Evolving Practice Patterns for Clear Cell Renal Cell Carcinoma - Episode 7

Intermediate/Poor-Risk mRCC: I-O/I-O Vs I-O/TKI Therapy

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Variables that impact one’s decision to treat metastatic renal cell carcinoma with an immunotherapy-based regimen that includes a targeted agent vs additional immunotherapy.

Martin H. Voss, MD: I don’t think anyone would doubt that these trials have made a major impact on how we practice and what options we have available for our patients in the first line. In summarizing what all of you explained to us, one thing that is notable is that the 3 TKI [tyrosine kinase inhibitor]-I/O [immunotherapy] trials had a statistical design that was not specifically set to test 1 subgroup per the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk stratification. The CheckMate 214 study, which was the first to come about, with ipilimumab-nivolumab, very much did so. For better or worse, it forced upon us this way of thinking about patients in ways of IMDC favorable risk vs intermediate and poor risk.

It’s also very clear that physicians are now left with a lot of choices as they come across patients. The NCCN [National Comprehensive Cancer Network] Compendium, its counterpart in the European guidance, and other expert panels around the globe are helping us through this a little, and yet we do have a lot of options left. We should talk a little about that and our thinking currently being limited to segregating patients by IMDC risk. If we were to focus on the IMDC intermediate- and poor-risk disease, we have several options available to us.

Tom, I have a question for you. Pembrolizumab-axitinib and ipilimumab-nivolumab have been head-to-head in that space as commonly used options. Through the last few years, ipilimumab-nivolumab was always galloping ahead with more follow-up than any other studies. The investigators reporting it could lean upon these long 42 months of follow-up data and look to the longer-term outcome: that much sought-after tail of the curve that’s been much discussed. With this year’s ASCO [American Society of Clinical Oncology annual meeting] data, we finally have comparable follow-up data for axitinib-pembrolizumab, and we can look at intermediate- and poor-risk patients in that space as well. I was curious to hear your thoughts as to how you think about one vs the other now that axitinib-pembrolizumab has finally caught up. Do you think differently about the long-term data that we see for both of these regimens?

Thomas Powles, MD, MBBS, MRCP: There are more similarities than differences between the VEGF-TKI/ [immunotherapy] combinations. While the discussions around different dosing and different efficacy are interesting, the most important issue is there are more similarities than differences. Learning how to give the drugs well is probably more important than the differences between the 3 combinations, which have many more similarities than differences.

However, there are differences between ipilimumab-nivolumab and PD-1 VEGF-TKI. The VEGF-TKI combinations are better at getting initial control of the disease, and ipilimumab-nivolumab is less good at that. The VEGF-TKI combinations have much longer PFS [progression-free survival], and that’s been demonstrated pretty clearly. Then there’s the issue about the good-risk group as well, which is a separate discussion.

The question you’ve asked, which is really important, is around the duration of follow-up. There were 2 components of the ipilimumab-nivolumab conversation that made me nervous. The first was the CR [complete response] rate. Initially, we were told the CR rate was higher, it was 10% or 11%, vs 8% or 9%. I never bought into that concept. There are more similarities between numbers 11% and 9% than there are differences. And as Sandy described, we now have a VEGF-TKI/[immunotherapy] with a 16% CR rate. I don’t think 16% is very different from 11%, for what it’s worth. I think 25% is different, but it’s all in the same ballpark. I think we should park that CR argument.

The strongest argument for ipilimumab-nivolumab, if there’s not better response, CR, or PFS, is durable PFS and the translation to that survival curve. With the survival curve, from a landmark perspective, the ipilimumab-nivolumab and the VEGF-TKIs are essentially tracking upon each other. There doesn’t appear to be any difference in survival. But the big question is, is there going to be a 30% tail on the curve? And is the ipilimumab driving that, in the knowledge that the PD-1 VEGFs are not receiving that ipilimumab?

At the moment, as I see the current VEGF-TKI data, because the original PFS curves were so much better, of course they’re tracking down. But we don’t yet know in terms of the long term whether these drugs are all going to end up somewhere between a 25% and 30% progression-free group. The data I’m seeing suggest that is the case. Cross-trial comparisons are very different. But I have not bought into the concept that just because ipilimumab-nivolumab has longer follow-up, which shows great PFS data, that it’s the right regime to give. I don’t think that’s going to translate for me long term into the only one that has those results.

Transcript Edited for Clarity