Looking at First-Line Options for Advanced Clear Cell Kidney Cancer

The first-line treatment options for advanced and metastatic clear cell renal cell carcinoma (RCC) are growing, and various long-term updates on phase III trials were presented at the American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field: Moderator Elizabeth Plimack, MD, from the Fox Chase Cancer Center in Philadelphia, is joined by Amishi Y. Shah, MD, from the University of Texas MD Anderson Cancer Center in Houston, and Tian Zhang, MD, MHS, from the University of Texas Southwestern Medical Center in Dallas, for a virtual roundtable discussion. This first of four exclusive episodes focuses on first-line treatment for clear cell RCC.

Following is a transcript of their remarks:

Plimack: Hi, I’m Elizabeth Plimack. I’m at Fox Chase Cancer Center. I’m a GU [genitourinary] medical oncologist. I’m joined today by Dr. Shah and Dr. Zhang, who’ll introduce themselves in a moment. And we’re here today to talk about the data coming out of ASCO 2023 — we’re fresh off of ASCO, it was just a week ago — and how it pertains to clinical practice. Dr. Shah, can you introduce yourself?

Shah: Good afternoon. Thank you so much for having us. I’m Amishi Shah. I’m a GU medical oncologist at the University of Texas MD Anderson Cancer Center.

Plimack: Dr. Zhang?

Zhang: Hi, I’m Tian Zhang, GU medical oncologist at UT Southwestern Medical Center in Dallas, Texas. Happy to be on with you.

Plimack: Great. And for full disclosure, two close friends, so it’s nice to have this conversation with you both.

So let’s start talking about first-line clear cell renal cell. This is always a hot topic. We’re blessed with many choices, many phase III trials. We saw updates at ASCO on CLEAR and [KEYNOTE-]426. What are your thoughts now in the front line? Have they changed since ASCO? And how do you think about the patient in front of you when you’re making these choices? Dr. Shah, let’s start with you.

Shah: Okay. Yes, you’re right. This is always the million-dollar question, and I always joke that if you put 10 GU medical oncologists in a room, you’re going to maybe get 10 different opinions on this. There was a couple pieces of data this ASCO that I thought were really, really impactful.

So Dr. Albiges had a discussion about doublet versus triplet therapy, and she had some really nice summary slides and that was also highlighted in Dr. Braun’s discussion during the oral abstract session for bladder/renal. And bottom line, all of these trials now have many years of follow-up. So that data is evolving where we have longer follow-up. So for the IO/TKI [immunotherapy/tyrosine kinase inhibitor] data, for pembro-axi [pembrolizumab (Keytruda)-axitinib (Inlyta)], for cabo-nivo [cabozantinib (Cabometyx)-nivolumab (Opdivo)], and for len-pem [lenvatinib (Lenvima)-pembrolizumab], initially of course, we were all very impressed with the improved progression-free survival over sunitinib [Sutent].

Now what’s interesting now with longer follow-up is we’re getting that longer overall survival curve, and the IO/TKI Kaplan-Meier curves are starting to converge the longer we go with the IO/TKI. Nivo-ipi [nivolumab-ipilimumab (Yervoy)], on the other hand, those curves are remaining fairly divergent. And when you look at the overall survival of these patients, they’re actually all pretty neck-and-neck with these doublet therapies. Somewhere in the 48- to 55-month range for all four of these big phase III trials when you compare it to sunitinib, which the overall survival is shorter.

And so based on that data and the fact that you get that true durability with the nivo-ipi patients, to me right now in 2023 my frontline preferred option is nivo-ipi. That being said, if there’s somebody who’s very, very symptomatic, has bad disease and you quickly need a response, I do think the addition of an IO/TKI is really helpful to get that quick response for a sick patient.

Plimack: Great, thanks. Dr. Zhang, what’s your take on the updated long-term follow-up data?

Zhang: Sure. The more we see, the more accurate the data are, so the more events that are actually happening. So it’s not surprising that we saw all of the IO-containing regimens continue to show improved progression-free survival and overall survival compared against sunitinib monotherapy.

I thought it was really encouraging to see, and in the frontline setting Dr. Braun had a really great discussion about treatment decision making. And I think that’s the million-dollar question. When somebody walks in to our clinics they have one shot on a first-line treatment, so let’s try to find the optimal first-line treatment for them. So how do we do that? So, I thought, Dr. Shah, your points on ipi-nivo, especially for sarcomatoid histology for example, is really important.

The thought about early disease control of patients who can’t afford to have primary progression on their first-line treatment and to look for those patients to get a VEGF [vascular endothelial growth factor]/IO combination, that’s really important. And then if patients can’t afford and are shooting for durable responses, we’re thinking ipi-nivo upfront. And all the time we’re thinking about first-line trials, and we still do have multiple clinical trials in the frontline setting.

But I think it’s great that we are achieving better progression-free time and also getting patients to live longer with higher-end overall survival rates out 5 years or more.

Plimack: Yeah, I’ll just chime in briefly. I’ll agree. The long-term data are just amazing. We could not have imagined sort of seeing this years before.

I guess in my own practice, one of the things I struggle with is that idea that you have one shot at first-line therapy and really, and we’ll talk about this in a minute in the second-line module, one shot at IO perhaps, right? And so I worry with ipi-nivo about the overall low response rate relative to something like CLEAR with len-pem, that when you’re treating a large population of patients to focus on the potential outcomes for the few, worries me a little bit.

And the other thing that having been part of these trials for a long time, you know, how good are we at capturing progression when patients come off of study and how clean are those curves? And that’s something we have to pay really close attention to as we look ongoing. Because ultimately, Kaplan-Meiers are estimates based on available data and it’s been better captured in more recent studies.

So all things, it’s hard to predict, again, what the future will be for the patient in front of you when we know and hope that data and treatment will evolve over the time that we’re able to keep them alive and in response, ideally long term. Great.