Clear Cell RCC: Strategies for Selecting Appropriate Frontline Treatment


Robert J. Motzer, MD, provides insights on factors that influence treatment decisions for patients with clear cell renal cell carcinoma.


Robert J. Motzer, MD: There are multiple options for first-line therapy for clear cell RCC [renal cell carcinoma] that have been based on the large, randomized phase 3 trials. These combinations include ipilimumab plus nivolumab [ipi-nivo], axitinib-pembrolizumab, lenvatinib-pembrolizumab, or cabozantinib-nivolumab. Each of these large pivotal phase 3 trials compared the IO combination [with] sunitinib and showed a benefit. In each case, there was a benefit in overall survival and in response rate. [At the prime time of the primary analysis], the TKI-IO [tyrosine kinase inhibitor/immuno-oncology] combinations also showed an outstanding benefit in progression-free survival [PFS]. Initially, the CheckMate 214 trial [NCT02231749]with ipi-nivo compared [with] sunitinib showed a trend in benefit for [PFS] with ipi-nivo compared with sunitinib [but] did not quite reach statistical significance. [However], with longer follow-up, it’s clear that ipi-nivo [also] results in a longer [PFS] compared with sunitinib.

The ipi-nivo regimen in CheckMate 214 was primarily targeted toward patients with intermediate- or poor-risk features. In the smaller subset with favorable risk, the response rate was actually higher with sunitinib compared with ipi-nivo. So, the approval for that program was in the intermediate- and poor-risk patients. [Because] that study was the first to read out, we really have the longest follow-up. What’s very impressive with that program is the durability of response and the durability of benefit over time. One of the other benefits of that program is that there is an end to the treatment. After 2 years, treatment is stopped. And for the most part, although there are adverse events [AEs] related to both drugs, these are immune-related [AEs]. I found that once the patients are past the ipi-nivo part, when they’re receiving nivo alone, their quality of life is very good for the most part. So, I’ve been an advocate for ipi-nivo for most patients with intermediate- and poor-risk tumors.

The [TKI] and IO programs—pembrolizumab plus axitinib, lenvatinib plus pembrolizumab, or cabozantinib plus nivolumab—showed a benefit compared with sunitinib regardless of risk group, including the favorable-risk group, regardless of PD-L1 status or PD-1 status in terms of staining. [These] really are characterized by a very high response rate, a long [PFS], and a survival benefit. Now, these trials don’t have as long of [a] follow-up as ipi-nivo, so there has still been a question [regarding] durability of response with these programs, although the recent updates at [the American Society of Clinical Oncology Annual Meeting] suggest that these programs are durable and that there are complete responses achieved with these programs. In my view, they’re particularly applicable to the favorable-risk group [and] patients who have a very rapidly progressive disease who may wind up in trouble in a short run. The high response rate is certainly comforting with these TKI-IO combinations. In that group, I generally recommend lenvatinib-pembrolizumab as a treatment of choice.

[Regarding] the 3 different TKI-IO combinations, they haven’t been compared in a cross-study comparison, so one can’t say one is better than another. In general, my go-to regimen is lenvatinib plus pembrolizumab based on the exceptional efficacy demonstrated in the trial and my own experience in terms of taking care of patients and managing toxicity. But I think others prefer other regimens. It’s been said that whichever one of these you use, use it well. In other words, if you get experience with the regimen, if you can manage adverse effects [AEs] with the regimen, and if you’re very comfortable with it, [then] that may be the best one for you. In addition, these programs have different [AE] profiles, so individualized treatment based on patients’ own needs and comorbidities is important. For example, in a patient who has a history of autoimmune disorders, [such as] rheumatoid arthritis [or] psoriasis, there would be a tendency to minimize that effect by using a TKI-IO. In contrast, if hypertension is a big issue for a patient and perhaps not managed as well as it should be, then use of a program like ipi-nivo may be a better fit for the patient, [as] hypertension is not an [AE]. There are a lot of factors that go into the choice of a regimen, and they include the published data, the individual needs of the patient, and the experience of the prescriber.

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

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