Transcriptomic Insights: Revolutionizing Kidney Cancer Biomarker Integration

In the first video of this series, Katy Beckermann, MD, PhD, of Vanderbilt-Ingram Cancer Center, and David Braun, MD, PhD, of Yale School of Medicine, discuss the evolving significance of biomarkers, particularly sarcomatoid histology, in guiding treatment decisions for kidney cancer, alongside the transition from conventional IMDC criteria to a more biological understanding of the disease for tailored therapeutic approaches.

View their further conversation on JAVELIN Renal 101 and Integrative Approaches.

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Dr. Beckermann: What biomarkers are out there, and do we use anything as standard of care to guide treatment? Also, what is the current clinical picture of biomarkers?

Dr. Braun: This has been elusive for some time in kidney cancer. One might argue that until a number of years ago, biomarkers may not have been as useful because they are most helpful when you have effective therapies, especially when there are multiple potential effective therapies. Biomarkers can assist in prognosticating overall patient outcomes and in choosing between different types of therapy, such as a pure immunotherapy strategy versus immunotherapy combined with an anti-angiogenic approach, particularly in front-line therapy for kidney cancer.

Understanding toxicity is also important, although I do not usually think of biomarkers in that vein as much. It is an important emerging field. A relatively recent development in kidney cancer is the potential effective adjuvant therapy with pembrolizumab, prompting consideration of who is more likely to benefit from it.

There are numerous reasons to have good biomarkers, but it has been a tough road. In kidney cancer, particularly, there has been exploration of biomarkers used in other tumor types, such as PD-L1 expression by immunohistochemistry and total mutation burden within a tumor, which seem to have predictive value for PD-1 axis blockade in other tumor types but haven not consistently panned out within kidney cancer.

One clinically actionable biomarker today is potentially one of the oldest: looking under the microscope and identifying sarcomatoid differentiation, and to an extent, rhabdoid differentiation as well. These de-differentiation states, which can occur in clear cell and other RCC histologies, are historically associated with aggressive disease biology and often poor responses to tyrosine kinase inhibitors. However, they seem to respond well to immune checkpoint inhibitors.

The most robust data comes from a post-hoc analysis of the CheckMate 214 trial of ipilimumab plus nivolumab, where patients with sarcomatoid differentiation who received pure immune therapy, nivolumab plus ipilimumab, had tremendous responses, with nearly a 20% complete response rate and probably around a 60% objective response rate. This indicates a flattening out of the progression-free survival curve.

Of all the technologies and approaches explored, the main clinically actionable thing right now would still be the presence of sarcomatoid histology, pushing towards the use of immune therapy, particularly dual immune therapy with nivolumab plus ipilimumab.

Dr. Beckermann: That is a wonderful point to highlight – the enriching response with that really aggressive feature on pathology.

There is a lot of discussion out there about IMDC criteria. We have used it for a long time, developed during the era of sunitinib TKI therapy. But ultimately, it was used to design some of the stratifications and how we were looking at the overall groups, for example, in CheckMate 214 and all these IO/TKIs. How do you think about the IMDC criteria, and do you let that be a decision-maker when you are thinking about front-line therapy?

Dr. Braun: This is something that has truly evolved over time as we have seen some longer-term follow-up from these IO-based front-line trials. Overall, the IMDC has been a really wonderful contribution to how we think about kidney cancer, particularly in prognostication. Even though it was created in the TKI era, we still see these associations in the immune therapy era, which is wonderful. From a practical standpoint, it is very usable. It is based on clinical factors and laboratory values, making it easy to implement in a wide range of clinical settings.

I think the field is likely to move towards a much more biological understanding. We are starting to get there with the tremendous work, such as the transcriptomic analysis of a large phase 3 clinical trial, IMmotion151, and subsequent work in other trials. There are really distinct molecular subtypes of clear cell kidney cancer. If you look across IMDC risk categories, the ones that are favorable risk are enriched for angiogenic biologies, while those that are intermediate and poor risk show more of an immune subtype emerging.

I strongly suspect that the strong efficacy of TKI-based therapy in favorable risk might be related to the fact that those subtypes are enriched for angiogenic biology. Right now, the IMDC is what we have and has been a valuable tool. But my hope is that in the coming years, as we understand the biology better, we will be able to use it to guide us. The OPTIC RCC trial, which is trying to tailor therapies to different molecular subtypes, is what I think the future will bring.

In terms of how I use it practically on a day-to-day basis, it has evolved. Nivolumab plus ipilimumab was approved in the intermediate and poor-risk groups, while other IO/TKI regimens were approved across the board, including favorable risk. For a number of years, I took that to heart, using more IO/TKIs in the favorable-risk setting.

However, the latest data calls that into question. In the early days, sunitinib seemed to perform better than IO therapies, but as time has gone on, those curves have crossed, and with long-term follow-up, patients who received IO-based therapy seemed to be living longer. Additionally, the value of IO/TKIs over TKI alone may be diminished. If we look at overall survival, the hazard ratio for overall survival is hovering around 1.

We don’t really have an answer for that favorable-risk group. Dr. Mike Atkins had a well-done study of nivolumab monotherapy, where favorable-risk patients had around a 50% response rate just to nivo monotherapy. So, there is an argument for TKI alone, IO monotherapy, dual-IO, and IO/TKI.

We need better understanding of that subtype, both biologically and clinically, and trials that tease that out. Practically, it is a conversation with my patients. If patients do not seem like the phenotype of rapid progress and could do well, I often discuss IO/IO-based therapy, again with the idea of durability. But it really ends up being a conversation with the patient because we do not have strong data to point us in one direction or another.