Second-Line Treatment Options for Patients With Clear Cell RCC


A comprehensive review of second-line treatment options for patients with clear cell renal cell carcinoma.


Robert J. Motzer, MD: There were certainly some notable abstracts at ASCO [American Society of Clinical Oncology Annual Meeting] this year in terms of sequential therapy or second-line therapy for renal cell carcinoma. Now, in terms of the scenario, for the most part, the paradigm that we have followed in the past has been based on tyrosine kinase inhibitor [TKI] monotherapy as first-line therapy. And so there have been a number of different therapeutics that have been tried and approved in the setting of patients who have progressed on prior sunitinib or pazopanib. But that’s changed now with the advent of IO [immuno-oncology] therapy combination in first-line treatment. And so it’s kind of a whole new setting here where we really have not established a true paradigm or the best treatment for patients who have progressed on ipi-nivo [ipilimumab-nivolumab] or lenvatinib-pembrolizumab or the other TKI-IO combinations. And so for the most part, there have been some data with regard to cabozantinib in that setting for patients who progressed on first-line therapy, and lenvatinib-everolimus. There have been some studies looking at belzutifan in that population. And one of the areas of high unmet need is to identify whether there’s a role for continued immunotherapy in patients who have progressed on immunotherapy in the first line.

A very significant abstract and trial was reported by Toni [K.] Choueiri, MD, et al. And that was CONTACT-03 [NCT04338269], which looked at cabozantinib plus atezolizumab vs cabozantinib alone in patients who had progressed on a prior IO therapy. That was a very large randomized trial, and the results showed that there wasn’t a benefit from the addition of atezolizumab to cabozantinib. The median progression-free survival in either arm was in the order of 10 months. There was no benefit in overall survival, but there were certainly more toxic effects for the combination of cabozantinib plus atezolizumab compared with cabozantinib. And so that provided important information in terms of helping us select second-line therapy. I think for the most part, cabozantinib has become the de facto standard of care in second-line therapy based on that trial as well as one of the other earlier phase 2 and phase 3 trials.

There were limitations in that, though. One point that has been raised is atezolizumab to date has not shown the same level of activity as PD-1 inhibitors, like pembrolizumab or nivolumab. And also the eligibility [requirements] of the trial were that patients had to go on this study within a very short time, about 6 months, of the prior IO therapy. So it didn’t really answer the question with regard to PD-1 inhibitors. It also didn’t answer the question as to whether there’s a benefit later on in later-line therapy in the third line or fourth line. If a patient has been off an IO for a while and is coming back to an IO therapy, I think that those were the 2 remaining questions.

And there is a trial called the TiNivo-2 study [NCT04987203], which is looking at tivozanib, an approved TKI in third-line therapy, or tivozanib plus nivolumab in patients who have progressed on prior IO therapy. And I think that will help us answer the question in terms of whether PD-1 inhibitor combination programs are beneficial in second- or third-line therapy. That was really a very important study that was presented at ASCO.

One of the other abstracts of presentations that caught my attention was one with lenvatinib plus belzutifan. Now, belzutifan is a first-in-class novel HIF inhibitor that has shown activity in a phase 1/2 trial published in Nature Medicine by Toni [K.] Choueiri, MD, et al, and it is currently in a pivotal trial compared with everolimus and in a more refractory setting. There have been some data to suggest that belzutifan adds efficacy when it’s added to a tyrosine kinase inhibitor. There were phase 1/2 data with cabozantinib plus belzutifan, which has been reported previously at a meeting and now published. And then at this meeting, for the first time, there was a rather small series of patients, but very important, with lenvatinib plus belzutifan, that really showed promising efficacy with regard to response rate and a favorable toxicity profile for that particular combination. That has moved forward, and there is a large randomized phase 3 trial that is actually comparing lenvatinib plus belzutifan with cabozantinib in patients who have progressed on IO therapy. And I think those data are eagerly awaited, particularly given the phase 1/2 study that was reported at ASCO by Laurence Albiges, MD, PhD, of Gustave Roussy, and the earlier cabozantinib-belzutifan data. And that may give a different option. It’s not an IO combination in the second or third line. It’s lenvatinib plus this novel belzutifan program. So I thought that abstract was very important and is on my radar to follow up with the phase 3.

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

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