Selecting Second-Line Agents in Renal Cell Carcinoma

Transcript:Daniel Heng, MD, MPH, FRCPC: So, Carlos, how do you decide for second-line therapy, axitinib versus everolimus? What goes into that decision?

Carlos H. Barrios, MD: There are data for both, favoring changing the mechanism of action, which would be one thing in the absence of a specific mechanism for resistance. Changing the mechanism of action is what we have been doing with chemotherapy, for example, for a long time so it makes sense and we have some evidence in that regard. However, if the patient actually has tolerated, very well, the initial therapy and eventually can benefit from further VEGFR inhibition, those patients can prolong therapy—and there is a subgroup of patients that can prolong therapy.

My personal view tends to be of the changing the mechanism of action and sometimes even just stopping therapy and giving the patient a break, or the tumor a break. Some of the resistance mechanism may not necessarily be genomic and may be just temporary, so just waiting for a while may actually restore sensitivity in certain situations. We don’t have data for that, but this is what we do in clinical practice. So I think that both alternatives [axitinib or everolimus] are things that can be considered.

Daniel Heng, MD, MPH, FRCPC: And Susanne, in your country, are there any limitations to what you can prescribe or how do you choose things?

Susanne Osanto, MD, PhD: Up till now there are hardly limitations. I think there are no limitations. I do think that most of us believe that switching the agent in terms of the mechanism of action makes sense. Although, if you look at the switch trials, the trials where they have been alternating tyrosine kinase inhibitors (TKIs), I don’t think that it really holds. But it’s what I do. I give everolimus in second-line. I find it easy.

If there’s no longer any remission, you can continue with a TKI again, at this moment, now that we do not have proper third-line or new second-line treatments yet that are accepted by the EMA, which I presume will soon happen. I think that the whole picture like you described is much more complicated because doing basic science is, I think, extremely important— but it’s also very complicated. And the more you do the more layers of complexity are added to it. If you look at the Swanton data from the UK and the whole heterogeneity within each tumor, between tumors, between metastases and also over time, it really gives you the impression that it’s much, much more complicated, but it’s the way to move forward. But it will be extremely expensive, of course.

Coming back to the fact that you just mentioned, what do I do? I try to get as much as possible out of my first-line treatment and I think you also alluded to that the RECIST criteria are sort of what we live with but they’re not very logical because we look at the nadir and from there on we look at growth of some of the unidimensional measurements. Sometimes you have patients who initially had far larger RECIST; the sum of the RECIST criteria was much, much larger than [before] that you would say, yes, this is progressive disease. I’m not talking about patients with new lesions. So are you all continuing treatment even if you would have 100 wonderful drugs available and also which are reimbursed? Or would you say, no, this is a sign of resistance within all tumor cells?

Nizar M. Tannir, MD, FACP: Well, I think, clearly new metastasis.

Susanne Osanto, MD, PhD: Now, new metastasis is clear.

Nizar M. Tannir, MD, FACP: Yeah … or symptomatic progression. Frequently, a patient may have slight progression radiographically by RECIST.

Susanne Osanto, MD, PhD: But the radiographic ones, the ones that have a nice nadir and then start to grow slowly, they fulfill criteria of progression. I think that you are allowed to continue therapy because it’s still much, much smaller than the mass that was there initially. What do you do, do you switch?

Nizar M. Tannir, MD, FACP: I think there are two considerations here when we’re thinking about a second-line agent and whether we switch and which MOA we switch to. How long they’ve been on the first-line therapy and how they have tolerated it [are important considerations]. Obviously, if the patient has had difficulty tolerating that first-line VEGFR TKI, let’s say they developed hypertension, the patient is already taking now three, or four, or five antihypertensive medications, I think even if they’re progressing then I would definitely switch.

Susanne Osanto, MD, PhD: Sure, but there are circumstances.

Nizar M. Tannir, MD, FACP: It’s hard not to consider toxicity or tolerability when deciding whether it’s time to change to something else and what do I change to. So, I think, numerically another VEGFR TKI such as axitinib is going to have a more impactful medical debulking than an mTOR inhibitor such as everolimus in the salvage setting. So if I really would like to achieve a tumor reduction, debulking, if the patient is symptomatic, I’m going to go from sunitinib to axitinib to try to achieve that goal. If they have indolent disease and it is progressing slowly, this metastasis that’s progressing is not causing a threat to an organ, then I think I would go to an mTOR inhibitor, especially if they’ve had a hard time, as I said, with adverse events from the VEGFR TKI. So it would be time to switch track and go to an mTOR inhibitor.

Carlos H. Barrios, MD: But, again, you raise a very important point—that not every progression is the same. So a patient with brain progression, a patient with just a single oligometastases, symptomatic or asymptomatic bone lesion, may just require radiotherapy to that area if there is pain, and then they just continue with therapy. And we have been learning this with TKIs as a routine. So we need to identify exactly how the patient is progressing and [consider] them apart. And that’s an important part of what we do in clinical practice. And sometimes clinical trials do not reflect this because of their structure, this kind of behavior in practice. So I think that that’s actually an important message that you are raising.

Transcript Edited for Clarity