Posted by Jeff Berk, BOLT International;
When I published my last blog I sort of hinted at getting through a single one without sarcasm. This, folks, is the one! So before we talk about melanoma, I have a public service announcement (non-sarcastic item #1): We are collecting donations from anybody who wishes to help to provide water to people who are going to need it desperately this summer in the desert. We got a license from the City of Scottsdale to solicit charitable contributions , and our goal is to buy 500 cases of water for Phoenix Rescue. If you or your company would like to help out, please contact me through this blog. Tax deductible contributions will go through McDowell Mountain Community Church (www.mcdowellmountainchurch.com) and I personally guarantee that 100% of every dime will buy water. The photo, btw, shows the signage that the bears on each side of Tricia are holding. This was taken this weekend. Note that THERE’S STILL ROOM IN THAT DONATION JAR!
Okay, non-sarcastic item #2. The main purpose of this blog is to help patients get access to the wisdom of thought leaders. I got a new blog subscriber a couple of nights ago who made me cry with her story. The woman’s fiancée is perfectly healthy six weeks ago, and today has received his first (of 6) cycle(s) of chemo for stage 4 melanoma before the guy gets on a BRAF inhibitor. They’re looking for a clinical trial and a miracle. So I obviously blog a lot on melanoma. One reason is that the clinical science is really interesting right now. But the other reason is that it is a horrible disease. Anyway, this woman / patient are in the UK, and we contacted a bunch of our international melanoma thought leaders for referrals. They’ve started to filter in, and we’re passing them along. So any of you trialists out there in the UK, give me a shout.
So some melanoma stuff…
- MDX-1106 (Medarex) is a fully human monoclonal antibody directed against PD-1, which is (similar to CTLA-4) a negatively regulating molecule expressed on the surface of activated T cells. Tumor regression in melanoma patients was seen in a Phase I study of this agent without significant toxicities. It is thus viewed as an interesting and promising approach, as with ipilimumab, for use in combination therapy for melanoma
“The interim results of the phase I study was presented at ASCO and there was a 30 percent response rate in renal cell, 30 percent response rate in melanoma. There was a responder in non-small cell. It definitely has activity at all those levels tested. And so this is definitely going to go forward in melanoma. There is no doubt about it. That study is going to be expanded. It is going to accrue probably another 30 or 40 melanoma patients as well”.
“Obviously the PD1 antibody is going to forward. That has clear activity. That will have a role in the future as well, although that is a bit further away”.
“What do you think of PD1 as a target? The data that was presented by Mario Sznol this year at ASCO was just impressive even though it is a rather small phase II study but multiple indications. There were responses in nearly all indications including non-small cell lung cancer. The responses in melanoma were on the higher range or beyond the confidence intervals of what we know that ipilimumab or tremelimumab can do. And the toxicities were better tolerated than CTLA4 blocking antibodies even though they went through the same kind of classes of toxicities; the diarrhea and the endocrinopathies. So telling us that they are both impacting on the immune system and maybe anti-PD1 and anti-PDL1 are doing it better. But that is early data. It will need to be developed in larger studies. The problem is what does BMS do with trying to develop a drug that directly competes with their own drug. Exactly. So what would you do and the other way to look at that is so that becomes BMS’s problem but any other company that is looking to develop similar kind of product what do you look at as a development strategy. In other words, what if it was not controlled by BMS? I would go head-to-head with ipilimumab. In first line? First, second, tenth line. It doesn’t matter. That sounds like a long trial. Yeah, it does because the response rate, if anything, is going to be a little bit higher if we look at the current data, but not dramatically higher. The toxicity is going to be a little bit lower but not dramatically lower. Ipilimumab and PLX-4032 have raised the bar. So the next ones coming behind will have more difficulty even though it has been really difficult to get into melanoma”.
“Actually there is one, the anti-PD1 antibody, the immunotherapy. Whose is that? That is Medarex I think, MDX-1106 something, Medarex BMS. And why are you interested in that? Because it is an immunotherapy target the program cell death receptor, the PD receptor. And again, the same idea as ipilimumab”.
- The safety profile for MDX-1106 is notably cleaner than ipilimumab. MDX-1106 doesn’t cause colitis. Rash and pruritus is much less common. Thus far there have not been any other significant immune toxicities.
“Although people lump this with CTLA4 targeting it is definitely a different molecule. And it has actually a remarkably different side effect profile that has fewer toxicities we have seen when compared to ipilimumab. It doesn’t have the colitis. Rash and pruritus is much less common. And any other significant immune related toxicities, although we have seen them, have been less common. So where this is going to sit with ipilimumab I am not entirely sure, but it is definitely a promising agent”.
- BMS is funding a Ph-I study of combination immunotherapy with Yervoy (ipilimumab) + MDX-1106.
“Jedd Wolchok here and Mario Sznol, there is already a combination in phase I of PD1 and CTLA4 targeting. So that is PD1 plus ipilimumab? Yeah. Here is my cynicism. Is that coming out because BMS owns both of those drugs? Of course.”
“What other immunologic approaches come after ipilimumab? There is an agonist antibody, so GITR (glucocorticoid induced TNF related) has been something of interest, but it is quite early. The PD1 ligand has been the target. What is GITR? GITR is important in modulating T-regulatory cells. So this is something that I am just kind of learning about. But certainly there are agonist antibodies that are being studied now are being developed for this. So it is going to be a newer target. I know PD1 ligand is going to be a target. Who has got that? I don’t know. But there are certainly studies on more small molecules guys and I am going a little bit out of my PD1 ligand. I can’t actually find it right now. The vaccine approaches and of course adoptive T-cell transfers is worth pursuing, although it seems only the NCI can do that. And this is all Steven Rosenberg’s work. It is just such a labor intensive and specialized therapy that was really developed by Steve Rosenberg and his group. As you know, the activity that he has reported is quite impressive. But these are heavily, heavily selected patients who one might argue that they would have done well regardless. Now other groups are starting to replicate his work as well and I know there is a group in Israel working on adoptive T-cell transfer as well, but this is making a therapy from a patient’s own tumor, this is as personalized medicine as you can get. It is very time intensive”.