The evolving classification and molecular characterization of non–clear cell renal cell carcinoma (RCC) are shaping novel treatment strategies and informing the design of precision-based clinical trials, according to Joseph Vento, MD.
“The more we can break [non–clear cell RCC] down by molecular drivers, molecular features, and how those correlate to clinical presentations and response to treatments, the better we’re going to be able to design trials in this space,” he explained.
In an interview with OncLive®, Vento discussed how defining molecular drivers of this disease could shape clinical practice and trial design in the non–clear cell RCC landscape, and highlighted findings from two recent trials: a single-center phase 2 study (NCT03635892) of cabozantinib (Cabometyx) plus nivolumab (Opdivo), and the phase 2 KEYNOTE-B61 trial (NCT04704219) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda).
Vento is an assistant professor in the Department of Internal Medicine and a faculty member in the Division of Hematology and Oncology at UT Southwestern Medical Center in Dallas, Texas.
OncLive: How does the latest World Health Organization (WHO) classification distinguish between the different subtypes of non–clear cell RCC?
Vento: It’s important to look at the history of how these variant histologies and variant non–clear cell kidney cancers were classified—and are currently classified—to better understand the data about how to decide on treatments for these very unique types of cancers.
[With] papillary renal cell carcinoma, historically, we used to use this kind of type 1/type 2 dichotomy, to highlight type 1 being a less aggressive, MET-driven kidney cancer, and type 2 being a more aggressive phenotype. However, more recently, we’ve seen enough heterogeneity with this classification system that it has kind of fallen out of favor—to use that type 1/type 2 dichotomy.
Now, we have a lot more molecular tools to better classify these non–clear cell subtypes. With the development of molecular subtyping—and its emphasis in these 2022 WHO classifications—papillary RCC in particular is largely now what we previously thought of as this type 1, maybe more benign, MET-driven subtype. And the type 2—what was previously type 2 of this papillary RCC—has been broken up into a lot of different molecularly defined subtypes.
When we look back on trials before this classification came about, we have to acknowledge that even papillary RCC, how it was defined when these trials were run, may be different than how it’s classified [in] the patients who are now [seeing] us.
How have these classifications translated into current research efforts and, ultimately, influenced your treatment recommendations?
Having more molecularly driven subtypes is very helpful for studying these very unique non–clear cell subtypes. A lot of times, we throw around this term of non–clear cell RCC as if we’re referring to one disease, but we’re really referring to a lot of different diseases, and they’re all very different.
That’s already come about with a lot of translational studies looking at specific subtypes, really emphasizing what molecular drivers we’re seeing. How can we target this specific disease, instead of trying to apply treatments that work in clear cell kidney cancer to all other types of kidney cancer?
What emerging treatment strategies or approaches are we seeing in the non–clear cell RCC space?
Most recently, there have been two large IO/TKI studies in the non–clear cell subtype space—one being the single-center study at Memorial Sloan Kettering Cancer Center looking at cabozantinib combined with nivolumab, and the other being the KEYNOTE-B61 study looking at lenvatinib combined with pembrolizumab, which showed very convincing overall response rates for a variety of subtypes of non–clear cell kidney cancer.
For specific subtypes such as papillary RCC, this kind of notion of unclassified RCC or RCC [that is] not otherwise specified, and maybe even chromophobe RCC and translocation RCC, this IO/TKI approach is a reasonable frontline treatment in the current setting. However, as we are doing more studies looking at molecular drivers of disease, we’re starting to break these down even more.
What about MET-driven papillary RCC? Can we target that with MET inhibitors and pick out specific subgroups who are going to respond to those drugs? And in chromophobe RCC, there’s been a lot of recent translational research into the pathways involved. Can we target pathways involved with IL-15 or apoptosis?
There’s a lot beyond just an IO/IO or IO/TKI approach in these [subtypes]. It is nice that we have very reasonable frontline treatments for some of these subtypes with these 2 IO/TKI regimens and high response rates, but we have a lot of work to do. There’s still a large percentage of patients who don’t respond to these agents, and the more work we can do to expand treatment options beyond clear cell regimens, the more options we’ll have to present to our patients.
What were some of the logistical challenges involved in conducting sub-stratified research across the different non–clear cell RCC subtypes?
When we look at these trials where we have these large trials focused on one subtype of kidney cancer, suddenly we’re applying one regimen across a diverse subgroup of different RCC, non–clear cell subtypes. And it is tricky to interpret, because a lot of the data we have for, let’s say, chromophobe RCC or translocation RCC, are subtype analysis from these phase 2 trials that are already not a large number of patients to begin with, and then they’re not designed to power for these subgroup analysis. However, this is the best we have, and we have to use the data that we have and say there, maybe there is a small number of [patients with] chromophobe RCC who seem to be responding to mTOR inhibitor approaches. It may be a reasonable treatment to use, but it’s very hard to, I assume, design these trials. I haven’t personally done it, but from my end, [it can be difficult to] interpret data when we have multiple subgroups that break down an already small population into even smaller subgroups, and then trying to draw takeaways from that.
Should patients with non–clear cell RCC currently undergo molecular sequencing to identify potential alterations, or is this approach still limited to the research setting?
[In my current] practice, I try to get somatic next-generation sequencing on all non–clear cell subtypes. It helps develop precision medicine approaches. Maybe we’re not frequently finding things like these ALK fusions that are targetable, but on the off chance we do find something like that, it can be life changing for a patient and really offer another line of therapy for them.
The more data we collect on genomic sequencing of these patients to identify things like [MET]-driven papillary [RCC], we may find some of these tumor-agnostic pathways activated that we’re able to use, as more and more tumor-agnostic approvals are being given for targeted agents.
[Molecular testing] it’s very reasonable to do in patients with RCC in the advanced and metastatic setting, which are mainly the patients that I’m seeing.