Choosing Second-Line Therapy in Treatment of mRCC

Daniel J. George, MD: With that, I want to move now to the second-line setting. We’ve talked about all this change in landscape in the frontline setting. The rapid uptake of these TKI [tyrosine kinase inhibitor]/IO combinations. Right now, it’s axitinib and either pembrolizumab or avelumab, but there may be more coming. We mentioned the Checkmate-9ER study, and there’ll be other studies with pembrolizumab, lenvatinib, and others.

I want to think now as we start to use more of these combinations in the frontline setting: what does that do to our second-line setting? How are we thinking about second-line therapy now in renal cell carcinoma? Does it mean that we have to start all over again, or can we apply some of the older data? What are some of our goals in these second-line settings, and how do they differ from the frontline settings? What is the impact now on the tolerance and quality of life of patients in second-line and beyond? Neeraj, you want to kick us off in this area?

Neeraj Agarwal, MD: Yes. It’s an interesting question. Nivolumab was one of the standard second-line agents until just last year, and now with ipilimumab/nivolumab being used in first line or axitinib/pembrolizumab and soon cabozantinib/nivolumab combination, I’m sure it will show fantastic results based on the known efficacy of cabozantinib as a single-agent TKI, which you have established, Dan, in the first-line setting. What is the role of nivolumab in the second-line setting ?

We are seeing rechallenge data: there are data coming out after using these PD-L1 inhibitors again in second line after prior use of PD-L1 inhibitors in the past, but most of them are being used in combination with VEGF/TKIs.

Right now, if you asked me about second-line nivolumab, what is the potential, what is the market, or what is the use of second-line nivolumab in my practice? It is pretty much nil. It’s nothing because most of my patients are getting one of the PD-L1 access inhibitors first line, barring a small number of patients who are getting single agent VEGF/TKI. In those patients, I sometimes tend to use VEGF/TKI again because they’re responding so well to the first VEGF/TKI. That’s how it is panning out. With pembrolizumab being used in the upfront setting, or ipilimumab/nivolumab being used up front, the default choice for me is cabozantinib in second-line therapy. This is the most efficacious monotherapy in metastatic RCC.

Once patients progress on single agent monotherapy with cabozantinib, the most commonly used regimen in my clinic is lenvatinib with everolimus. Now, if the cabozantinib/nivolumab combination gets approved next month, I hope, then I’ll start using the cabozantinib/nivolumab combination in the first-line setting. I’m going to struggle because I’m sure this is going to be an effective combination based on whatever experience we have with these 2 drugs. The second-line agent may end up being lenvatinib with everolimus, or lenvatinib with pembrolizumab if it gets approved based on second-line data presented at ASCO. It’s going to be fascinating to see how things are going to evolved in the next 1, 2, or 3 years.

Daniel J. George, MD: Fantastic. Let me ask you 1 quick follow-up question because we talked about IMDC in the frontline setting; is there an IMDC in the second-line setting? Do you use it? How do you use risk stratification in the second-line setting?

Neeraj Agarwal, MD: I don’t use it.

Daniel J. George, MD: You don’t use it, okay.

Neeraj Agarwal, MD: No. I only use IMDC in the first-line setting.

Daniel J. George, MD: In the second-line setting, you treat them all pretty similarly?

Neeraj Agarwal, MD: Yes…but I don’t treat them similarly; I look at many other nuances. For example, what kinds of drugs have been used in the past, their performance status, the patient’s wishes, their choices, and so on. The IMDC criteria do not play as much of a role in the second-line setting as they play the dominant role in first-line setting in my clinic. The IMDC doesn’t have much of a role in the second-line or third-line settings.

Daniel J. George, MD: Monty, any thoughts on this? Do you think about risk stratification?

Sumanta K. Pal, MD: I tend to agree with Neeraj. Although you certainly can opt to use the IMDC second-line criteria, it’s that clinical nuance that helps me decide what treatment to allocate to patients. At this point in time, I don’t think the second-line IMDC criteria are refined enough to help us allocate to 1 treatment or another.

Daniel J. George, MD: It’s interesting, isn’t it, because it seemed like it had some relevance early on when we’re using TKI monotherapy, but now that we’re using these combinations in the frontline setting, it’s almost like everybody who progresses is at least an intermediate risk. There’s at least some biology there that’s a little bit more aggressive. It’s also interesting to me, now that there’s been data out about rechallenge with agents. For a long time, we’ve known you can rechallenge with TKIs, and you can use different TKIs 1 after the other. In fact, some of these drugs got their approval in the setting of frontline TKI failure and then a subsequent TKI. We’re now beginning to see some data with IO studies that you can challenge with 1 IO after another, maybe with a treatment break of something different in between, but there can be continued response. Therein lies the hope, Neeraj. Even though we may be using some of our best agents and combinations up front, we’re not emptying the tank. There’s still opportunity to revisit these strategies. It may be in newer combinations over time and get continued, maybe not complete responses, but at least some disease stabilization and clinical benefit.

Transcript Edited for Clarity