Overall Survival Approaching 5 Years for Metastatic Renal Cell Carcinoma

Recent findings show that the prognosis of patients with metastatic renal cell carcinoma (RCC) has significantly improved, according to James Brugarolas, MD, PhD, director of the Kidney Cancer Program, professor of Internal Medicine, and the Sherry Wigley Crow Cancer Research Endowed Chair at the University of Texas Southwestern Medical Center,

Research conducted by Brugarolas and peers highlights improvements made possible by targeted therapies and the combination of immunotherapy (IO) and tyrosine kinase inhibitors (TKIs). Today, the median survival of patients with metastatic RCC appears to be approaching 5 years.

The combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) has also gained attention in regard to its activity against kidney cancer. Leveraging and combining 2 drugs that have substantial activity in RCC has concluded very high response rates, especially in patients that present with very aggressive disease.

In an interview with Targeted Oncology^TM, Brugarolas, discussed promising updated survival data in metastatic RCC and investigational biomarkers to further advanced the field.

Targeted Oncology: Can you explain the prognosis of patients with metastatic RCC?

Brugarolas: The prognosis of patients with metastatic RCC has improved significantly. The first improvement was with targeted therapies. Now the second wave was immunotherapies. And now with the combination of IO/TKI therapies. So, the most recent data we have is that patients nowadays, their median survival could be approaching five years, which is quite significantly improved compared to prior.

What is known about the tumor microenvironment of RCC? What role does it play in disease progression and resistance to available therapies?

It is interesting that the treatments that we use for renal cell carcinoma are treatments that don't target for the most part, the tumor cell itself. They appear to leverage cells in the microenvironment. So, we have the anti-angiogenic agents that target endothelial cells that target VEGF receptor expressing cells in the tumor microenvironment primarily. Obviously, some of the TKIs that we have other targets that could be mitigated that are anti-tumor activity. What they all have in common, which is likely to be important, is VEGF receptor to innovation and that's specifically in endothelial cells in the tumor microenvironment.

Of course immunotherapy immune checkpoint inhibitors, the way they function is by stimulating an anti-tumor response, so they are also not directly targeting the tumor cells. The tumor microenvironment plays a critical role in anti-tumor response. At the University of Texas Southwestern in our program, we have taken several different approaches to try to understand the tumor microenvironment. One approach has been leveraging tumor graphs. We've generated a very large collection of patient derived tumor graphs where we take the patient tumor implanted into a mouse, and what grows in the mouse is just the tumor.

The tumor microenvironment cells become replaced by the mouse. We can do subtractive approaches where we take the patient tumor, and we take the tumor grown in the mouse and when we compare those tumors in the patient tumor, the tumor microenvironment is human, whereas in the mouse, only the tumor is human. We can extract RNA to look at gene expression, and we can focus on the human signature. By doing that subtraction analysis, we can do an empirical characterization of the tumor microenvironment. Those studies led us to identify that there is an inflamed tumor microenvironment and there is a non-inflamed tumor microenvironment. It cuts across histological types, not just clear cells but also popularity and chromophobe and other histologies. Some factors that have been traditionally used for prognosis, in other words, the International Metastatic Renal Cell Carcinoma Database Consortium factors. Specifically, one of the factors that we found a correlation with was anemia.

Patients whose tumors induce inflammation were more likely to have anemia, which makes me think that these prognostic factors are likely linked at some level with a tumor and maybe systemic manifestations of inflammation induced by the tumor. Along those lines, we also found that the BOB1 gene is mutated. When the tumor is mutated for BOB1, that tumor has a higher likelihood of inflammation. Work from others suggests that there may be a link between BOB1 mutation expression of human endogenous retrovirus sequences which could contribute to inflammation in the tumor microenvironment. It’s interesting that the term microenvironment that is not inflamed tends to be enriched for angiogenesis and we made the same observation in the supplements that I'm discussing.

There might be some tumors that are preferentially programmed to respond to the immune system manipulation. They already have some baseline information, whereas other tumors may be more likely to respond to interventions that target angiogenesis. I think an example of the former sarcoma tumors and an example of the latter may be more indolent tumors that metastasized to endocrine organs, including the pancreas. The tumor microenvironment plays a critical role in renal cell carcinoma.

Can you discuss the combination of pembrolizumab plus lenvatinib in the treatment of metastatic disease and what results have been shown? Do this combination resistance?

Lenvatinib and pembrolizumab build upon a concept that has gotten substantial traction in kidney cancer therapy. It leverages two drugs that have substantial activity in renal cell carcinoma and combines them. The combination of lenvatinib with pembrolizumab brings two drugs that have activity against kidney cancer. That combination was very powerful, with very high response rates, perhaps numerically higher than what we have seen in other combinations.

The question that remains unanswered, in my opinion, is who are the patients that specifically benefit from these combinations where this combination is truly synergistic opposed to the patients that benefit from pembrolizumab and benefit from lenvatinib. Then because you're bringing in a heterogeneous patient population that benefits from one or the other drugs in these are two drugs that have substantial activity against kidney cancer, we are seeing very high response rates. To me, one of the most critical questions is to identify those patients for whom this combination may be synergistic. This is definitely a combination to be considered for patients that present with very aggressive disease, that could run into complications soon after they have been diagnosed with metastatic kidney cancer.

Are there any other agents or combinations showing promise for these patients?

In my view, the combinations that we are developing ideally should be based on the biology of the cancer. I am excited, broadly speaking about the concept of trying to bring in activation of the innate immune system along with the adaptive immune system, which is where most of the research has focused. Going back to my previous comment, identifying patients whose biology is predictive of response to one agent, the other agent, the combination, really the field is moving towards triple therapy combinations. I think we need more active regimens, but triple therapy is not going to offer greater benefit than a single agent or the dual therapy. Those patients may not necessarily benefit from the triple therapy and may have more toxicities. We really need to as a field try to identify predictive biomarkers of responsiveness and use those to guide how patients are treated.

What are some novel biomarkers that are in research?

One biomarker that I'm particularly interested in, or I should say one biomarker approach is something we have ongoing currently at UT Southwestern, is leveraging molecular imaging. Many of the immune checkpoint inhibitors, in fact, probably across cancer types, the majority of mean checkpoint inhibitors, target these PD-1, PD-L1 pathways. PD-L1 has been shown to be predictive of response to these classes of drugs in other tumor types but not in kidney cancer. The reason for that might be that kidney cancer is very heterogeneous, which is something that we know. In fact, in a way kidney cancer is a poster child for tumor heterogeneity.

The approach we've taken has been an imaging approach where rather than relying on a biopsy sample where PD-L1 levels can be measured or archival tissue from a surgery that was performed years ago, we have taken a PD-L1 antibody, and we have labeled it with zirconium-89. That can be administered to a patient and now we are able to visualize PD-L1expression across all of the signs of disease. We are following here on work that was previously done in the Netherlands. We've deployed this strategy that they developed and applied it to kidney cancer. We have a clinical trial that is currently ongoing that has accrued 50% of the patients. The data so far clearly shows that PD-L1 expression is very heterogeneous. There are some sites where PD-L1 expression is very high, where other sites below one expression are quite low.

While it's early to tell, there may be a signal where tumors that have higher levels of PD-L1 may be more likely to respond to the PD-L1 inhibitors. In fact, we've seen this in a couple of patients where the primary tumor had lower levels of PD-L1 and failed to respond as well as the metastasis to combine therapy. I think one area of interest revolves around molecular imaging. In leveraging in particular therapeutic antibodies, we define targets by looking at that expression of those targets in the tumor and the tumor microenvironment through labeling those antibodies and turning them into pet tracers.