IO-TKI Regimens in Advanced RCC: Recent Data Updates


A panel of experts on renal cell carcinoma review updated data on IO-TKI regimens in advanced RCC, including the CheckMate 9ER, KEYNOTE-526, and CLEAR trials.


Elizabeth Wulff-Burchfield, MD: We’ll review some of the existing data. The real gold here is all of your perspectives. So, I want to make sure that we leave most of our time for that discussion. But since this gentleman received cabozantinib/nivolumab, I can talk a bit about the CheckMate 9ER trial for context.

This trial did in fact use Q2 [every 2]-week dosing. However, this was a trial for first-line treatment, majority clear cell, meaning they had to have a majority clear cell component to their advanced RCC [renal cell carcinoma], of any risk stratification group. This was one of the final trials that was reported comparing the new investigational regimen to sunitinib. The investigators were looking at progression-free survival [PFS] as the primary outcome here. As we see here, this did lead to approval of this regimen. Looking at that primary outcome, which we have pulled out on this slide, we see that the investigational regimen of cabozantinib/nivolumab did have superior median PFS for the patients who received that compared to sunitinib and a really impressive hazard ratio.

In looking at the overall response rate and complete response rate, with the complete responses in the darker color of each of these columns, it’s pretty clear that not only is the overall response rate superior for the investigational regimen, but we also see that that complete response rate is superior. This was preserved across all risk groups for patients who received this regimen. We do see that the [patients] who had more aggressive disease, the intermediate- and poor-risk groups, seemed to derive the greatest degree of benefit relative to those with favorable risk. However, it really was preserved.

In looking at safety, for those of us who have used a fair bit of cabozantinib/nivolumab, and sunitinib, at least in the prior days, we do see that the toxicity profile looks a bit different between these regimens. Based on my clinical experience, this didn’t pull out anything that was a huge surprise to me. I think some foreshadowing in this trial is to see the bit of a liver signal with elevated AST [aspartate transaminase ] and ALT [alanine transaminase] having additional grade 1 to 2 toxicity in cabozantinib/nivolumab compared to sunitinib. We’ll talk further about my perspective on that and why I think this is interesting foreshadowing. But otherwise, generally speaking, the toxicity profiles were more or less as expected, which is always encouraging to see when we’re looking at new data.

In looking at some of the other regimens that have approved, and getting back to a couple of highlights of these trials, KEYNOTE-426 was one of the earliest on the scene in looking at axitinib and pembrolizumab compared to sunitinib. This had a dual primary end point of overall and progression-free survival in the entire intent-to-treat population. This was, again, an essentially identical population. Folks had to have no prior systemic therapy, clear cell renal cell carcinoma. In looking at the co-primary end points, we did see that this investigational regimen delivered here. What we’re seeing is that the pembrolizumab and axitinib combination had superior progression-free and overall survival for both. The hazard ratio is a bit more favorable in that PFS signal. This is a theme we’re seeing with time. We always are going to see that when we’re looking at first-line trials, if a significant portion of those folks get subsequent treatments. However, we do see this hazard ratio in PFS was about 0.68 here. I think it was about 0.58 with CheckMate 9ER. Again, in comparing this overall response rate, there is such a dramatic difference here. I think it’s interesting to see this complete response rate was a bit of a lower proportion. However, the overall response rate is clearly superior in the investigational regimen.

In looking at treatment-related AEs [adverse events], we have a bit of a smaller table this time, but generally speaking, they were pretty commensurate with the known properties of these agents. We certainly did not see any overwhelming increase in toxicity in the investigational regimen. Things were overall pretty similar, a few differences were just related to the properties of the agents used.

[Moving] to CLEAR, one of the newest [trials] looking at lenvatinib and pembrolizumab. It was a 3-arm trial. A lot of what I might refer to here would be related to the lenvatinib and pembrolizumab arm compared to the sunitinib arm, as we have seen that comparison made in other trials. Again, this is the same type of population. The primary end point here was progression-free survival. In looking at some of the key end points, including that primary end point, we do see that PFS was profoundly improved in the investigational regimen of lenvatinib/pembrolizumab, which are the 2 I’m referring to here, compared to sunitinib. [There is] a really stark hazard ratio looking at the difference between the arms. The overall survival hazard ratio was around 0.7 in this group. The response rate is dramatically different between them, 71% vs 36.1%. We’ve even seen maturation of the complete response rate with time. It has crept up from those initial reports. [There are] quite durable responses here too, which I think is important to note. We certainly do see this preserved across different risk stratification groups. The patients who completed their pembrolizumab at 2 years and continued lenvatinib…showed a substantial degree of ongoing clinical benefit.

…I would summarize by saying I don’t think there were any surprises per se, having prescribed lenvatinib/pembrolizumab previously. We do see, and I don’t have any comparisons here, but the treatment-related discontinuations looked a bit different for this regimen, particularly seeing the rate of dose reductions was by far the highest with this regimen compared to the others. However, I think additional context would say that we’re seeing these clinical outcomes in spite of these reductions. So I think while that’s clinically important and does factor into our decision-making, we need to remember that we’re still seeing the outcomes we are in spite of that. So clinicians need to dose reduce when their patients need it.

Transcript edited for clarity.

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