Treatment Options in Advanced RCC in the Second-Line Setting


RCC experts discuss second-line therapy options following progression on first-line IO-TKI regimen.


Elizabeth Wulff-Burchfield, MD: If the patient in this case is started on cabozantinib-nivolumab and then had progression of his cancer, what is the group thinking about as the preferred next line of therapy? What are you factoring in? Is it related to the patient, to the mechanism [of action], or to their tolerability of the regimen? Dr McKay, would you mind jumping in on that first?

Rana McKay, MD: Absolutely. In my experience, cabozantinib-nivolumab is a really well tolerated regimen. I think if somebody were to progress on first-line cabozantinib-nivolumab, they still have a lot of treatment options. Lenvatinib-everolimus is an option, tivozanib is also an option. So I do think there are still a slew of treatments that can be considered.

It’s interesting, we recently saw the CONTACT-03 data in a press release. We don’t have all the data, but basically the trial did not meet its primary end point. That trial was looking at IO [immunotherapy] continuation post progression [on an IO]. In clinical practice, I think a lot of us want to keep that IO backbone going if somebody is progressing and layer in the TKI [tyrosine kinase inhibitor]-based therapy. [That has] been a practice that has been done a bit off label, but that trial showed us, and hopefully we’ll see the data at a future meeting, that maybe that is not the best strategy. Maybe stopping the IO agent, having them be maximized on their TKI instead of necessarily needing to be on a reduced dose or something like that, is likely the preferred strategy. But [there is] more to come on that. There are still a lot of treatment options that can be available in this setting.

To comment on that second bullet, I think there are very rare instances where I’m using ipilimumab in a later-line setting for somebody who didn’t get ipilimumab front line. I think the best data we have are from the FRACTION-RCC trial. The response rates are less than 20%, and there was a 0% CR [complete response] rate, so it’s a very select individual who would get ipilimumab in a post-IO setting.

Elizabeth Wulff-Burchfield, MD: That kind of gets into some of what all of you have commented on with regard to the appropriateness of offering it earlier. Dr McGregor, would you mind sharing any particular considerations you factor or prize highly when you’re thinking about subsequent line therapy for your patients? Is it metastatic pattern, is it how they presented at the beginning, or is it just completely individualized?

Bradley McGregor, MD: I 100% agree with Rana. I think when you look at the NCCN [National Comprehensive Cancer Network] guidelines for the second line, it’s very interesting that they don’t have a preferred option because a lot of the data have been developed in the second line prior to the use of an IO-TKI regimen. So there are all these considered options. I think it’s based on if you got immunotherapy in the front line, which most patients should be getting at this point in time, now what do you do? I think it’s going to depend on what you got. If someone got cabozantinib-nivolumab, I agree with Rana, I like lenvatinib-everolimus or tivozanib. We have good data for both of those. I think we can look forward to seeing phase 3 data on belzutifan, the HIF-2 inhibitor, vs everolimus. That will be hopefully a new weapon in the armamentarium.

I echo Rana’s thoughts on the role of maintenance IO. CONTACT-03 [showed] atezolizumab-cabozantinib was no better than cabozantinib. So I do share the concerns that when we give IO plus TKI, we end up having to jeopardize the dose of that TKI, and we may have to give a lower dose of the TKI than we would with monotherapy. We’re not helping our patients, we’re actually harming patients by giving this IO because we’re not able to give them the maximum dose of the TKI. So it does depend on that shared decision-making, how they tolerate the first TKI, and what their status is going forward.

Elizabeth Wulff-Burchfield, MD: Thank you so much. I think the TiNivo-2 trial will also give further insight using a different IO backbone than atezolizumab. Thank you all so much for your rich insights.

Transcript edited for clarity.

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