ASCO 2023 Data in Frontline RCC: CLEAR and KEYNOTE-426 Trial Updates

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt-Ingram Cancer Center, focused on treatment considerations for frontline and refractory renal cell carcinoma, including a discussion of new data presented at ASCO 2023. Dr. Rini was joined by a panel that included Tian Zhang, MD; Pedro Barata, MD; and Michael Atkins, MD.

In the next segment of the roundtable series, Dr. Rini describes data from 2 RCC studies presented at ASCO 2023. The first, CLEAR, offered 4-year follow-up information on the combination lenvatinib/pembrolizumab. The second, KEYNOTE-426, provided 5-year follow-up data on the combination axitinib/pembrolizumab.

Watch the next segment in this roundtable series.

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Dr. Rini: I’m going to ask you all how the data at ASCO changed your opinion once I summarize it. It’s an interesting time in kidney cancer, we kind of go back and forth and ipilimumab goes in and out of favor and immunotherapy (IO)/tyrosine kinase inhibitor (TKI) are great. No, they’re not so good. I suppose that’s what makes our job interesting. Let me summarize what we heard at ASCO about the frontline setting and then I’m going to ask you each, what do you think of the data, and is it going to impact your practice and if so, how?

We heard two updates at ASCO. One was KEYNOTE-426: axitinib/pembrolizumab was a 5-year minimum follow up. It’s the longest; it’s the most mature data. We finally have that 5-year minimum follow up for those patients. Then we had the CLEAR trial: lenvatinib/pembrolizumab, which was 4-year minimum follow up. Both reasonable follow up; they’re all 2 and 3 years behind ipilimumab/nivolumab, just the way the trials played out. What we’ve seen with IO/TKI regimens is really impressive early effects. A really good split of the curve, response rates, disease control, PFS [progression-free survival] of almost 2 years for lenvatinib/pembrolizumab and CLEAR. Then what we’ve seen over time is those hazard ratios drift up, and they were in the 0.8 range, maybe it was 0.79 for CLEAR, I don’t remember the numbers, but they’re certainly drifting up over time.

The way I take it, I’ll be interested in your all opinions, is you have this early inflammatory-driven group of patients that if they just get sunitinib, they’re going to do poorly. Maybe it’s sarcomatoid or whatever other biologic features we haven’t yet defined. But if you take that group of patients out, if you will, if you treat them early or don’t, well then you’re left with patients who are going to be able to get multiple treatments. The data at ASCO, the sunitinib arm of KEYNOTE-426, I mean many of the patients got 2, 3, 4 treatments. If you knew that on day 1, well this patient’s going to be able to get multiple treatments, I think that would be different. You might approach that patient different. I don’t think we really know that. I suppose volume of disease might give you some surrogate of that, but I don’t think we know that.

I think we saw pretty consistent response rates, pretty consistent PFS (progression-free survival). I don’t think any of that number changed. The other question I think that I’d like to address is stopping therapy. In all the IO/TKI studies, except for axitinib/avelumab, IO was stopped at 2 years for just the way the programs were designed. We have, I know in KEYNOTE-426, about 28% of patients who are completers in that analysis. Not surprisingly, those patients are characterized by more favorable risk, lower disease burden, 85% response rate. I think the CRA was 16%. Patients have to do well to make it to 2 years. Not surprisingly, I think it was 70% are alive at 5 years and I think 30-some percent are progression-free at 5 years. It really gets to the question of should we be stopping IO?

Is stopping IO sort of part of that drifting up hazard ratio? That’s a question that I had when I saw these data. None of the trials have stopped TKI. I would much rather they continue IO and stop TKI. But it is what it is. But we can talk about that. To me, I think in part the data we’re reinforcing for everything that’s good about an IO/TKI regimen—response rate, PFS, disease control—I think they were a little more wobbly when it comes to durability and that tail of the curve. Again, we’re comparing across trials and all the normal caveats that we’re all aware of, but that’s what we do when we’re picking a treatment for a patient. We can only give them 1 regimen and you can talk to the patient all you want, but at the end of the day you’re probably making the decision of what am I going to give this patient?

I think the data were interesting. I think it’s super important to have these long-term data. I give the companies credit for doing the analysis. I know for KEYNOTE-426 it’s after the final analysis. The final analysis was the last one that was protocol specified. But we all realize these data are important.