Olaratumab Efficacy in Soft-Tissue Sarcoma

Transcript:William D. Tap, MD: We can talk a little bit about olaratumab. So, Mark, why don’t you talk to us a little bit about olaratumab.

Mark Agulnik, MD: I think this is so exciting. We’ve just discussed three drugs new to the market. We’re not able to discuss another drug that, hopefully, will come to the market shortly. This is a drug that several of us have had an experience with starting with since the phase I trial days through to the phase II trial days. And, now, there is a phase III trial that has just completed accrual.

So, this is probably the first monoclonal antibody that’s been used for sarcoma patients. It selectively binds for PDGFR alpha, and I think that the excitement at last year’s ASCO was really over this overall survival advantage of 25 months versus 14.7 months for the group that got Adriamycin as a single agent. The clinical trial was created for the 1B portion of the phase 1D. All patients received the Adriamycin day 1, every 21 days. And they got olaratumab days 1 and day 8 every 21 days. For the phase II portion, they were randomized. And, so, there was that ability to compare the two for a single agent versus combination.

For those of us who used it quite a lot on our patients, it seems to be exceedingly well tolerated. There are responses seen, and one would anticipate we’d see responses because it was used with Adriamycin. Adriamycin is an active drug, so that doesn’t come as a surprise.

What does this do for us? I think, just as a community, it brings a discussion of how do you treat patients in first-line? It probably throws the door open. And what do you do with AI, versus A, versus A plus olaratumab? But, I don’t know if we want to get into that discussion. That throws it wide open. Really, what do you do as a first-line, assuming this comes to market? But, I certainly think the ability to combine a chemotherapeutic with a monoclonal antibody new to our field is exciting for our field. One can’t negate if the phase III trial mimics the phase II trial, and you see this really impressive overall survival advantage. We didn’t see this in other phase III trials when we looked at Ziopharm’s palifosfamide trial. That was a negative trial. We didn’t see it with the threshold data. And, so, really we’re seeing something that’s probably about in the order of 9 to 12 months longer than what we would have anticipated things. I think it certainly brings something to the table, and it’s really something exciting.

William D. Tap, MD: Yes. I think what’s interesting, too, is when you looked at the eribulin data, there was an overall survival benefit that was a little out of proportion to the progression-free survival benefit. And, I think when we look at the olaratumab data, we do see 2-month improvement in progression-free survival, but then you see this large overall survival.

One of the things, and George alluded to it with trabectedin, is what is this teaching about the biology of our diseases? Is there something that’s happening in the mesenchymal tumor environment? Is there something happening with PDGFR of alpha signaling? Is there something that’s happening with eribulin and what it plays in this mesenchymal environment? We are forever looking at our diseases from the auspice of what people are doing in the epithelial malignancies. But, I think there’s a tremendous amount of learning that we have, and then a contribution to other diseases once we begin to figure that out. Are any of these drugs being considered in the pediatrics sarcomas?

Damon Reed, MD: I know that olaratumab is being considered. They’re working on a phase I trial quickly, and that is very exciting. So, we’d like to bring that in, to get that as soon as possible.

Shreyaskumar Patel, MD: And, you have finished the eribulin trial.

Damon Reed, MD: Eribulin was studied specifically in osteosarcoma, being able to use the adult data down to the age 12. They were able to, very quickly, in about three-and-a-half months, complete the first phase of a phase II trial. Unfortunately, it did not show activity for osteosarcoma, which is not a soft tissue sarcoma, but it does still have potential to be explored in soft-tissue sarcomas.

George D. Demetri, MD: This also brings up the point that drug development really starts when a drug gets an FDA approval. So, I am very nervous about saying that drugs don’t work when they’ve been tested in certain subsets, especially of sarcomas because they’re so different. Just like you said, osteosarcoma is not synovial sarcoma and is not liposarcoma. We have to be careful that we don’t tar and feather a whole set of cancers. It’s like saying a drug that works in breast cancer is definitely not going to work in pancreas cancer. Maybe it won’t, but maybe it will.

William D. Tap, MD: I agree. Some of the work just begins with the FDA approval. And the other thing, which we have to really pay attention to, is that we have to figure out how to bring these drugs into the pediatric populations in the appropriate setting early on because we shouldn’t have these long periods of lag time. I think these are all potential options.

George D. Demetri, MD: And the exciting thing about olaratumab is that that should combine beautifully with almost everything we use.

William D. Tap, MD: Almost everything, that’s right.

George D. Demetri, MD: So, if that phase III trial is positive, that’s extraordinarily interesting. It builds potentially off the fact that we don’t know why pazopanib was positive. Maybe it’s PDGF receptor-alpha there, too. It hits that target, as well. We’re very much waiting for those data to show up.

Mark Agulnik, MD: And, if you’re able to change the biology, and actually change the microenvironment, what better population than the pediatric population. Because if you’re really going to change and this becomes a chronic disease, if you could give longevity in that population, you’ve achieved something incredible.

Transcript Edited for Clarity