Transcript:Mark Agulnik, MD: When we start to look at patients who walk in our door at my institute, in particular, and we start to look at those with locally advanced disease not amenable to surgical resection or patients with metastatic disease that are felt to be not curable with surgical resection, then we have to look at chemotherapy as a standard of care approach. At our institute, we tend to use, as a first-line therapy, Adriamycin (doxorubicin) with olaratumab based on the phase II and Ib data, which were very impressive with respect to an overall survival advantage. If we didn’t have the availability of olaratumab previous to that, we were using Adriamycin as a standard of care first-line agent. However, there are certain histological subtypes that perhaps would benefit from the addition of ifosfamide. There has been some thought, maybe certain patients would benefit from gemcitabine/Taxotere as a first-line agent. However, some data would suggest that that’s more toxic than single-agent doxorubicin. And, therefore, in my institute, mostly what we’re going to is a doxorubicin-based first-line therapy, usually in combination with olaratumab.
Brian Van Tine, MD, PhD: I think the most recent advance in our field is actually surprisingly hit upon as monoclonal antibody. That monoclonal antibody goes to the platelet-derived growth factor receptor, and its name is olaratumab. This is a molecule that I’ve been involved with since its very beginning. It’s an exciting drug that actually was used in combination with doxorubicin. And, as the frontline mainstay drug, finding a partner that works with doxorubicin besides ifosfamide is highly exciting.
I think a lot of people are curious what olaratumab is going to do in the paradigm of how we’re going to treat soft tissue sarcoma. I think part of this is going to come from the recent Lancet paper with how we did the original phase I/II trial. It was a randomized phase II where doxorubicin was used with olaratumab in combination, and they took any patient that was anthracycline-naïve. And so, as long as you hadn’t had an anthracycline, adding this to it seemed to give approximately 1-year overall survival benefit. I think where this drug is first going to come into play is in any metastatic patient that you’re going to give doxorubicin to. And so, what we’ve seen is if you compare this to, say, the Judson trial—where we looked at overall survival with Adriamycin and ifosfamide—this one stands out because we’re over 1 year greater in the metastatic setting. I think there’s still going to be a bit of an appropriateness to when to use Adriamycin and ifosfamide if we’re going for some sort of curative intent where we need shrinkage. But, I think the mainstay anthracycline treatment would be used in combination with olaratumab.
Richard F. Riedel, MD: The recent FDA approval of olaratumab, I think, is paradigm shifting for the treatment of soft tissue sarcoma. For the better part of 4 decades, we had been relying on anthracycline-based chemotherapy as the backbone. And while a lot of agents have been combined with anthracyclines to try to improve outcomes, up until the data from olaratumab in combination with doxorubicin, the trials have largely been negative. I think with the approval of olaratumab in combination with doxorubicin and, importantly, the improvement in survival that was seen in the phase II study, I think that combination will quickly supplant single-agent therapy in the treatment of patients with soft tissue sarcoma who are appropriate for anthracycline-based chemotherapy.
Victor Villalobos, MD, PhD: The availability of olaratumab has great implication on how we treat metastatic soft tissue sarcoma, and it may also become more relevant as well in bone sarcomas, but that’s still being studied. Really, I think it depends, on large part, on how the phase III study comes out, and if it corroborates the data we see from the phase II, which has been extremely exciting. It will change how we approach, in general, the treatment of metastatic disease. There has been a long argument of how aggressively to treat these with multiple different trials. More recently, an EORTC study looked at AIM, which is a combination of doxorubicin plus another drug called ifosfamide, compared to doxorubicin alone. And, that combination, while it did increase the progression-free survival, did not affect the overall survival significantly. This is really one of the few drugs now that we’ve seen in soft tissue sarcoma that actually has dramatically increased overall survival benefit and is something we haven’t seen before. So, I am very excited about the drug, but I still want to make sure that we can corroborate that evidence with a phase III blinded study.
Richard F. Riedel, MD: Olaratumab is a monoclonal antibody that targets a protein known as PDGFRα, also known as platelet-derived growth factor receptor alpha. And PDGFR is a transmembrane tyrosine kinase receptor. It sits on the surface of cells, and binding of the ligand to the receptor results in activation of the receptor and signaling through the receptor into the cell for growth signals. The target is an attractive one in cancer, in part because there is increasing recognition that many tumor cells and, in fact, the cells surrounding the tumor in what’s called the tumor microenvironment or the stroma actually overexpress PDGFR. And so, the strategy of targeting a protein that drives the growth signals of tumor cells is an attractive one.
Brian Van Tine, MD, PhD: The FDA label for this will be within combination with an anthracycline. It doesn’t necessarily have a line of therapy. There are certain soft tissue sarcomas that a lot of medical oncologists have a preference for a different first-line therapy. And so, when you go to use doxorubicin, this should be in combination with it.
So, more specifically, I think the label really does state that it’s for use for any soft tissue sarcoma for which doxorubicin is appropriate and in use in combination for 8 cycles with doxorubicin followed by maintenance, which is an important part of the efficacy of this drug. It’s then used as monotherapy.
Richard F. Riedel, MD: Olaratumab recently received FDA approval for the treatment of soft tissue sarcoma that is not amenable to surgery nor radiation therapy, and for whom treatment with an anthracycline-based chemotherapy backbone is appropriate. The dosing schedule in the phase II study was 15 mg/kg administered intravenously on day 1 and 8 of a 21-day cycle.
Victor Villalobos, MD, PhD: The appropriate dosing for this, in the first-line setting or even in the second- and third-line setting, is to give doxorubicin on day 1 of every 21-day cycle at 75 mg/m2. It’s typically given as a push over 15 minutes. Olaratumab, in the prior studies, has actually been given first, typically within that regimen to watch for any potential reactions, and that’s given at a 15 mg/kg on days 1 and day 8 over 1 hour.
Transcript Edited for Clarity