Expert Highlights Frontline Treatment Options in the Molecular Age of Sarcoma

Brian Van Tine, MD

Brian Van Tine, MD

As more frontline treatment options become available for patients with soft tissue sarcoma, selecting therapies based on individual patients’ needs continues to become more complex, says Brian Van Tine, MD.

Based on their histological profile, patients can now be treated with up to 5 frontline therapies, in addition to the ongoing trials that continue to add to the complexity and evolution of the field.

“Sarcoma is no longer a static field,” Van Tine said. “It is this rapidly evolving field where the molecular age matters, the new drugs matter, the focus on histology matters, and what you’re trying to accomplish now matters.”

In an interview withTargeted Oncologyduring the 2017 Chemotherapy Foundation Symposium, Van Tine, assistant professor, Department of Cancer Medicine, Washington University, discussed the recent discoveries made for the treatment of soft tissue sarcoma and the ongoing trials for this patient population.  

TARGETED ONCOLOGY: Can you provide an overview of your talk, “What’s New in Sarcoma?”

Van Tine:I had the privilege of being invited to talk at the Chemotherapy Foundation Symposium about the advances in the treatment of soft tissue sarcoma, which has become a very complex field right now. A number of things have happened over the last 4 years, and we have begun to recognize that sarcoma is not a one-size-fits-all disease anymore. There has been a number of studies, including the GeDDiS study, which looked at gemcitabine/docetaxel (GemTax) versus doxorubicin, the JGDG study, which led to the FDA approval of olaratumab (Lartruvo), and the Judson study, looking at doxorubicin with ifosfamide, which has made frontline therapy really complex. At the same time, the molecular age has come into sarcoma. So, we are beginning to find that there are offshoots of these diseases that should be treated very differently.

In my talk, we walked through standard classic therapy with doxorubicin and ifosfamide, the new data with olaratumab, the GeDDiS looking at GemTax, and then the old standard of care, which was to give doxorubicin. We need to get a handle on what to do in the frontline setting, which is to refer the patient to a sarcoma center so that the right histology can be matched in the right clinical situation to the right patient. By guideline, we’re still suggesting that patients should be managed by experts who see a high volume of patients, but not necessarily treated.

Now that there are about 5 frontline options, we’re starting to look at patients as: do you need a response or do you need overall survival (OS)? That may be a question of when they walk in your office. If you really need a response, you probably want to reach for something like doxorubicin with ifosfamide, but if you have a low-burden disease, given the OS advantage of our new monoclonal olaratumab, you will probably want to reach for that. If you throw in something more complicated, like synovial sarcoma, an ifosfamide-based regimen is still probably preferred. This isn’t a very easy schematic to follow right now. It’s becoming a much more complex field. With the recent publication of the GeDDiS trial, where GemTax versus doxorubicin really gives you the same progression free survival (PFS) and the same OS, you then begin to wonder: is it a sequencing matter, and are there certain tumors where you can get away with not using an anthracycline frontline?

If you take our 3 other new advanced-line drugs, trabectedin (Yondelis), eribulin, and pazopanib (Votrient), what you find is that they are not all appropriate for every histology. Liposarcoma patients have a good response to eribulin and trabectedin, but they are not on label for pazaopanib, where as eribulin isn’t on label for leiomyosarcoma patients. Now that we have a lot more drugs in the field, it becomes kind of a spider web, where the order of things changes depending on who you are treating. Additionally, advances that are still being made on clinical trial are in the upfront setting and second-line setting and third-line setting will constantly continue to evolve.

The other thing that is happening is that we are finding there are subclasses of patients where they should probably be sequenced upfront. There is a whole class of undifferentiated pleomorphic sarcomas that may have an NTRK fusion. There’s a new drug for that. Those patients may go off in a whole new direction, just like the gastrointestinal stromal tumor (GIST) patients have evolved over time when we first found mutations in KIT. These are new fusions that may alter what we do. So now that the molecular age has come in, knowing what you’re actually treating is probably more important.

I ended my presentation by discussing the new ALLIANCE trial, with ipilimumab (Yervoy) and nivolumab (Opdivo), and the results that came into our field with immunotherapy and some of the responses that are being seen. Sarcoma is no longer a static field, it is this rapidly evolving field where the molecular age matters, the new drugs matter, the focus on histology matters, and what you’re trying to accomplish now matters.

TARGETED ONCOLOGY: What are the next steps with olaratumab now that is has been approved by the FDA?

Van Tine:The development of olaratumab Is being continued by Eli Lilly in a number of clinical trials. They are looking at olaratumab and a backbone of gemcitabine and docetaxel, which is an ongoing clinical trial in both patients that have had prior exposure to olaratumab and patients that are naïve. This may be an agent that is continued from line to line, like bevacizumab is in other cancers. Or, we may find that there is something special about giving doxorubicin, where you should only give it with doxorubicin. That question is being answered.

In addition, they are running a clinical trial with doxorubicin and ifosfamide to see if the triplet has the same efficacy and advantages as the doublet because the addition of another drug may also alter biology. These are ongoing trials that are very important right now. There are biomarker trials that are also ongoing, so this a drug that is being fully developed within our field right now.

TARGETED ONCOLOGY: You briefly mentioned the early promise that we are seeing with the checkpoint inhibitors. Can you comment on the data and what we have seen so far?

Van Tine:Presented by Dr. Sandra D’Angelo at the ASCO Annual Meeting this year, there was a well done and rapidly done trial of immunotherapy in soft tissue sarcomas. This added on to the data where pembrolizumab was studied in soft tissue sarcoma by the Sarcoma Alliance for Research Through Collaboration (SARC) group. What we are seeing is that there are certain histologies, such as undifferentiated pleomorphic sarcoma, that are more likely to respond to immunotherapy. The ALLIANCE trial — which was a randomized, but parallel trial, so the arms weren’t meant to be compared, but we are probably going to compare them anyway — found that the combination is much more toxic, but the response rate is higher. There is about a 16% response rate, which is amazing in advanced patients. There were a number of complete responses on this trial, some that actually weren’t captured by the trial because patients came off for serious adverse events, but were continued on and still have no disease to this day.

We are still learning who to give what to. This is really a rapidly evolving field. I’m really excited, because to have patients with a therapy that could be managed in our field, just like melanoma patients and lung cancer patients, is really exciting.

TARGETED ONCOLOGY: Are there any ongoing trials exploring NY-ESO-1 as a target?

Van Tine:There are 2 trials that are ongoing with the NY-ESO-1 target, in both synovial sarcoma and myxoid round cell liposarcoma. The first is by immune design, which should report soon using a dendritic-cell based vaccine with atezolizumab to see if they can get the immune system to go after the tumor. The earlier data on their phase I, but not their phase II, was reported last year at ASCO. But, we have yet to see where that is going to go formally. I believe there are plans for moving that forward once it’s reported and their trial designs are underway.

There is also a trial by Adaptimmune using a modified T cell to go after NY-ESO-based synovial sarcoma and myxoid round cell sarcoma. GlaxoSmithKline exercised its rights to buy this and so we are waiting to see what they will do to further develop this. These trials have yet to be reported.