Ipilimumab/Nivolumab for Favorable-Risk mRCC

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Ulka Vaishampayan, MD: Moving on to a slightly more controversial topic, ipilimumab and nivolumab are approved by the FDA for patients with intermediate- and poor-risk disease, which is the population studied in CheckMate 214, where they showed a benefit over sunitinib therapy. But should this combination also be used in favorable-risk patients?

Tian Zhang, MD: That’s a really important question, and it is one that we face often in our clinical practice. There is really a spectrum of choices that we can present to our patients with favorable-risk disease. There’s active surveillance alone, where we monitor for growth on repeated imaging. There are VEGF monotherapies. This sector of patients seem to be more angiogenesis-dependent, and some of them have good responses to VEGF monotherapies. And then there are also the VEGF/immunotherapy [I/O] combinations that are approved as well.

The ipilimumab/nivolumab combination is also a possibility. I would argue that it has the highest rates of complete responses in this population, 13% based on the most recent 42-month data. And so, when we’re talking in clinic and are discussing these options with our patients, I think it really depends on their own goals. I can sit down with 4 different patients and talk through these options and come out with 4 different outcomes. And so, depending on patient goals, or what their hope is and what their treatment goals are for the outcomes in terms of efficacy, as well as their tolerance for potential adverse effects, I think all of these options have to be presented and discussed. Then a choice can be made with the patient, depending on what their goals for treatment are.

Ulka Vaishampayan, MD: Yes. I do think it is somewhat counterintuitive that these favorable-risk patients did not have a clear benefit with immune-based regimens in the frontline setting. I wonder if there are some biomarkers or serum markers that we can use to try and guide us as to which way to go in terms of treatment. What do you think, Asim?

Mehmet Asim Bilen, MD: Ulka, I think this is a very important question. I think this is a key area of study. We need something in our clinical practice. We now have all of these wonderful agents that we can use in the clinic, but we really don’t know how to select the right patient for the right drug. We have I/O-I/O, I/O-VEGF, or VEGF alone, and we really don’t have any biomarkers. I think there is still a lot of effort going on in this area. As we all know, there are some genomic markers such as PBRM1. There are 2 different cohorts being looked at by the Dana-Farber Cancer Institute group, and hopefully we can see the data for validation and can apply it in clinical practice. However, we are not there yet.

We have tumor mutational burden. That is not so great in kidney cancer, but is very effective for other tumor types. We have microbiome markers, which have been tested in different cohorts, including kidney cancer. But I think the readily available marker is PD-L1 [programmed death-ligand 1] expression, especially for the favorable-risk population. If a patient has a high PD-L1 expression, I am comfortable giving them nivolumab-ipilimumab because those patients can have more CRs [complete responses] and PRs [partial responses] if they are PD-L1—high. If they are PD-L1–low, we can do I/O-VEGF, or VEGF alone. I think we can use PD-L1 in our clinical practice.

We still don’t know if those patients are mainly angiogenic or immunogenic. There are some gene signatures that have been presented from the atezolizumab-bevacizumab trial and the JAVELIN Renal 101 trial, and those also look very promising but still need to be validated further before we can apply them in clinical practice. There was very nice discussion at GU ASCO [the American Society of Clinical Oncology Genitourinary Cancers Symposium] on inflammatory markers such as NLR [neutrophil-lymphocyte ratio]. This is a very powerful marker for prognostics, per se, especially for favorable-risk patients for which we consider whether we should we surveil them or start systemic therapy. I think if they have a minimal NLR, I’m very comfortable to follow up without any systemic therapy. We can also start using those markers by themselves or as a combination. I think this is a growing area. We still have to figure things out, but I think the movement is headed in the right direction.

Ulka Vaishampayan, MD: Yes, I agree with you, Asim. I think PD-L1 may be a really good marker to use in this setting. PD-L1—positive patients clearly did much worse with anti-VEGF TKI [tyrosine kinase inhibitor] therapy. This may be a way to separate out the patients within the favorable-risk group who are likely to have a similar benefit as compared to the intermediate- and poor-risk groups with immune checkpoint therapy. Any other comments?

Matthew T. Campbell, MD, MS: The only other thing with PD-L1 is that it’s so dynamic. We’ve seen that there is significant heterogeneity between different sites of metastasis. So if you have a fresh biopsy that’s PD-L1—positive, I think that is helpful. I don’t want to suggest that I think doing a PD-L1 stain on an old nephrectomy specimen would help guide therapy. I think it really needs to be a fresh specimen if you’re going to use that.

Ulka Vaishampayan, MD: Matt, you bring up an excellent point. With the heterogeneity within kidney cancer, as well as having old tissue that is not quite representative of the recent biomarkers and what’s going on with the tumor, those are critical things to be considered, especially when we’re making therapeutic decisions.

Transcript Edited for Clarity