Ramaprasad Srinivasan, MD, PhD, on the Results of MK-6482 in VHL Associated Disease

Study results indicated that MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau disease-associated clear cell renal cell carcinoma, pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.

Findings presented at the 21st Annual Meeting of the Society of Urologic Oncology (SUO) indicated that MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC), pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.

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, explained the study results and what he thinks the results indicate for this patient population.


We put on 61 patients on the study across multiple centers in both the US and in Europe. The primary end point of the study, as I said, was evaluating the overall response rate in patients with renal tumors. And the renal overall response rate for the study was 36%, which is quite impressive. What adds even more interest here is that, in addition, another 11% or so of the patients had achieved a partial response. But by RESIST criteria, we need to make sure that those partial responses persist at least over an 8-week period. So, they need to be confirmed after the first time we identify somebody as a partial responder and in this 11% of the patients, that has not occurred, and it's possible that we will see those patients responding as well. Or having confirmed response as well, so time will tell.

It's also possible that some other patients who will now have tumor regression not making the 30% cut off that we need for RESIST classification as a partial responder may continue to have tumor shrinkage, and this is something we've seen this with this drug, you can get ongoing tumor regression. So, it's possible that some of those that have not made the cut off for partial response eventually do. In fact, if you look to see how many patients on the study had some degree of tumor regression, the answer is that the vast majority had well over 90%. So almost everybody who went on the study had some degree of tumor regression. It was more pronounced in some and less in some. And so really time will tell what the eventual confirmed response to a person with this drug. But what we have already is, I think, quite encouraging.

We also looked to see whether you could see tumor shrinkage in other organ systems as a set. And, you know, when we look at pancreatic neuroendocrine tumors, which, you know, malignant tumors that occur in the kidney, I’m sorry, in the pancreas, that are also managed surgically, for the most part, when they reach a certain size threshold, we saw that those were shrinking as well. In fact, we saw an overall response rate of around 80% with those tumors. Now the number of patients with those tumors was less than the number of tumors with kidney cancer because we didn't require that all patients who entered the study have a pancreatic tumor. …there was a sizable number of patients with pancreatic neuroendocrine tumors and we've seen some very, very convincing responses in these tumors. I'd mentioned that with the… targeted agents, we don't really see that much effect on CNS… And that's different with this drug. We are seeing tumor regression in the central nervous system. And when you look at brain… approximately 30% of the patients had lesions, and we used slightly different criteria for evaluating these patients than we do for the kidney and pancreas because of... But with the criteria we used, we did see approximately 30% of the patients have an appreciable tumor response that we were able to classify as partial responses.

Last but not the least, significant morbidity in these patients because of lesions in their eye, they also don't have these vascular lesions called angioma… in the retina. And depending on the location, frequency, size, and other factors, they can have a significant impact on the vision of these patients. And again, to date, I have not had encouraging results with any other drug that I have implied in these patients. But, you know, very encouragingly, we see that most patients who had a… to begin with, had either an improvement or stability of their disease. So, we had around 15 patients that we thought were evaluable. From this perspective, 11 of those had an improvement as assessed by both, you know, ophthalmologist centers, but more importantly by a central group of ophthalmologists who looked at all the data. And 4 of the patients who didn't have, you know, notable improvements had stability of disease. So, on the whole, I'm very, very impressed with the activity we see this see with this agent.

The other aspect we were trying to look at with this drug was tolerability. As I mentioned, some of the earlier agents that we looked at, including… were hampered to some extent by the ability of patients to continue taking these drugs for a reasonable period of time. We haven't seen that the vast majority of patients remained on study over the one year… over the 60 to 68 weeks that we've actually followed these patients on the study to date. Most of them have remained on study. Side effects we've seen have been very mild for the most part, most common side effect has been anemia which we would predict will occur, it actually tells us the drug is doing what it's supposed to because HIF-2α is responsible for transcriptional activation of a protein called erythropoietin, which is very important in making red blood cells, so when you interfere with the process, you are going to see a drop in hemoglobin levels. And so, anemia was not clinically significant in everybody. You know, in a small number of patients anemia was sufficient to require intervention. And that intervention usually took the form of either supplementing… which we can do or, you know, in rare cases, transfusion, or in some cases, a reduction in the dose of the drug to see if they were going to come back. The vast majority of patients again, it has not been a clinical problem. And those in whom it’s been an issue, we've been able to manage the anemia fairly well.

So, on the whole, you know, I'm very encouraged with activity. And I'm also encouraged by the fact that we have a tolerability adverse event profile that's at least to date much better than what I've seen with other agents. Longer follow up is obviously needed. But what we have today, I think is, you know, sufficiently encouraging for me to feel very optimistic about the goal of such strategies in patients with VHL.