Rationale for Combination Therapy in mRCC



Thomas E. Hutson, DO, PharmD: The biology of renal cell carcinoma continues to evolve, and it certainly has over the past decades. Initially felt to be immunogenic, it was predominantly treated with interleukin 2 and interferon. This somewhat left our attention over the past 10 to 15 years as the science underlying the most common subtype of renal cell carcinoma, the clear cell histologic subtype, was elucidated in a famous publication as being associated with the Von Hippel-Lindau (VHL) gene. Lack of function in the Von Hippel-Lindau gene, whether acquired somatically at birth, resulting in a hereditary Von Hippel-Lindau syndrome, or sporadically for reasons we don’t fully understand, results in increased hypoxia-inducible factor (HIF) that ultimately gets transported into the nucleus of the cell and is transcribed into a variety of progrowth and proangiogenic factors, most notably VEGF. And so, for the longest time, we’ve been focused on VEGF inhibition as being a primary driver of the biology of, at least, the most common subtype—clear cell RCC.

Kind of running parallel to that understanding was the recognition that there are these other histologic subtypes. We collectively call them non—clear cell RCCs, but they have their own natural histories, their own genetic abnormalities, and their own responses to therapy. They were kind of sitting out there as orphan illnesses, if you will. We could still use VEGF inhibitors for them, but we generally would expect the response rates to be lower. Then we entered the past 5 or 6 years, when immunology really took off in cancer. Now we’ve really been able to manipulate some of the checkpoints, which actually takes away the immune brakes that cancer seems to put on the immune system. In kidney cancer, we’ve discovered that these immune checkpoints are very much at play, at least in a large group of patients. And so we’ve been able to design monoclonal antibodies that target either PD-1 or PD-L1 or other components of the immune system, such as CTLA-4, taking off the brake for the immune system. And now we’ve seen responses, some of which are durable in kidney cancer.

In 2018, when one asks a question about biology, we’re looking at both immunologic areas as well as the underlying VHL mutation as a driver. It’s a very exciting time. You can imagine combination approaches that not only combine various types of immune-stimulating agents but also target VEGF. Combining it with an immune-stimulating agent is certainly in the mainstream. We are anxiously enrolling patients onto these trials and hope that we can push the bar up even further in complete responses, quality of life, progression-free survival, and the elusive overall survival or cure.

Chung-Han Lee, MD, PhD: When we think about clear cell kidney cancer, it’s long been understood as a disease of loss of VHL, which is an E3 ligase for HIF. HIF is a translational factor that is critical for things like the hypoxia response, and it generates multiple growth factors, including VEGF. That is really the central dogma of most of the targeted therapy that we do. However, when we think about inhibition of VEGF, this is still fairly removed from the original inciting mutation that caused it. So there is this gap between what the actual target is and what we’re actually attacking.

Nizar M. Tannir, MD, FACP: The holy grail, as they say, for identifying which patients are more likely to respond to which therapy is still illusive. Our therapies, while effective for a good number of patients, unfortunately do not produce the desired effects for every patient. They do have adverse events that may be challenging to manage. It’s important to identify or predict which patients will benefit from which therapies.

So far, while this is a laudable goal, and it’s important to identify those predictive markers that can help us or guide us in the selection of therapy for the patient who we think will most likely respond to that therapy, we’re not there yet.

Transcript Edited for Clarity

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