Soft Tissue Sarcoma: An Increasing Number of Options
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
Saketh Guntupalli, MD: Victor, can you talk to us a little bit about pazopanib and eribulin? In the press, we’ve heard a little about these drugs as possible treatments and targeted therapies for sarcomas.
Victor Villalobos, MD, PhD: Eribulin has now been approved for use in liposarcoma, particularly dedifferentiated liposarcoma. Interestingly, the data showed that it was equivalent to dacarbazine in the leiomyosarcoma subset. That being said, dacarbazine is actually quite an active drug in leiomyosarcoma. So, I think it does have activity there. If you can get it approved, I think it can work.
Pazopanib is another drug that has been approved for soft tissue sarcomas, all except for liposarcoma. It did not meet the prespecified endpoint for response in liposarcoma, although there might be some activity there, as well. Interestingly, we’ve done some research looking at pazopanib in community use. I think it is favored by several doctors because it’s an oral therapy, and because there’s a thought that oral therapy is less toxic than intravenous therapy. That’s not always the case. Pazopanib can have some pretty significant toxicities.
But in my clinical practice, I tend to use it in the third- or fourth-line setting, depending on the subtype of tumor that it is. It can be tolerable. Dosing is always a question, and I think there’s some controversy in regard to that. We often will use the same dosing as we use in renal cell carcinoma, 800 mg a day. But I often will actually start it off at 400 mg, and then go up for tolerability.
Eribulin is quite tolerable. I think the major drawback for that is most patients that are getting eribulin had docetaxel previously. So, you’ve got to monitor neuropathy, obviously. Otherwise they’re all good options. In most cases, there are many different options for sarcomas. It’s not like you’re limited to 2 or 3 drugs. You have quite a few drugs available to you.
Saketh Guntupalli, MD: The important thing, here, is that we have entered an era finally, with sarcomas, where we do have options and things that we can offer to our patients rather than just kind of throwing very broad drugs at patients. We now have phase II data and phase III data, which is coming out, for a lot of these drugs. This data looks to see if they are beneficial and efficacious in the treatment of sarcomas.
Victor Villalobos, MD, PhD: In leiomyosarcomas of the uterus, how often do you utilize dacarbazine, either by itself or in combination with gemcitabine?
Saketh Guntupalli, MD: We would utilize it, likely, far down the line. It’s just not a drug that we generally use a lot in gynecologic cancers. So, we’re not quite as familiar with it. But we have used it before. It generally tends to be used more in third-, fourth-line refractory disease.
Victor Villalobos, MD, PhD: In uterine and non-uterine leiomyosarcomas, we’ve been using gemcitabine/dacarbazine, fairly frequently. It’s actually quite tolerable. There is no hair loss or alopecia. Counts are relatively well tolerated, as well. It has quite good activity in uterine leiomyosarcoma. It has good activity, particularly in patients that had a really difficult time with docetaxel. If they were to recur, even if they had docetaxel before, and gemcitabine, I would consider giving the combination rather than the single agent.
Anthony P. Conley, MD: There are 2 broad categories to how I look at innovation and sarcoma management. First, we have targeted therapies. These are essentially therapies that are chosen based on unique profiles of the individual patient. This is usually achieved through methods such as next-generation sequencing or, sometimes, other methods such as fusion testing.
This is important because while a patient may have leiomyosarcoma, there may be a unique genetic change within their leiomyosarcoma that could improve our ability to treat that particular patient, as opposed to just using general therapies without any molecular basis.
Molecular targeted therapies, such as those that inhibit NTRK (neurotrophic tyrosine kinase 1) fusions, have become important in recent months. It’s been shown that regardless of the histology, if a patient has a NTRK fusion, it appears that they’re much more likely to respond to therapy than if they did not have the NTRK fusion. This is similar to gastrointestinal stromal tumors, where it was found that the KIT mutation and drugs that blocked KIT-mutated tumors were paramount to the future success of this disease. I think it’s important that patients that have developed resistance to common therapies be offered options such as genetic sequencing, so that we can hopefully uncover other therapies for them.
Separate to this, the other broad category I think that’s of importance would be immunotherapies. It’s not a surprise that immunotherapy has impacted a number of different areas of oncology, especially with what we’ve seen in melanoma. Fortunately, there have been recent studies, such as SARC-28, which was recently published in a major journal, that show that certain types of sarcoma appear to respond well to medicines such as pembrolizumab. This is important because our second-line therapies and beyond often may have response rates as low as 9%. Pembrolizumab was shown to have response rates of around 18% to 19%. And in certain populations, such as patients with undifferentiated pleomorphic sarcoma, the response rates have appeared to be as high as 40%. This is providing us with tremendous new ways to treat our patients and hopefully extend and improve their quality of life.
The future treatment of sarcoma should involve both genetic sequencing of the tumor as well as a careful discussion regarding many types of therapies beyond standard therapies. While it’s important that we consider the usual types of therapies that have been well-studied with good evidence to support their use, we need to be able to think beyond that point, such as whether or not my patient may have a unique genetic mutation that will allow us to treat them in a way that may be less toxic and, perhaps, more beneficial to them. Also, we should learn more about the patient’s fusion profile.
Just as we’re doing genetic sequencing, I see, in the future, that we will likely also be doing testing that allows us to understand whether or not a patient may be a better candidate for immunotherapy. In the future, we need to do a better job of incorporating molecular testing for targeted purposes, but also for immunotherapeutic purposes, as well.