First-Line Combination Options in Advanced Renal Cell Carcinoma


Discussion centered around available first-line combination options for patients with aRCC as well as factors influencing treatment choice.

Dr. Robert Motzer: The main first line options for RCC are these TKI IO combinations or IO IO combinations. And Dr. Plimack, can you review for us what the options are in terms of first line therapy for advanced RCC presently?

Dr. Elizabeth Plimack: Sure, absolutely. I think in the past our standard was a frontline TKI, typically sunitinib. And then we had the good luck to have a number of phase three studies, all of which were positive of IO combination therapy against sunitinib, with sunitinib being the control arm. So ipi and nivo is the IO IO combination that you referred to Bob, and that was sort of the first randomized trial to read out. It actually read out or finished enrollment before IO was available clinically for the most part. And that showed an overall survival benefit of that combination. And since then we've had three or more, but three that are in clinical practice, combinations of TKIs with immunotherapy. So we have KEYNOTE-426, which was axitinib with pembrolizumab, which we'll talk about. The CLEAR trial, Lenvatinib with pembrolizumab and cabozantinib with nivolumab. So all of these showed really nice results. I think what I really like about the TKI IO combinations, especially len pem, is the very low primary progression rate. So you're really controlling disease in most patients. The response rate is very high with these combinations, really higher than ipi and nivo. And so those short term benefits are sort of clearly there with the IO TKI combinations. And then longer term, that's what was so exciting about ASCO is we're slowly year by year starting to see the long term results of this. Obviously with ipi and nivo, Bob, you published last year, the five year long term overall survival outcomes with that. And then the progression free survival as well. And then with the IO TKI combinations, we saw an update to 426, axi pembro and to the CLEAR trial, which are really showing that the landmarks are all hitting. I know Brian tweets out these tables and we'll ask him to comment on them in a second, but really the landmarks are kind of all hitting the same with the experimental arm. The hazard ratios are different, I think because of the different eras when the trials read out. But it's really nice to see durable long term benefit. And we can talk in more detail about the comparison of one versus the other, if you like, but I'm just going to ask Brian to weigh in on the doublet combinations and his thoughts on the data at ASCO.

Dr. Brian Rini: Betsy, great summary. Of course, I think of frontline kidney cancer as being a PD-1 based doublet for all patients that you might pair with ipi, a CTLA4 inhibitor, you might pair with your favorite TKI I guess axi, len or cabo. But those are the four that have extended survival. I think it's the standard of care in all patients, unless they have some absolute contraindication to one or the other component, which is possible, but relatively rare, at least in my practice. I agree with you, it's really important to see long term follow-up data. It's not that it's more important than short term, but they're all important. So there are short term benefits when you add a VEGF receptor inhibitor to your regimen, i.e. response rates, long PFS. And then there are durable benefits to the immune therapy component. And we can certainly discuss and debate the durability of one regimen versus another, but to me, the ASCO updates, I think provided some reassurance that there could be a tail of the curve. It may be a little early to say with certainty, but I think we're starting to see that tail emerge. Again, perhaps not surprising given the immune component of the IO TKI regimens. And I think reaffirming those short term benefits of response and PFS.

Dr. Elizabeth Plimack: Absolutely. And so how do you choose, Brian? What do you use to consider choosing first line therapy?

Dr. Brian Rini: My general algorithm is- part of it is that thumbnail assessment of a patient's fitness. Are they going to be able to tolerate ipi or not. Are they going to be able to tolerate Lenvatinib or not. So I give ipi nivo in a subset of patients who are younger, healthier, quite obviously that I estimate can tolerate ipi. Certainly, those patients with sarcomatoid changes. There's good subset data from CheckMate 214 that those patients do especially well durably with ipi nivo. Many of my patients though, can't tolerate ipi or need an upfront response for bulkier symptomatic disease. And so I turn to IO TKIs. I was giving a lot of axi pembro first. I give more len pembro now, although the 20 milligrams is difficult, and we can certainly talk about dosing. Again, the very imperfect comparison across trials. It has the highest sort of tumor shrinkage endpoints. So if a patient can tolerate 20 or whatever dose they end up at, I think it probably produces the benefit. I don't know that long term durable benefits are different for any of them. Again, we've not seen a cabo nivo update where we saw a three year updates. We have a three or four and a five year update, so it's hard to compare. But I have a feeling they're all going to sort out in the same place long term among the IO TKI regimens, but that's generally my algorithm.

Dr. Elizabeth Plimack: That's my feeling as well. Just to speak briefly, and you and I talk about this a lot, but the studies have been done with an eye towards long term follow-up lately, the more recent ones. I remember when we did ipi and nivo, and Bob will remember this too, we didn't really expect people to live so long that we had to follow them for progression after they stopped treatment. Usually people progressed and stopped treatment, it was one event. But the 214 data is really missing a lot of progression events because people either did well and stopped treatment or stopped it for a side effect, and then things weren't captured. So I do, I really have- we all have an eagle eye on sort of the long term follow-up, and some of the TKI studies are a little bit behind. But Bob, do you want to comment on frontline and what you choose?

Dr. Robert Motzer: Yeah. So I follow the same paradigm as you and Brian I think that when the CheckMate 214 data came out, I was very impressed, obviously by the outcome in the intermediate and poor risk patients. And I was somewhat surprised that in the favor risk patient, there was actually a flip in kind of the response rate and the PFS in favor of sunitinib. So my paradigm has been to primarily give the intermediate and poor risk patients ipi nivo, and then to provide primarily the favorable risk patients with a TKI IO combination. Now I do think that there is also- there was also clearly a role for TKI IO combinations in other patients. And one group is the patients I think who are progressing very rapidly that are going to run into trouble very quickly. I'm very assured by the high response rate in the low patients that progress directly through the TKI IO combinations. And I think also, over time I am using TKI IO combinations, kind of more and more. Getting away strictly from the IMDC class and the favorable, intermediate, and poor, because I think that there certainly are weaknesses in that sort of prognostication. And I think it's probably the outcome is driven a little bit more by the underlying biology.

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