Ramaprasad Srinivasan, MD, PhD, on Upcoming Research for Kidney Cancer

In an interview with CancerNetwork®, Ramaprasad Srinivasan, MD, PhD, investigator and head of the Molecular Cancer Therapeutics Section in the Center for Cancer Research at the National Cancer Institute, discussed up-and-coming research in the field of kidney cancer.

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So, in the field of kidney cancer in general, I think there is a lot of… things that are happening. You know, I think we've talked extensively about what's going on in VHL. I'll turn my attention briefly to what's going on in other fields in kidney cancer.

For the longest time, I think a lot of attention has been paid in the kidney cancer field to the more common form of kidney cancer. And as you know, today there are a number of very effective interventions available for treating these patients. The field is very, very rapidly evolving. Patients typically today are treated with either, in the metastatic setting, an immunotherapy agent that targets typically a checkpoint like PD-1 or PD-L1 in combination with another immunotherapy agent like a CTLA-4 antibody such as ipilimumab (Yervoy), or with… targeting agents, such as axitinib (Inlyta), cabozantinib (Cabometyx) or now there's some recent data with Lenvatinib (Lenvima), which is a fairly broad tyrosine kinase inhibitor that inhibits multiple targets. And there's also exciting research going on in patients who don't respond to these kinds of therapies, who have progressed after responding to these therapies, and these investigations take the form of either additional immunotherapeutic strategies that will overcome resistance to initial immunotherapy, or other novel targets, or other novel strategies, including the HIF-2a inhibitor MK-642, which is the subject of an ongoing phase 3 study in patients who have previously failed therapy and the agent is being compared to everolimus (Afinitor) in the study.

There's also a lot of work going on in trying to understand better the mechanisms underlying either the ability of a particular group of agents… to induce a response, as well as the mechanisms of resistance. And I think that I feel that it's time to pick up and I'm hoping to see more in that field in the coming years.

Very, very interestingly, and a topic that's very close to my heart, there's a lot of progress being made now in the treatment of patients with non-clear cell forms of RCC. So, the second most common form of kidney cancer today is something called papillary kidney cancer, which in itself is a very heterogeneous group of diseases. Now, papillary kidney cancer has traditionally been divided, based on this… into type I and type II papillary kidney cancer. But we know that the story is a lot more complicated, and in fact at our center and several other centers we recognize that while type I papillary kidney cancer is a fairly homogenous entity, at least at the histologic level, type II is really a very, very diverse group of malignancy, so we shied away from using the term type II, and instead describe in depth what the given tumor represents. And we are also in the process of better characterizing on a molecular level what these individual subtypes of papillary tumor present.

One of the better characterized forms of what used to be called type II papillary kidney cancer is hereditary form of kidney cancer called HL-RCC, or hereditary lyomitosis and renal cell cancer associated kidney cancer. This cancer is caused by a deficiency of metabolic enzymes, a krebs cycle enzyme, called Fumarate hydratase. And because of a variety of changes that occur because of deficiency phenotype tests, we think this, you know, tumors in these kidneys occur. These this type II diabetic kidney cancers, which are very, very aggressive, and until recently did not have effective treatment strategies available to combat that. Now, these tumors typically don't respond to the classic… agents, such as sunitinib (Sutent) and cabozatinib, at least not as impressively as they do in the… kidney cancer in the population. The more recent immunotherapeutic strategies have not been adequately validated in this population, but we are in the process of doing so.

So, there's really a need to identify new therapeutic strategies in this group of patients. And one of the studies that we did at the NCI was to look at a combination of 2 drugs, fairly old and well-known drugs. Bevacizumab (Avastin), which is a major antibody or antibody targeting the… factor, and… which is a drug that's been used in other cancers such as lung cancer, and targets cell surface receptor called EGFR receptor, which we believe plays an important role in patients with HL-RCC associated tumors and saw a, you know, fairly unprecedented response with this combination in HL-RCC patients. Response rates of about 70% or so, very durable responses patients, median time, median progression free survival was approximately 21 to 22 months with this combination. We also saw that those patients who didn't actually have an objective response did have stability, in many cases lasting four or five years. So, we are very, very encouraged by the activity of this combination in this particular disease.

This combination also seems to be very effective in a subgroup of patients with other forms of papillary kidney cancer. So, response rate in other forms of papillary kidney cancer is around 35% or so which is also not, you know, it's not negligible. I think I think this is better than many, many agents we've seen, I think the trick is really going to be in trying to identify the subgroup of patients with papillary kidney cancer that best respond to this agent so we don't, you know, unnecessarily give this to patients who are not as likely as other people to respond and focus on those that are most likely to respond.

So, this is one of the areas where I think there has been significant development lately in in the field of kidney cancer. So, these are just a couple of areas I think that show a lot of promise and to me are very, very exciting. There are numerous others that I may not necessarily have time to go in the context of this session.