Case Analyses in Renal Cell Carcinoma - Episode 3

Case 1: Intermediate- and Poor Risk First-Line mRCC Treatments

Renal cell carcinoma experts discuss key efficacy data for first-line immunotherapy combinations in intermediate- and poor-risk patients with mRCC.

Tom Hutson, DO, PharmD: To review, it’s important to go through the efficacy and characteristics of the various options. On the left of the slide we have data from the ipilimumab-nivolumab CheckMate 214 study, which is what we refer to as an I/O–I/O [immuno-oncology] regimen, and the other 3 to the right of that—the pivotal axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab studies—are what we call I/O–TKI [tyrosine kinase inhibitor]. Even today, Bob, it’s still somewhat controversial. I don’t want to use the word controversial, but it’s somewhat debatable what the ideal approach would be. Many of us feel that 1 strategy is probably not going to be utilized across the board for all patients in the frontline setting.

When we start looking at the data, we can tell that the ipilimumab-nivolumab data set, the I/O–I/O data set, is the oldest and most mature with median follow-up data of 55 months. We recognize, as already mentioned by Bradley, that this was a trial predominantly done in the intermediate- and poor-risk patient population, and that’s where it sits with its guideline recommendations. It was the regimen that heralded immunotherapy as a backbone in the frontline setting. The trial is notable for an overall response rate, which was greater than the comparator arm of sunitinib, and strikingly a CR [complete response] rate of 11%, which is something we hadn’t seen with that. That trial heralded this concept that with immunotherapies, we could put patients in a state where there was no evidence of disease.

The overall response rate was also better than with sunitinib, so this trial, for the first time, showed that we could do better than a TKI. As you recall, and the audience will recall, sunitinib had been the gold standard globally for the management of this disease for well over a decade. The trial brought a lot of excitement. With that CR rate, the question is now about the durability of the response. Even in patients who may have a deep partial response [PR], how durable is that? The data, with the maturity at 55 months, allow us to make certain statements: that there’s a durability, and that patients who have CRs have been able to be maintained off therapy, which is a very attractive setting for kidney cancer for many years, and we’re able to report that.

Unlike the I/O–TKIs, we don’t have that maturity there. The closest 1 would be the axitinib-pembrolizumab, which was the first of the I/O–TKIs approved. The advantage from the clinical trial production of it was that it was involved with the favorable, intermediate, and poor risk, so we allowed all 3 patient populations there. We see a hazard ratio in median overall survival, which is very attractive. Certainly, when 1 looks at hazard ratio, it looks very similar to ipilimumab-nivolumab. The progression-free survival [PFS] appeared to be somewhat better, and the overall response rate with the combination of I/O–TKI was 60% vs 39% with sunitinib. The CR rate, however, was only 9% vs 2% with sunitinib. When 1 looks at that, 1 sees that the combination of an I/O–TKI is doable across all prognostic groups. The PFS and the partial response or response rate is greater than what we see with I/O–I/O, but the CR rate is a little less, and there’s concern about the durability. With an I/O–TKI, although we’re getting greater responses and maybe more patients benefiting, is that quality of response and duration of response going to be equivalent to an I/O–I/O regimen? That’s where we’re focused, waiting to see the durability.

As we go into cabozantinib-nivolumab and lenvatinib-pembrolizumab, the follow-ups are much shorter. Although we see efficacy signals much greater than what we saw with the original ipilimumab-nivolumab, when it comes to progression-free survival in the case of lenvatinib-pembrolizumab, there’s a profound difference—almost 24 months of progression-free survival vs 9 months with sunitinib, and response rates around 70%. Greater than what we’ve seen reported in any of the other trials, and a CR rate equally attractive, also better than we’ve seen in all the other trials. We’re still left with this thought: is it durable? That’s where we’re focused at now. Is I/O–TKI going to be a comparable regimen to I/O–I/O? Will we get patients who are able to have durable responses off therapy? Is there something unique to the I/O–I/O regimen?

I chose for this patient to do what’s the most powerful, at least based on numbers, of the I/O–TKI regimens. The patient was symptomatic with hypercalcemia, so I chose this regimen because it would give her the greatest chance of having a benefit, the highest response rate, and a very attractive CR that we need more data on to see if it’s durable. I chose this regimen for that purpose. We could spend a lot more time on this slide, but I wanted to give a high-level overview that there are some nuances. It’s difficult to make exact cross-trial comparisons; populations were slightly different. But the I/O–TKIs across the board have shown benefit across favorable, intermediate, and poor-risk patients, and the I/O–I/O regimens have shown benefit just in the intermediate and poor-risk patients, although the efficacy PR rates and PFS may be less with the I/O–I/O. In the case of lenvatinib-pembrolizumab and cabozantinib-nivolumab, the CR rates seem to be a little less. We have the longest-term data about durability of response with I/O–I/O, which makes it difficult in clinic to make a decision on which to choose.

Transcript edited for clarity.