Clinical Trials Shaping Treatment in Relapsed/Refractory mRCC

Daniel J. George, MD: I want to go back Monty. He did such a good job summarizing our frontline phase 3 studies that got us into this frontline space. Monty, in the second-line space, it’s a bit older. These studies aren’t quite as fresh, but they’re still the best studies we have in the second-line space, and they’ve led to a lot of the approvals of these drugs and drug combination that we have in these patients with previously treated metastatic renal cell carcinoma. Can you walk us through what data we have and what’s shaped the NCCN Guidelines and other guidelines based on those studies?

Sumanta K. Pal, MD: I can try. I’m still scarred because you gave me an A-minus, and I’ve never gotten and A-minus in my life.

Daniel J. George, MD: I believe that actually. I believe that.

Sumanta K. Pal, MD: I’ll dial it way back. I’ll go back to RECORD-1.

Daniel J. George, MD: Wow.

Sumanta K. Pal, MD: Yeah, it was way back, right; everolimus versus placebo, a very modest benefit in terms of progression-free survival. We then go to AXIS, which was a comparison of axitinib against sorafenib, not a placebo control. It was a modest gain: about 2 months in terms of progression-free survival with no overall survival OS benefit. Then came the slew of studies that reset the bar for second-line treatment where you had to have an OS advantage to demonstrate effectiveness. CheckMate 025 compared nivolumab versus everolimus; it showed benefit in terms of response rate and overall survival. You then have the trifecta: The METEOR trial came with an improvement in progression-free survival, response rate, and overall survival; cabozantinib over everolimus. Another study that becomes important in the context of the current first-line discussions that we’re having is lenvatinib with everolimus. This was examined in the context of a randomized phase 2 trial looking at lenvatinib-everolimus versus lenvatinib monotherapy versus everolimus. With that comparison of lenvatinib-everolimus against everolimus monotherapy, you see a significant benefit in terms of progression-free survival with a modest benefit in OS. However, it was certainly not the statistic that demonstrated that, with only about 50 patients in the treatment arm. That’s a quick rundown of the available second-line data sets that we have. Dan, am I missing anything there?

Daniel J. George, MD: No, I think that’s pretty good.

Sumanta K. Pal, MD: All right.

Daniel J. George, MD: We won’t ding you on the AXIS study. That’s OK. That’s great, but all those studies were done in the era when we weren’t using frontline I/O. If there were some frontline I/Os, then it was a small proportion of the patients. We’ve now got both frontline I/O and frontline TKI. How do you interpret these now? Do you say, “Well, there are those same robust benefits and everything up front?” Are you now rethinking it? Do we need a whole new set of phase 3 studies in this refractory setting to guide us?

Sumanta K. Pal, MD: I’m leaning a lot on these retrospective data sets. They come with all the caveats of encompassing a highly selective patient population, and a lot of these are limited to robust academic medical centers. The signal that seems to be emerging is that there is good, if not better, benefit in the second-line setting with agents like cabozantinib and similar data for axitinib. I’m leaning heavily on those to establish what I use in the second-line setting.

To echo something that Neeraj said earlier, the cabozantinib has become my preferred second-line treatment if I haven’t already used it front line for a patient.

Daniel J. George, MD: That’s exactly right. It’s interesting. The same logic holds true in the second-line as it does in the first-line setting. We can’t necessarily count on patients getting to third- or fourth-line treatment. If you look at the number of patients who get to second-line therapy but don’t necessarily get beyond that, at least when you look at some of these larger outcome databases, it’s about half. It suggests that we need to choose wisely in the second-line space.

Rana, what are your thoughts on the guidelines in the second-line space? Where do you use the guidelines to help you? Are they helpful at all? Do you have any thoughts on how you tease out what to pick next in these patients?

Rana R. McKay, MD: Unfortunately, right now, I don’t think the guidelines for second line reflect how we’re practicing for first line, because all these trials, as you’ve stated, were conducted in the VEGF era, with VEGF/TKI alone in the frontline space, which is not how we currently practice. There is a critical unmet need there for deciding the best treatment option post–I/O. How do we select therapy in somebody who has received an I/O combination, whether it’s ipilimumab-nivolumab or whether it’s pembrolizumab-axitinib, golimumab-axitinib, nivolumab-cabozantinib, or what have you? Our frontline treatment is changing. Therefore, not to say it has to change, but we need to evolve the second-line treatment to match the frontline setting.

This segues into the CONTACT-3 study, which is ongoing. It is a critical trial that is definitely meeting an unmet need in several aspects. One, it is a post–I/O trial, and it’s designed that way: post checkpoint inhibition. It’s also a trial that includes non–clear cell. Largely everything we’ve been talking about thus far has been clear cell. All the trials were designed for patients with some clear components. This trial includes patients with unclassified and papillary histologies, which is a great unmet need. The trial is randomizing patients to cabozantinib with atezolizumab versus cabozantinib alone. It’s going to answer an important question about what the role is of I/O, post I/O, and what the best strategy is in the second-line space post–I/O–I/O or I/O–VEGF strategy up front.

I agree that cabozantinib is the best TKI we have to treat kidney cancer. It combats that mechanism of resistance to VEGF inhibition with enzymic activity, and it’s the best drug out there from a VEGF standpoint. When cabozantinib first came around, we didn’t know how to use it well: the dosing was a bit off, but I find that it’s probably 1 of the easiest TKIs to use. Whether somebody starts at 60 mg, 40 mg, or 20 mg, it’s an easy TKI to use, and the adverse effect profile is predictable. It is my go-to if somebody has not received it in the frontline space. That may all change with the nivolumab-cabozantinib data, where we’re going to have to wait and see what that data look like when you use your best drugs up front.

Piggybacking on that, COSMIC-313 is also looking at the triplicate of nivolumab-ipilimumab-cabozantinib versus nivolumab-ipilimumab. It’s an important trial where the control arm is an active I/O–cabozantinib regimen. The field is going to continue to evolve over the next couple of years, but we need strategic trials looking at sequencing. What is the best sequence, and what do we do for the non–clear cell cases? Do we mirror what we’re doing for the clear cells? Those are unmet needs, but I don’t think the guidelines reflect right now what we’re doing in frontline treatment. They’re a little outdated, so we’ve got to wait for the trials to read out.

Transcript Edited for Clarity