IO/TKI and PD-L1 Approaches, Trials in nccRCC

In a roundtable focused on non-clear cell renal cell carcinoma, moderator Daniel Joyce, MD, of Vanderbilt University Medical Center, led panelists David McDermott, MD, of Beth Israel Deaconess Medical Center; Katy Beckermann, MD, PhD, of Vanderbilt University Medical Center; and Laurence Albiges, MD, PhD, of Institut Gustave Roussy in a discussion on the management of differing disease states, new approaches such as IO/TKI and PD-L1, novel trials, and adjuvant treatments.

In the second part of this series, new trials in the nccRCC treatment landscape are reviewed, and the use of IO/TKI and PD-L1 therapies are discussed.

Watch the third segment of this roundtable: Nephrectomy Versus Systemic Therapy and Risk Stratification in Papillary, Non-Papillary nccRCC

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Dr. Joyce:
Does the durability of adding an IO agent, does that influence your decision-making in these patients? Or is their standard of care now IO/TKI because of the recent data? Or are you saying, “Ah, let’s pump the brakes on that,” maybe TKI single agent, thinking about what’s coming down line and how you’re going to treat these patients as well?

Dr. McDermott:
If you’re asking me, I think, based on the exciting single agent activity, with a variety of these combos. So Laurence was part of the pembro-lenva trial. There’s NIVO-CABO data. You alluded to the IO/IO data, the recent data at ESMO with SUNNIFORECAST. All of those show interesting provocative data with PD-1 based combinations.

And one of the reasons they’re interesting is, Dan, the point you alluded to, is there are some patients who get a durable benefit. Which is the most exciting part in my mind of any IO approach is, it’s not the early impact, which is marginal. It doesn’t dramatically increase the response rate, doesn’t dramatically improve PFS, but there are patients out at the tail of those curves and we like to believe that that’s being driven by the IO portion. But it’s going to take randomized trials which are now ongoing to prove that and we’ll see. And it’s debatable whether the SUNNIFORECAST trial proves that or not. We can talk about that.

But that’s the reason to do it. That’s the reason to expose patients to the increased risk, because it probably improves durable benefit and we hope it improves survival for patients.

Dr. Albiges:
To me, the IO/TKI approach overall in non-clear cell, but we can restrict to papillary, has really provided a move forward. Because for the first time we saw a response rate that was actually higher than 50%. And that is true for CABO-NIVO data that has recently been updated. But also the LEN-PEM data you’re referring to. Because it’s a huge trial, the LEN-PEM trial was over 158 patients, the vast majority being papillary. 98 were papillary. And with more follow up, we now have a response rate that is 54%. So that compares extremely well with historical data we had with single agent, either IO or TKI. And I think it’s not related to the TKI only, it’s because we’re having both strategy.

Now with regard to the duration of response, we’re just generating those data now, because we’re so behind when compared to clear cell. But with LEN-PEM, we now have a median progression for survival that is in the range of 18 months compared to six months we had in the past with single agent TKI. This is major step forward. Sustainability with regard to this response is something that we are still waiting to hear from, and I would be happy to hear from you, David, what about the NIVO-IPI data? Do you feel that SUNNIFORECAST data were convincing from what you’ve seen at ESMO?

Dr. McDermott:
So the SUNNIFORECAST data is interesting. We have to commend the investigators for doing that trial. I think to me that’s one of the biggest innovations over the last decade, is junior faculty have been able to do trials that we couldn’t in our day, that prove that you could actually enroll non-clear cell patients. That’s an exciting step forward because we’re going to learn a lot more about these diseases, and we’re going to come up with better therapies.

When you talk about SUNNIFORECAST, you see the trial met its primary endpoint, which in some ways is an interesting primary endpoint, of one year overall survival. I like novel endpoints as a general rule. Although they picked the exact perfect endpoint, because had they picked a endpoint that was slightly longer in time, which I might’ve encouraged them to do, they might not have had a positive result. You see more tox when you add CTLA-4. They certainly saw that, but it may be worth it in the right patients.

And one of the interesting things that comes out of that trial, which sort of backs up what we saw in keynote 427, is that the PDL-1 high patients did better. And I think we’re a ways away from selecting patients in either clear cell or non-clear cell based on PDL-1, but testing for it and considering increasing the risk to patients if they were a PDL-1 high, to me, that’s something I would like to try to incorporate into our practice going forward, because that’s probably a real thing. It’s not a great biomarker, but probably enriches for success. And if you’re trying to decide should I expose my patient to more risk, to me you want that information before you make that decision, it feels like.

Dr. Joyce:
What about you two? Are you using PDL-1 status and everyone checking it, in all your patients with metastatic papillary or non-clear cell?

Dr. Beckermann:
No, I mean I think that we’ve seen it does enrich in the clear cell population. We don’t use it, but we know that those who are PDL-1 high, we hope that it is a helpful biomarker, but we don’t routinely use it in practice.

And just a comment on the IPI-NIVO data, I think it was that perfect time point. I think it goes along to say that combination therapy to me, this just hammers that nail in, that really we should be giving patients… I don’t think we’ll get more… There are a few phase three trials going on that maybe we’ll get a little bit more information for non-clear cell, but I think that this just is another study that again says to me, we don’t know how to pick the patients right now. Maybe PDL-1, but I think we should give patients the opportunity with a combination treatment.

Dr. Joyce:
I want to narrow in on one other aspect of the SUNNIFORECAST trial. Subgroup analysis. Understand, don’t want to draw a lot of conclusions there, but lymph node metastasis, hazard ratio 0.62, those patients did significantly better. Why? Any ideas of why that might be? Or is this just a red herring?

Dr. McDermott:
Right. So I think the short answer is, we don’t know. If you want sort of a hand-waving explanation, I think in general we think if there’s a prior immune response to the tumor ahead of time, all of these immune checkpoints are more likely to work.

And to me, that lymph node involvement, which in many ways could be not just cancer in the lymph nodes, but potentially immune cells in those lymph nodes. So if you have an immune response in the places where it’s supposed to be, you’re probably more likely to benefit from an immune checkpoint therapy. That’s a lot behind the rationale of pre-surgical PD-1, is you treat the patient when the tumor is still in, and the tumor antigens are still in, and the T cells that recognize those antigens are still in.

So if I had to guess, that’s what you’re seeing in those patients. You’re seeing a helpful immune response that then with checkpoint blockade is unleashed to proper effect.