Second-Line Therapy Options: Role of Trabectedin

Insights From: Victor Villalobos, MD, PhD, University of Colorado School of Medicine; Saketh Guntupalli, MD, University of Colorado School of Medicine; Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center; Anthony P. Conley, MD, University of Texas MD Anderson Cancer Center


Anthony P. Conley, MD: Second-line treatment for sarcoma can be just as challenging as frontline treatment. We usually recommend that the agent of choice be dictated by the patient’s side effect profile from prior treatment. In other words, did they have edema? Did they frequently experience febrile neutropenic events? Is the patient more fatigued as a result of their prior therapy? Aside from that, we also look at the histology. In other words, if the patient has leiomyosarcoma, is there a particular therapy that will benefit them more than if I use another type of therapy?

For many years, we simply had 2 general options: doxorubicin-based therapies or gemcitabine-based therapies. As a result of fantastic work done across multiple institutions around the world, we now have several options at our disposal, including the use of pazopanib, trabectedin, or eribulin for use in patients that progress on frontline chemotherapy.

In the past, if a patient progressed on doxorubicin-based therapy, we would recommend gemcitabine as the go-to drug. The opposite was also true. If the clinician first treated their patient with gemcitabine-based therapy, we would generally recommend doxorubicin-based therapy. Now that we have medicines such as pazopanib, trabectedin, and eribulin, I think we need to better evaluate what their needs may be.
Pazopanib is a medication that was FDA-approved as second-line treatment for any patient that developed resistance to anthracyclines. While the selectivity was across multiple subtypes, it’s important to know that very few patients actually had a substantial response. Its FDA approval was contingent upon its effect on progression-free survival, compared to placebo. So, I generally consider this type of option for a patient that has a low side effect profile, who is yearning to step aside from intravenous-based chemotherapies.

On the other hand, if I have a patient with a leiomyosarcoma or a disease such as myxoid liposarcoma, trabectedin is a very appropriate choice. Trabectedin is a medication that got FDA approval on the basis of progression-free survival, compared to a control arm of dacarbazine. Importantly, patients with leiomyosarcoma and myxoid liposarcoma appear to derive better benefit than other subtypes studied in this particular trial. While we do need to take into account the side effect profile, as this is an intravenous medication, if you have a patient with metastatic leiomyosarcoma who has progressed on doxorubicin-based therapy, I think trabectedin should highly be considered. Separate to this, if the patient has a liposarcoma such as a dedifferentiated liposarcoma, eribulin was FDA approved on the basis of an overall survival advantage, compared to dacarbazine.

Lastly, if a patient has progressed on frontline treatment options, there should be a discussion regarding the utility of clinical trials. This is important. This oftentimes may be dependent on the center from which you’re providing care. Now that many of our community practices are also running clinical trials on a regular basis, I think it’s a fair discussion point to have between the local oncologist, the consulting physician, and the patient.

Trabectedin is a well-studied medication that has been under investigation for several years. Because of a pivotal phase III trial that compared the efficacy of trabectedin against dacarbazine, we now have an FDA approval for trabectedin for patients specifically with leiomyosarcoma.

Patients that have myxoid liposarcoma or L-type sarcomas are also amenable to treatment with trabectedin. Importantly, the response rate to trabectedin is actually low. It’s under 10%. However, it has the ability to improve progression-free survival, compared to dacarbazine. This is important because while we all want to shrink tumors as much as possible, I want to keep my patients progression free as long as possible, as well. And so, sometimes we have to think about what effect this may have on the patient. If I have a patient with a low symptom burden who has leiomyosarcoma, trabectedin is an excellent choice to consider. It does have certain side effects that are similar to those from other cytotoxic chemotherapies. But generally, we can manage these well and can maximize the benefit for the patient.

When we think about the long-term strategy for our patients, we have to be aware of both their overall health at the initiation of treatment and how therapies may impact their health over time. We need to think about their organ function, their performance status, and what effects the medicines, themselves, may have.

When we have patients that have cardiac abnormalities, it’s clear that we should consider medications that will lessen the impact to their heart. Patients with no problems from a cardiac standpoint should be considered for doxorubicin-based therapies. Importantly, if we are thinking about medicines such as trabectedin, it is important that the patient have echocardiograms before treatment. Oftentimes, cardiotoxicity has been seen with medicines such as trabectedin.

In general, when we sequence therapies, we need to make decisions based on an individual basis. There needs to be clear communication between the local oncologist, and the treating oncologist, as well as with the patient, so we’re meeting the expectations of our patients.

Transcript Edited for Clarity 
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