Targeted Therapies for Adult STS


William D. Tap, MD: What about the other FDA-approved drug for general soft tissue sarcomas, except for liposarcomas, such as Votrient (pazopanib)? What role does that play? I also want to bring us to more of the targeted discussion. What targeted therapies are out there? That could open up Pandora’s Box.

Richard F. Riedel, MD: Pazopanib was approved in 2012 based on a phase III study that was largely an unselected patient population, an all-comer study, with the exception of liposarcoma and GIST (gastrointestinal stromal tumor). Those 2 histologies were excluded, and it showed improvement in progression-free survival versus placebo. I think it’s an important therapy in our current armamentarium. For me, it sits in the third-line setting or beyond. I will typically have an anthracycline-based regimen in the frontline and a gemcitabine-based regimen in the second-line setting. This is a gross oversimplification because every patient is different. Anthracycline in the first line, gemcitabine in the second line, and depending on the histology, pazopanib may sit in the third line or further down.

William D. Tap, MD: Drugs like trabectedin and eribulin?

Richard F. Riedel, MD: For leiomyosarcomas, I will actually use trabectedin prior to pazopanib. For liposarcomas, I don’t typically use pazopanib.

William D. Tap, MD: Would you also think about drugs like eribulin, which was recently FDA approved as well?

Richard F. Riedel, MD: I would.

William D. Tap, MD: What are some other thoughts? That’s great. It’s nice to actually hear how you would sequence things. I think that can also be helpful to the community.

Jonathan C. Trent, MD, PhD: In our practice, we do not use gemcitabine/docetaxel in frontline therapy, basically based on the GeDDiS study that you mentioned. There was a trend toward superiority of doxorubicin, but not statistically significant. That aside, if you’re saying they’re equal, why would you choose the more toxic regimen first, which is gemcitabine/docetaxel? At least not the way that it was given in that setting. That’s our approach: anthracycline, gemcitabine, and then other. Even after anthracycline—or actually, even before it—you, as we all do, pay attention to the histology. Votrient is an interesting drug because it is a targeted therapy, but we don’t generally use it that way. We use it in almost any type of soft tissue sarcoma. There are a few caveats that we have with Votrient. We use it in second-line therapy for synovial sarcoma. We don’t use gemcitabine/docetaxel. Our patients with synovial sarcoma in retrospective series are resistant to that regimen. We actually use Votrient in a few settings, as frontline therapy for solitary fibrous tumor and for extraskeletal myxoid chondrosarcoma. It may be reasonable for alveolar soft part sarcoma, too.

William D. Tap, MD: There are interesting data coming out looking at combinations with gemcitabine. I think this ASCO has a study with doxorubicin, so we’re looking at that. What about targeted therapies? We use that term loosely or specifically, but with 80 different diseases, what do you think about when you think about targeted therapies?

Victor M. Villalobos, MD, PhD: I think the terminology “targeted therapy” is a misnomer. Taxol (paclitaxel) is a targeted therapy. But you’re right. I think it depends on the biology. These are very, very diverse tumors. I think that’s why more and more, if you’re getting these vague answers as far as pathology—a Spindle cell carcinoma, if you will—actually getting next-generation sequencing data can help us define what it is, as well as define targets for therapies that may actually respond. I think we’re moving toward that direction.

If you look at a lot of these fusion-related or rearrangement-type tumors, whether they be ALK, ROS1, or NTRK1, 2, or 3. We’ve seen some dramatic responses with these tumors. Chemotherapies don’t work. In sarcomas, in general, it’s a rule of thumb that you cannot predict how a patient will respond to any of the drugs based on how they responded to other drugs before. I’ve had many patients who blew right through doxorubicin and responded dramatically to gemcitabine/docetaxel. I’ve had many patients who responded to no chemotherapy, and then their tumors evaporated with pazopanib. That’s why almost everyone gets everything.

William D. Tap, MD: Clearly, though, there are diseases with an understanding of the molecular abnormality.

Victor M. Villalobos, MD, PhD: Absolutely.

William D. Tap, MD: Inflammatory myofibroblastic tumors, ALK inhibitors, DFSP (dermatofibrosarcoma protuberans) with PDGFR (platelet-derived growth factor receptor) beta.

Victor M. Villalobos, MD, PhD: GIST.

William D. Tap, MD: Definitely GIST with KIT, which we’re not talking about too much. Even diseases like PEComa with TSC (tuberous sclerosis complex) abnormalities, liposarcomas, MDM2 or CDK4 amplification, and intimal sarcomas. Are there any others that you can think of?

Jonathan C. Trent, MD, PhD: PVNS (pigmented villonodular synovitis).

William D. Tap, MD: PVNS or tenosynovial giant cell tumors that rely heavily on CSF1R, and there are CSF1R inhibitors.

Jonathan C. Trent, MD, PhD: Giant cell tumor of bone with RANK ligand, which responds 80% to 85% of the time to a RANK ligand inhibitor like denosumab.

William D. Tap, MD: Even if we don’t have definitive treatments yet, there’s a lot of interest in the molecular subsets of these diseases. It’s one of the things that we very much look for, such as chondrosarcoma potentially with IDH mutations.

Victor M. Villalobos, MD, PhD: Angiosarcomas with VEGF inhibitors.

Victor M. Villalobos, MD, PhD: And endoglin inhibitors as well. There are a lot of things in development right now that look very promising, and I think we need to continue with that.

Richard F. Riedel, MD: It really speaks to the continued process of understanding the underlying biology: not for sarcoma as a whole, because there is no whole. It’s 100 different diseases. We’re really delving into the weeds and understanding individual histology for the individual patient: What is the driver for that particular disease? We’re moving in that direction.

Transcript Edited for Clarity

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