Selecting Frontline Therapy for Patients With Advanced Clear Cell RCC


In the context of the available frontline treatment armamentarium for advanced clear cell RCC, key opinion leaders consider how they would select or sequence therapy.


Brian I. Rini, MD, FASCO: So, let’s move on to our next discussion point. I will go in reverse order, so Moshe, I’ll start with you. And this is a big topic, so I have to be…concise. We have 4 doublets, 3…a TKI [tyrosine kinase inhibitor], and ipi/nivo [ipilimumab/nivolumab], that have each extended survival compared to sunitinib, and they have their pluses and minuses, which we can touch on. But what’s your general approach to patients? What’s your algorithm…in brief, [if a] typical…[patient with] no contraindication kidney cancer comes in and they say, “I’ll do whatever you say, Doctor.” Just give me the best regimen.

Moshe C. Ornstein, MD, MA: It’s a difficult question to answer. But the first thing I always do when I see a patient with newly diagnosed metastatic disease is I ask myself, Does this patient need therapy? And I would say there’s probably about 10%, maybe even 15%, of patients with metastatic RCC [renal cell carcinoma with a] very indolent course of their disease. They have slow-growing pulmonary nodules, some adenopathy. They have 0 or 1 IMDC [International mRCC Database Consortium] risk factor. And I try to delay therapy for patients who really do have a minimal disease burden and this slow trajectory of growth. Once I’m deciding on therapy, I do initially consider am I going to use an IO-IO [immune-oncology–-immuno-oncology] regimen or an IO TKI regimen. In general, once I decide that I need to treat someone, I’m deciding that based either on symptoms or trajectory of their disease growth. And I’m really starting to think to myself that I need something that’s going to work.

And the first definition of work is either disease stability or response to therapy. And the IO TKI [regimens] in general have higher response rates and PFS [progression-free survival] as compared to the IO-IO regimen of ipi/nivo. So, in general, I’m leaning more toward the IO TKIs because I’m looking for a higher response rate and I’m looking for that initial disease control. And as was previously mentioned, especially with lenvatinib and pembrolizumab and cabozantinib and nivolumab, the primary PD [progressive disease response] rate for these patients is about 5%. In other words, almost 95% of patients are having at least stable disease as their best response, which is a remarkable thing…to be able to tell patients, that we can get things under control and then figure out the long term.

Brian I. Rini, MD, FASCO: Two quick follow-up [questions], then we’ll move on to you, Betsy. It sounds like you’re leaning toward IO TKI. So which 1 of the 3 do you tend to use? And…is there any patient phenotype whom you’re giving ipi/nivo to?

Moshe C. Ornstein, MD, MA: I’ll answer the second question first. When patients have sarcomatoid features, an IO-based regimen is ideal…. If those patients don’t have a rapidly progressive disease, I might give a pure IO-based regimen for that patient, so, ipi/nivo. Then in deciding between these 3 IO TKIs, again, I’m giving it for that high response rate, I’m giving that for that initial disease control, and I’m generally leaning more toward lenvatinib [plus] pembrolizumab, which…comparisons notwithstanding, still has an incredibly high response rate.

Brian I. Rini, MD, FASCO: Thanks. Betsy, I think your approach is very similar to Moshe’s from what I know. But what is your approach? What would you have to add to that?

Elizabeth R. Plimack, MD, MS: So just in the spirit of being concise, I would say I don’t give ipi/nivo to any patient. Even [patients with] sarcomatoid [carcinoma] did so well in KEYNOTE-426 [NCT02853331]. Brian, you presented that back in 2019. There was lower primary progression even among the [patients with] sarcomatoid [disease]. The CLEAR [NCT02811861] data [are] unsurpassed in terms of response rate, 71%. I just can’t give an ipi/nivo combination with a 40% response rate because we know response is required in order to have durability of response. So... across the board to give patients the best chance, I usually go with len/pembro [lenvatinib/pembrolizumab]. The exception is for favorable risk, who...are going to do well regardless. The [KEYNOTE]-426 data with axi [axitinib]/pembro [were] really excellent in that group. Only about 4% of favorable risk had progression on the regimen. And I find axi…easier to give and titrate over the long term for patients who I am pretty sure are going to be on it for at least a couple of years.

Brian I. Rini, MD, FASCO: And then, Bob, how about you? What’s your approach? Anything to add to what’s been said?

Robert J. Motzer, MD: My approach is probably a little different.... I agree that in terms of certainly holding off on therapy surveillance until...the patient accepts therapy and I feel it’s necessary. And so...historically, I have offered nivo plus ipi to the intermediate- and poor-risk patients, right, based on the original data and a number of different factors. Now…it’s really for me an issue of IO-IO vs TKI IO and...the patients I offered nivo/ipi to are those [who] generally are intermediate to poor risk, but I don’t feel that they’re going to run into life-threatening toxicity within a month, or those patients with sarcomatoid features. The other patients [who] have more indolent disease, say, or a longer time between diagnosis and are starting therapy, then I usually use TKI IO in those patients. Or in some patients where I really feel we need to get a response immediately, I’m more comfortable with the TKI IO. And with regard to the TKI IOs...the mainstay that I use is lenvatinib/pembrolizumab. I’d say there are some patients...[where] another differentiating factor is the toxicity profile. And so there are some patients...where the toxicity profile probably is better for cabo/nivo [cabozantinib/nivolumab], less high blood pressure, I would say, than lenvatinib/pembrolizumab. So, in those patients predominantly [patients with] bone metastasis…you use cabo/nivo.

Transcript is AI-generated and edited for clarity and readability.

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