Read the Full Video Transcript

Charles Ryan: Hello from SOGUG 22. I'm here with Ignacio Peláez, a medical oncologist from Asturias, specialized in genitourinary cancer, but also in renal cancer. Today, we are going to talk about second-line treatments. Second-line treatments for kidney cancer. Welcome, Ignacio.

Ignacio Peláez: Thank you.

Charles Ryan: And second-line treatment is something that is loosely defined. It’s changing a lot, I think, because in order to talk about second-line treatment, you have to talk a little about first-line treatment first. The decision that medical oncologists have to make is about what the first-line treatment is going to be. And how does the second-line treatment depend on the first-line treatment? So the decision depends on what has been received. What is the state of the art now about what ... Spanish patients and patients around the world are getting for treatment?

Ignacio Peláez: Correct. In fact, the second-line choice of treatment depends primarily on what we have already used in the first line. And the front line is the result of a true therapeutic revolution in recent years, since TKI monotherapy, Sunitinib, pazopanib, to second-line monotherapy with TKI and with immunotherapy.

But now, with the therapeutic revolution occurring with the arrival of combos of…of combinations of immuno+immuno or immuno+TKI, in the first-line treatment, obviously, that determines what can be given in the second line.

In a specific scenario, let’s call it “antique” when there are patients who still come with a first-line TKI monotherapy, we have the most solid data for second-line treatment with monotherapy. Well, with TKI, which in this case would be cabozantinib with the METEOR study or with immunotherapy with nivolumab with the CheckMate-025 study.

Both are randomized phase-3 studies and increase overall survival in the second line after TKI. But what we are seeing now is that combinations are being imposed, not only in the first but also in the second line. Most of the data we have in this setting is different. Most are retrospective trials or derived from small series.

After a TKI, we have the option of a Lenvatinib-everolimus combination, which is a randomized phase-2 trial where everolimus was combined with Lenvatinib versus Lenvatinib and everolimus alone, where there is an increase in PFS (progression-free survival) and overall survival of the combination versus everolimus.

On the other hand, we also have the combination of the Lenvatinib-pembrolizumab. Here, it is based on a phase-2 trial with various groups depending on the first-line treatment, but we do have a group of patients treated only with TKI.

These are only a few patients, but we can see responses on the order of 58% and median PFS (progression-free survival) duration responses of nine, ten months, which is really important data.

If we go to the current and most modern scenario, that would be the first-line combos. Here, we need to distinguish the Ipi-Nivo combo (Ipilimumab-Nivolumab) or the immuno-immuno combo, versus the Immunotherapy + VEGF (TKI) combo that would be two different scenarios.

After failure for both of these treatment options, there is no randomized data for second-line treatment there are no phase-3 studies. Basically, because the first line is changing so fast and there has not been time for a solid second-line treatment study.

But the second line strategy would really be in the case of Ipi-Nivo (Ipilimumab/Nivolumab) inhibitors, the strongest data supports using a TKI. Probably, Cabozantib and Axitinib have the strongest data in that scenario. And after receiving Immunotherapy +VEGF (TKI), a TKI different from the one we have already used in the first line, if you already used Axitinib then cabozantinib, and vice versa.

The scenario of offering Immunotherapy alone after a combo in the first line ... Well, this has been explored with FRACTION-RCC
the OMNIVORE and TITAN studies. It really doesn’t seem like it is the best strategy, no... The strength of the immunotherapy seems to be more in the first line,m where there are complete responses and long-term survivors, with even the possibility of thinking of cured patients.

Good, that’s a bit up in the air.

So, the second line with immunotherapy only after immunotherapy they are percentages of partial responses on the order of 10-15%. There are no complete responses It doesn’t seem like the scenario. Well, where the immunotherapy can work at its best. And then there are studies underway, especially to see what immunotherapy can contribute after immunotherapy combined with TKI.

In this setting, we have the CONTACT-03 study, and the TIVO-2 studies to see what immunotherapy combined with a TKI brings to this scenario.

Charles Ryan: I mean, this last part. This means that some patients...it is believed that some patients can benefit from immunotherapy after… Receiving immunotherapy in combination in the first-line setting. But we don’t have the data. We don’t have phase-3 data in this setting.

Ignacio Peláez: We know that there are a few patients because there is a percentage of around 20%, but the patients are there What we can’t do is identify which ones would benefit.

Charles Ryan: So, 20% of patients who received Ipilimumab/Nivolumab as first-line treatment, that’s what you are referring to?

Ignacio Peláez: IPI/NIVO or even the studies where they do. Better Is after monotherapy with NIVO (Nivolumab) then try to salvage them with IPI/NIVO (Ipilimumab/Nivolumab) and then do a boost with Ipilimumab or the other option is to rescue them with the combination in patients who have received a combination with immunotherapy in the first-line which are the patients of the FRACTION-RCC study.

Charles Ryan: Okay, so the ideal patient for receiving ... TKI in the second line would be, for example, the patient who has already received a combination with immunotherapy. In other words, the ideal patient for second-line TKI is a patient who has received Immunotherapy, but the patient who has received Immunotherapy with a combo with TKI, would be ideal to receive TKI monotherapy or TKI combo. But we no longer know what the ideal treatment is.

Ignacio Peláez: Undoubtedly, we have data from the group of Dr. Heng of the IMDC, where a retrospective comparison. Indeed, it showed that TKI as second-line monotherapy provides better response after a combination of IPI/NIVO (ipilimumab/nivolumab) than after a combination of immunotherapy and VEGF (TKI). There is a statistically significant improvement in objective responses, not in PFS, but because there are only a few patients.

It does not have statistical power but it does suggest something that is logical, and that is after a combination of immunotherapy, a patient who has not received a TKI responds better than that patient who has already been treated with a TKI, and you’re going to retreat him, even with a different TKI, because not all TKIs are the same.

Well, they have different therapeutic targets, but really, the VEGF pathway has already been treated

Charles Ryan: And then, your recommendation to oncologists now would be to do a…a change of class of medications. If you have received immuno, switch to TKI, or vice versa.

Ignacio Peláez: Yes, in principle, when it comes down to it, we currently have two therapeutic strategies in renal carcinoma.

The VEGF strategy and the immunotherapy strategy. With the combinations, everything is mixed up but it seems logical that...I believe that today all patients. Both in first- and second-line have to receive both a TKI and immunotherapy.

The order is what we don’t know, or the ideal combination.

Charles Ryan: And you mentioned everolimus with Lenvatinib

And what fraction...What fraction of second-line patients are getting this...this treatment here in Spain?

Ignacio Peláez: No, in Spain, none, because it is not a combination that has been approved. Spain is very different regarding legislative approvals. for example, we are far behind the United States.

I wish we were as fast as they are, so that…people could get an idea.

The combination of IPI/NIVO, which was published in the New England Journal of Medicine in 2018 we obtained approval to use it in Spain in 2021. So there is a real gap of three years, which is significant.

The Lenvatinib-everolimus combination I have not prescribed it, but also for people who used it in the clinical trial, it comes with a significant toxicity profile, I mean, a patient has to be really fit, and a patient must have a good ECOG to be able to put up with it

Charles Ryan: And we must not think about. There is an ideal TKI in the second line ...Are they all more or less the same for you, or what do you think?

Ignacio Peláez: And finally, you have to go back to the data of what has been published. And the most solid data is, so to speak, the second-and third-generation TKIs,

That, in this case, would be Axitinib and Cabozantinib which I think has the strongest data in the second line. What happens is that Lenvatinib will be positioned in the front line, which also has very good data. In the end, what these second- and third-generation TKIs have is a more selective and more powerful inhibition of the VEGF pathway. Apart from that, in the case of Axitinib it is much more selective and inhibits fewer targets, but Cabozantinib and Lenvatinib also inhibit other therapeutic targets that probably also justify that increased activity but also, in certain cases, higher toxicity.

Charles Ryan: You have thought it out very well.

Well then, thank you very much for sharing your thoughts on this topic, regarding this matter here in Spain. And thank you for your time.

Ignacio Peláez: Thank you.