjuvant pembrolizumab and its implications for patients with renal cell carcinoma (RCC) who progress post-therapy. The panel also delves into the findings from TiNivo-2, comparing them to CONTACT-03, and discusses the challenges of re-challenging PD-1 therapy, the promise of dual IO combinations, and the role of TKIs in treatment sequencing.

Watch the fourth segment of this series: The Future of RCC Treatment Sequencing and Individualized Patient Care

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Dr. Beckermann:
One thing I’ve heard a lot about, so I want to ask the group here and get everyone’s collective knowledge, I think one of the questions that we were still left with as the field was moving forward while these trials were being conducted was that we got approval of adjuvant pembrolizumab. And while TiNivo-2 allowed for adjuvant pembrolizumab to be the IO that someone had progressed on, I think only about 16 patients were enrolled. So I don’t really think we got enough patients in TiNivo-2 to really inform us. And I wonder, though, if still CONTACT-03 and TiNivo-2, if they, I guess, influence how you’re treating patients that you’re treating with adjuvant PEMBRO, and then patients are perhaps progressing on therapy or after?

Dr. Hammers:
Yeah, I can say a few things on this. So I’m a little bit more the pessimist when it comes to re-challenging PD-1 after PD-1. Yes, you get one year of treatment. The truth is you actually have one and a half always, simply because receptor occupancy is so long. So you actually have a really long exposure to PD-1. And if you don’t eradicate the disease during the timeframe, I don’t think a rechallenge will do it.

I do think it’s important to then think about other immunotherapy targets. Often, patients come out of that space with minimal disease burden. They’re being watched very carefully and closely. And there is room for, for example, PD-1 CTLA-4. It’s a low number, but it’s a persistent number across different trials. Or there is space for development, quite frankly, for curative approaches or potentially curative approaches.

The TKIs, if choose, in my book, they’re all purely palliative. So it’s important to have selection criteria there, also options that may be more tolerable than others. That’s the value, I think, of Tivozanib, for example. But coming out of that, we shouldn’t always equate immunotherapy after immunotherapy. We should say what it was. So PD-1 after PD-1 or PD-L-1 makes just no sense. I mean, it should be a different target. And I would encourage the industry to develop more effective immunotherapies in that space, quite frankly.

Dr. Choueiri:
Yeah, I agree. The one thing, if you don’t mind, Katie, to add, the one thing that could be different is the combination of nivolumab and ipilimumab. There has been a study, a Phase 2 by the name FRACTION-RCC that showed that the combination of nivolumab and ipilimumab post-progression on prior PD-1 and PD-L-1 inhibitor, the NIVO3-IPI1, the Hammers regimen, provide around 17% response rate that are durable, around 40 patient.

And now is this related to the combo? This is probably IPI only, et cetera. So in patient that have maybe sarcomatoid histology, although it would be hard to feel that you experienced progression on PEMBRO. Or where the progression has been slow, I have used that. And I have patient I have cured. However, I went back to my database and these have been patient treated with PD-L1 inhibitor, mostly. But this is something I could do occasionally.

Dr. Barata:
And Katie, I just want to emphasize Hans’s point, which I think is truly important. And by the way, Toni put a really elegant algorithm of how to approach these patients on ASCO Daily News. So shout-out there. I just want to highlight Hans’s point about how you get to metastatic disease post-adjuvant therapy is actually, you can get it in different ways. You have different presentations.

And we all talk about local therapy. I think we’re going to learn a lot more what that means over time, as more and more patients are being exposed to adjuvant PEMBRO. And when we start getting more recurrences, I do have now almost a handful of patients who recur on one site, or one or two sites, or really think about resections. Also, the staging. I mean, two of my patients were found with disease outside chest, abdomen, and pelvis, including soft tissue in the limbs or shoulder, if you will.

So I would just say that it is an opportunity for us to understand about. And by the way, on the KEYNOTE-564, we actually see that, right? Well, we see less than 50% getting subsequent therapy. But also, when you look at the number of local therapies, offer radiation, surgery, 25%, 25%, I really think it does speak to the different biology. There are different ways for patients who get to progressive disease, into metastatic disease, and they’re not the same. And probably, they definitely don’t need the same approach.

So I just think as time goes by, as we’re going to have more and more patients, I think we’re going to see in the future different data sets for maybe the patient type that falls into these different categories. People who might get a dual IO base approach, recurrence too late, perhaps, disseminated disease, versus those who are going to have oligo-recurrence, who might be offering a lot more local therapy. And we see what they do over time, because we actually don’t have much data in that context. So I think just to highlight that point one more time, because it’s not a one-size-fits-all. And we will see this over time, I believe, as more data sets are filled into more patients getting there.

Dr. Beckermann:
And I think maybe the one thing we haven’t reviewed from the TiNivo-2 study, maybe to circle back is, and I know Dr. Hammers mentioned this a little bit regarding side effect profile, we saw in CONTACT-03 a little bit of increased toxicity in that combination arm, increased SAEs, I believe. It seems to my review that the TiNivo-2 had pretty similar side effect profile as what was seen prior on TIVO-3 with that full dose. And then in the combination arm here, that there weren’t. Of course, now the TIVO being reduced dose, but the combination there having pretty similar side effects.

So I guess one question to the group here is knowing it’s a selective VEGF and that you certainly are going to be needing to deal with hypertension, did anybody have any concerns about the side effect profile from TiNivo-2? Or is that something that would be the point that you would highlight to a patient when you’re choosing your next TKI?

Dr. Pal:
I have very much the same interpretation as you do, Katie, regarding the tox data from TiNivo-2. It looks pretty balanced between the two arms. It’s a little challenging to infer, because on the one hand, you’ve got a lower dose of the TKI in combination with a checkpoint inhibitor, versus a full-dose TKI. So counterbalancing the two, understanding attributions is always a little bit tricky in that context.

I didn’t see any really new or emerging safety signals. I think the data from TiVo-2 confirmed my clinical experience with the drug, which is that perhaps the most challenging side effects, which I think are quite manageable with TIVO, tend to be the hypertension and fatigue. Those really do stand out to me. I have had instances where I’ve gotten cardiology involved to manage refractory hypertension in my patients on TIVO, but for the most part, it’s something that I have been comfortable managing in my clinic. And that’s sometimes a stretch for me, because I know very little cardiology.

Dr. Beckermann:
That’s great to hear. And yes, I agree, we’re fortunate to have cardio-oncology colleagues, but certainly learning a lot about hypertension and management there.