Transcript:Brian A. Van Tine, MD, PhD: There is a drug that has been available in Kazakhstan, Cuba, pretty much everywhere in the world, but the United States, because of a bit of development that happened maybe 10 years ago. It’s a drug called trabectedin, and we’ve all been involved in the clinical trial that’s moving forward and it’s been reported and is now at the FDA.

Dr. Jones, since you’re actually able to use trabectedin when you want, why don’t you tell us a little bit about it?

Robin L. Jones, MD, MRCP: Trabectedin is a marine-derived compound derived from the Caribbean sea squirt. And as you rightly mention, it’s been available in the European Union and other countries for over 5 years now and has been evaluated in soft tissue sarcomas from the late 1990s.

In terms of the approval in the European Union, it was approved on the basis of a randomized phase II trial comparing two different schedules of the drug and additional information from three open-label phase II trials in soft tissue sarcoma. Interestingly, quality of life played some part in the discussions regarding approval in certain countries. The drug has now been, finally, filed with the FDA in November 2014 based on the results of a randomized phase III trial in patients with metastatic liposarcoma and leiomyosarcoma previously treated with an anthracycline plus one other schedule.

We’re all very eager to find out what the FDA’s final decision is because this is clearly an active drug in soft tissue sarcoma. Patients can have very good, durable benefit with good quality of life factoring into Andy’s earlier comment regarding some of my pronouncements on the clinical trials. It’s a very good drug. Fatigue can be a major problem. Liver toxicity is important to monitor, and very rarely the drug can cause rhabdomyolysis.

Brian A. Van Tine, MD, PhD: Dr. Patel, since George Demetri presented this at ASCO and you’re actually presenting an update at ESMO, do you have any comments on maybe the efficacy and safety results we’re all going to be discussing and maybe a little bit about the trial?

Shreyaskumar R. Patel, MD: So, this is a drug that clearly has shown consistent benefit over more than a decade. I think the original phase II data that Robin was just talking about held through in the current randomized phase III trial. The difference here was that it was compared to dacarbazine as an active control and that it had a significant improvement in progression-free survival, but not a significant improvement in overall survival.

I think the RECIST response rates consistently have been in the 8%-to-10% range. So, all of those numbers are the same as we have known for this drug for quite some time. I think there is a group of patients who can tolerate this treatment for a very long time. There are subsets, like myxoid liposarcoma, that are more sensitive to this drug than others.

So, the drug clearly has had a role. I think the sarcoma oncology community has been waiting for this to become available as yet another option for patients to use. And so we all anxiously await the final decision, whether it will be approved in the US or not.

Brian A. Van Tine, MD, PhD: Andy, really briefly: there was a nice little abstract on the use of trabectedin, whether to keep it going or to stop it after, I believe, 6 cycles. What are your thoughts on that?

Andrew J. Wagner, MD, PhD: That was reported by Axel Le Cesne from France, and they looked at what would happen if you just continued trabectedin—after 6 cycles, as you mentioned—and they found, not really surprisingly, that the tumors would progress more rapidly than for patients who remained on trabectedin. I think that reflects our general management of metastatic soft tissue sarcomas that, unless there’s toxicity or progression or the risk of significant toxicity, as we can see with anthracyclines, we usually continue treatment until progression or toxicity ensue.

Brian A. Van Tine, MD, PhD: What are your thoughts on liver toxicity with Yondelis?

Andrew J. Wagner, MD, PhD: Well, I think Robin alluded to it, too. This is one of the known side effects of the drug. We continue to use it as part of an expanded access study. And one of the mandates of the study is that you get laboratory data in between cycles.

It’s not unusual to see some abnormalities, some elevation in the liver function tests. That needs to be looked at, and sometimes the dose needs to be modified if that occurs. In most patients, it recurs by the time of the next cycle, but sometimes there can be significant liver toxicity, as well.

Shreyaskumar R. Patel, MD: I think a word of caution would be that transaminitis is not uncommon and transaminitis of grade 2 or 3 is usually self-limiting and maybe safe for re-dosing. I think community oncologists, if they have access to this drug, will need to understand that if the liver function tests have an obstructive pattern with alkaline phosphatase elevations, those are the patients who really got into trouble with some life-threatening toxicities.

Andrew J. Wagner, MD, PhD: I agree.

Shreyaskumar R. Patel, MD: I think that may be the one red flag that we need to plant.

Robin L. Jones, MD, MRCP: These transient elevations, if they’ve not resolved by the time of the next cycle, then it should be delayed until they have resolved.

Brian A. Van Tine, MD, PhD: Jonathan, let’s pretend that Yondelis or trabectedin is FDA-approved right now. Can you make a case on the back of a napkin of who you’d be giving what to, in what order, and how histologies are going to be incorporated?

Jonathan C. Trent, MD: Yeah, I suspect the approval will reflect its use in the phase III randomized clinical trial, which will be the so-called L-type sarcomas, liposarcoma, and leiomyosarcoma. As has been mentioned, trabectedin does have clear activity in these histologies. And if you look at the curves, far out to the right, there is 10% or 11% or so of patients who do very well for a very long time.

So, those may be the patients who we should better understand, who are benefiting from this drug. I don’t think that we know who those patients are a priori, although we do know the myxoid liposarcoma patients respond very well for a long time with this agent. Pazopanib, as you know, is approved for soft tissue sarcoma—excluding certain histologies such as liposarcoma.

So, the real key in figuring out how to make the optimal use of trabectedin and pazopanib in the current climate, in the current approval, is going to be with the patients with leiomyosarcoma. Is this something that can be moved up into second- or first-line? I don’t think we know. What are the appropriate combinations? But really figuring out in third-line whether to give pazopanib or trabectedin is going to be, again back to a personalized decision, based on patients’ expected toxicities, expected tolerance, and other factors that may be specific to that individual patient.

Transcript Edited for Clarity