Overview of First-Line Combination Therapy in Advanced Clear Cell RCC

Key opinion leaders on renal cell carcinoma management review first-line treatment options in the advanced clear cell disease space.


Brian I. Rini, MD: Hi, and welcome to this OncLive Peer Exchange® “Evolving Treatments for Advanced Renal Carcinoma: ASCO 2023 and Beyond”. I’m Dr. Brian Rini. I am a professor of medicine at Vanderbilt-Ingram University Cancer Center, and I’m joined today by expert panelists in renal cell carcinoma [RCC]. I’d like to welcome my esteemed fellow panelists to introduce themselves, and we’ll start with you, Stephanie.

Stephanie A. Berg, DO: Hi, my name is Stephanie Berg. I am at the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute [in Boston, Massachusetts].

Eric Jonasch, MD: Hi, I’m Dr. Eric Jonasch. I’m a medical oncologist at [The University of Texas] MD Anderson Cancer Center in Houston, Texas.

Elizabeth Plimack, MD, MS: Hi, I’m Betsy Plimack. I’m deputy director and professor at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Bruno R. Bastos, MD: Hi, I’m Bruno Bastos. I’m in medical oncology at the Baptist Health Miami Cancer Institute in Miami, Florida.

Brian I. Rini, MD:It’s really great to have you all here. It’s been an exciting time in kidney cancer over the last several years and [with] some new data at ASCO [the American Society of Clinical Oncology meeting] this year. We’re going to start with the landscape of kidney cancer, ASCO data, how it may impact your practice. We’ll go down some rabbit holes of other data and toxicity management and all the sorts of clinical practice. We’ll focus on clear cell first, frontline. We’ll move to the refractory space where we had a big phase 3 [study] presented, and then we’ll talk about non–clear cell. We have a couple cases to augment the discussion.

Let’s start off by talking about frontline clear cell kidney cancer. As you all know, this is a disease that predominantly [affects] men in their 50s and 60s. We see a lot of these patients; they can present asymptomatically incidentally, they can present with hematuria symptoms. We’ll probably not get into the debulking nephrectomy debate, but let’s talk about patients who have advanced metastatic disease and need treatment. The landscape has been immune-based doublets. Ipilimumab-nivolumab with long-term durable response data, and then 1 of 3 IO-TKI [immuno-oncology–tyrosine kinase inhibitor] regimens, all of which have shown survival advantages. Axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab, in short. Then just let me briefly summarize what we saw or what we heard about at ASCO. Then I’m going to ask each of you to comment about your initial reactions to the data. We’ll take it from there as a jumping-off point.

So we heard 2 updates. We heard a KEYNOTE-426 [NCT02853331] update, which was a 5-year minimum follow-up update. Then we heard from the lenvatinib-pembrolizumab CLEAR trial [NCT02811861], a 4-year minimum update. I think they were similar, and just to summarize, response rate advantages and PFS [progression-free survival] advantages were maintained as you would expect, because most of those events have occurred already. What we saw in the overall survival is that advantage was still maintained, but those hazard ratios are drifting up over time. Axitinib-pembrolizumab was 0.53; initially it was 0.84 at this analysis. Lenvatinib-pembrolizumab, I don’t remember the exact numbers, but 0.79 today. So they’re kind of moving up over time as patients get more therapy. Let’s start with that as a jumping-off point. Bruno, let me ask you to comment first. What were your initial reactions to the data? Do you think it’s going to impact your practice? If so, how?

Bruno R. Bastos, MD: I think as you said, we have many options at this indication. When we see this patient population and the numbers, the hazard ratio is changing a bit, but the PFS and the response rate is maintained. To me, I think it’s just corroborated that those regimens are effective regimens that can be used up front; combinations of VEGF [vascular endothelial growth factor], TKI and IO. It give us clinicians more confidence that we are providing good care to our patients. However, this overall survival may make us think about perhaps the second- and third-line therapies [that] are coming along, are improving in the main, and that probably changed a little bit, this hazard ratio, as opposed to a few years ago that did not exist.

Brian I. Rini, MD:It doesn‘t sound like it‘ll impact your practice. I should have asked you and the other panelists.

Bruno R. Bastos, MD: It will not impact in my practice at this point right now, up front.

Brian I. Rini, MD:Which is what? I‘m sorry. What‘s your standard go-to?

Bruno R. Bastos, MD: I tend to look at both options. The double IO-IO combination or IO-TKI. I tend to get a little concerned about the progression of the disease with IO-IO. And if I feel like there is a patient that is having a disease that perhaps is progressing very rapidly, I tend to stay away a little bit from the IO-IO up front and do IO-TKI. So it’s kind of patient characteristics that makes us, at that moment when I see the patient in the clinic, decide which way I’m going to go. I kind of like the TKI when they have a little bit [of a short half-life]. Mainly because down the line, if the patients need to have an emergency surgery or some sort of procedure like this, you don’t get that nervous about the long half-life of the VEGF-TKI. So that’s something that I see in practice and makes us clinicians a little bit more comfortable when we need to make a decision about that.

Brian I. Rini, MD: So, Betsy, we’ll go down the line here. What’s your current practice in a nutshell? And does the data impact [it]?

Elizabeth Plimack, MD, MS: I tend to really avoid the IO-IO, and that’s based on sort of some nuances as we go back and understand these trials, how they were conducted in different points in time. So ipilimumab and nivolumab, that phase 3 trial completed and subsequent nivolumab was not even approved until about 3 months before that trial ended. So very few people in that control arm ever got the option to get nivolumab; [it] just wasn’t approved in the United States or anywhere else. So I think when we look at the hazard ratio for that, we have to keep that in mind. The other thing that was really impressive with these data is that the overall survival curves had very little censoring. They kept really close tabs on the survival of patients in all the TKI combo trials. I don’t think they were as rigorous in the ipilimumab-nivolumab trial because when you came off nivolumab, you came off trial, and they sort of stopped following. I don’t think they expected the results to be as good. I think what’s really important is to look at the top curve, the combination curve, and look at landmarks along the way, if we’re going to cross-compare and note the relationship to a control arm where subsequent therapy changed over time. So in a nutshell, which is what you asked, my practice is either axitinib-pembrolizumab for someone I think is good risk and is going to be on it a long time and therefore can tolerate a long use of TKI, or lenvatinib-pembrolizumab in a patient who just really needs a response right now.

Brian I. Rini, MD:Because lenvatinib-pembrolizumab with higher response rates, but more toxicity is…

Elizabeth Plimack, MD, MS: Higher response rates, more toxicity, less primary progression. So you balance those.

Brian I. Rini, MD:Eric, what do you think?

Eric Jonasch, MD: I divide it up between favorable risk and then intermediate and poor. In the intermediate and poor [risk groups,] it’s those people who have threatening disease versus nonthreatening disease. The favorable, I’ll typically use axitinib-pembrolizumab. In the intermediate and poor, if they have nonthreatening disease, I’ll use ipilimumab-nivolumab, and then I’ll use either cabozantinib-nivolumab or lenvatinib-pembrolizumab in those people that have threatening disease.

Brian I. Rini, MD:Define threatening disease.

Eric Jonasch, MD: This would be large disease burden, metastases to bone, liver. Or disease that if you were to think of the trajectory that you know so far would cause problems if you don’t get a response. Back to Betsy’s point about… best response of ipilimumab-nivolumab being, depending on which group you look at, either 18% or 20%, this is a real consideration for that patient population.

Brian I. Rini, MD:So maybe not a solitary bone metastases per se, but some substantive disease in bone and or liver. Is that fair?

Eric Jonasch, MD: Correct.

Brian I. Rini, MD:Bulky, defined as?

Eric Jonasch, MD: Bulky, defined as something that’s going to perhaps cause some sort of end organ problem. For example, mediastinal adenopathy that if this continues to grow, you’re going to have obstruction.

Brian I. Rini, MD: I think that’s great and I’m only pushing you on it because we talk about that all the time. Bulky, we use these terms. I think we kind of all know as clinicians what they mean, but they probably mean different things to different people. But I think as a general algorithm that symptomatic bulky disease, IO-TKI, I think, is a relative standard. All right, Stephanie, your turn.

Stephanie A. Berg, DO: I agree with everyone so far. I think that the new data presented, like you were saying, Brian, about the CheckMate 9ER[NCT03141177]CLEAR study, and [KEYNOTE] 426. They’re all very similar. Over time, the hazard ratios were getting a little bit higher. Toxicities are pretty similar, response rates are pretty similar. I also noticed that the CR [complete response] rates are going up for a lot of these studies where we always used to use [CheckMate] 214 as the highest CR rate. We’re seeing now with the IO-TKI is increasing in CR rate. So, in my practice, I do actually like using ipilimumab-nivolumab. I do like that treatment response in that sense, where they can get that time off treatment. But I agree with Betsy about looking at what the trial actually did and how the trial was made up. Really talking about the patients using the IMDC [International Metastatic RCC Database Consortium] score and trying to see if they don’t qualify for a first-line clinical trial, because we do have our triplet studies available, looking into that. But nowadays, my IO-TKI, I have choice. I really do like the subgroup analysis that Andrea Apolo, MD, put out, looking at bone metastases for maybe doing a more cabozantinib-centered good response rate really quickly for lenvatinib. Even though those were all kind of with the different organs with liver and bone, you can’t really extrapolate a lot. But I do think that data is super compelling about if there is a difference between TKIs and where your metastases lie.

Transcript edited for clarity.

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