Transcript:William D. Tap, MD: Let’s talk about those. George, why don’t you tell us a little bit about the pivotal study? Tell us a little bit about the design, why it was designed like that, the subtypes you looked at, and delve a little bit into the results.

George D. Demetri, MD: The pivotal study is an interesting thing, because there are two pivotal studies. There was a little randomized study back in 2005 or so that was done with all soft tissue sarcomas in it, where it was a very low-dose regimen compared to the now standard-dose regimen. The standard dose regimen won. And after a lot of discussion, the European version of the FDA approved it as a therapy for patients who had already had anthracycline-based chemotherapy, because they said the sarcoma field needs something like this and this drug. Certainly, when you compare the homeopathic inactive dose to the active dose, it was doing something to control the disease.

The response rate, as Martee said, is quite low: 8% to 10% at best. But when it works, and if you’re one of those 8 to 10 percenters, it can actually have some very nice objective responses. And even beyond that, the benefit is not measured by the objective response rate. The benefit is the combination of the objective response rate and durable disease stability, which, to me, means more than 6 months of disease control. There were a good 40%, 50% or more percent of patients in that early study who had that kind of benefit. And then there was a tail in the curve of about 20% who were out past a year or 2 years. So, that was the first approval for Europe.

The United States FDA said, “Nope, we need a little bit more data.” We went back to the drawing board and designed the most recent phase III study along with Brazil and Australia, because they also had the same issues from their regulatory agencies. And essentially, we replicated the outcomes. The outcomes were the 24-hour infusion of trabectedin was compared to an older drug, dacarbazine (or DTIC), and it controlled the disease better, about almost a 3-month progression-free survival rate, very similar to what pazopanib did. But pazopanib was controlled against a placebo control. This was controlled against an active control of dacarbazine. And one can say, “Well, dacarbazine isn’t very active,” but I think we’ve undervalued the value of dacarbazine in leiomyosarcomas in particular.

William D. Tap, MD: That’s right.

George D. Demetri, MD: So, I actually think it was a high bar for trabectedin to jump over, and it did better both for the leiomyosarcomas and liposarcomas in terms of disease control. That actually came out of the older experience that the liposarcomas and the leiomyosarcomas conveniently have no biological similarity. Now, people think about using trabectedin for L sarcomas, both liposarcomas and leiomyosarcomas, and the data support that. I think those are the issues. It was FDA-approved on the basis of that. I think it was very interesting that the FDA then said, “Fine.” Now, we studied almost 600 patients, and I think it was a patient-friendly decision on behalf of the agency to let it go out commercially. I think the important thing, again, with this is to discuss the potential side effects.

We talked a little bit about the vesicant side effects. We always tell people, “Well, you have to have steroid premedication, so you’ll have those side effects. If you say, ‘I have some asthma, I’ve taken steroids, and I know what it’s like to be up at 6 in the morning vacuuming,’ it’s because you’ve got a lot of energy from the steroids.” So, that’s one issue. But it does decrease the risk of hepatic toxicity. And then you have to monitor for mid-cycle transaminases, because something about trabectedin can bump the transaminases. And, in some patients, it could indicate some more worrisome hepatic damage that would require a dose reduction to mitigate. The nice thing, though, is that even if the hepatic transaminases go up, they come back down again in virtually every patient so that patients can stay on their every-3-week cycle and there’s no cumulative buildup of this. Again, we’ve had patients who are on cycle 60 of this drug and have no cumulative problem with their liver. It’s a remarkable drug.

William D. Tap, MD: And monitor CPK (creatine phosphokinase), too, because that’s a parameter. So, one last thing: talk a little bit about the nuances of liposarcoma. Because I think it’s important. We spoke about diseases like synovial sarcoma, and we have this disease myxoid round cell liposarcoma that can often be sometimes very exquisitely sensitive to alkylators and very exquisitely sensitive to anthracyclines. But gemcitabine and docetaxel are probably not the best regimens for it. And how does Yondelis, or trabectedin, compare to the myxoid round cell versus, say, a well dipped D-differentiated liposarcoma?

George D. Demetri, MD: Well, I think most of us feel that trabectedin is a drug of choice for myxoid and round cell. And this does get back to the mechanism. If this is the double-stranded DNA, trabectedin tends to bind right in the DNA minor grove. It displaces the way the DNA is binding, and when that happens, it probably knocks off various transcription factors. The myxoid and round cell liposarcoma is characterized by special translocation that creates a weird transcription factor that probably is sticking to the DNA differently. Trabectedin can knock it off and that probably explains why it has such activity in myxoid and round cells.

It’s been published before that the activity can be upwards of even 60% benefit, maybe even 80% benefit, in the right patient population. Again, myxoid and round cell is probably a bit of a heterogeneous disease itself, so I never say to any patient, “You can bet this is going to work for you.” But it’s certainly got a higher chance of working in that than perhaps in well-differentiated liposarcoma, which tends just to sit there and stay stable anyways. But, again, you can’t predict, and I think part of this is sharing with the patient we don’t know what’s going to happen. We will find out quickly if this doesn’t work, and we’ll move you to something else. It’s back to that piece of paper with all the options on it. One of the decisions is, what options do you burn if you take one drug off the list and use that now as opposed to keeping it on the list for future reference?

William D. Tap, MD: Yes. Mark, how do you use trabectedin in your practice now? What are the diseases you think about based on the FDA approval?

Mark Agulnik, MD: With the FDA approval, it’s identical to what we’ve discussed and there isn’t anything off. I think that with an FDA approval for leiomyosarcoma, and liposarcoma, approved as a second-line agent, there is a role for it as a second-line agent, whether or not a patient is concerned about the 24-hour pump—which, in my practice, has not been a concern—and whether or not they’re concerned for hepatotoxicities. And the funny thing was, I think by the time it came to market, there was such a relief because we’ve all used it. We’ve all used it, but it was hard in some years to chase it down and find the access programs. And then, when the studies were open, the access program restricted some patients and patients weren’t eligible for the study.

So, it was one of these things where it was out there, but it wasn’t always available, and it created this inequality amongst these leiomyosarcoma-liposarcoma patients. For leiomyosarcoma, perhaps use it more as a third-line agent; for the liposarcomas, perhaps more as the second. But, certainly, they’re going to get everything. And so, I don’t know that splitting it as second, third, fourth makes all that much difference, as long we use it appropriately. I do think for the patient that gets a great response to this, it could be such a durable response, and it’s like nothing else, that it just becomes for the right patient, so impressive. The hard thing is, how do you determine the right patient? You have to do it in a lot of patients to get the right patient.

George D. Demetri, MD: And this is where I hope molecular diagnostics will give us an answer. We’re still doing the correlative science on the phase III study. And we’d all feel stupid if P53 mutations either predict a better response or a worse response. When we get the answer, we’re going to share it. But we don’t have a biomarker for that drug, just like we don’t have a great biomarker for most of the drugs we’re talking about.

Damon Reed, MD: On a blank sheet of paper, I would certainly put trabectedin much higher up for a myxoid liposarcoma than for a D-differentiated liposarcoma. And so, it is true that at the end of writing these options, I do solicit questions, for sure, but then also give a recommendation. And for a myxoid liposarcoma, it’s a great second-line option.

Transcript Edited for Clarity