Evolving Paradigms in STS: Perspectives With Shreyaskumar R. Patel and Jonathan C. Trent, MD

February 16, 2017
Greg Kennelty

Evolving Paradigms, Soft Tissue Sarcoma, Volume 2, Issue 1

Shreyaskumar R. Patel, MD and Jonathan C. Trent, MD discussed the use of trabectedin and the future of the treatment paradigms in soft tissue sarcoma.

Jonathan C. Trent, MD

On October 23, 2015, trabectedin (Yondelis) was approved by the FDA after promising results from the phase III ET743-SAR-3007 trial. Trabectedin is used to treat patients with advanced soft tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, and specifically those who have previously received chemotherapy that included an anthracycline.

In the open-label, multicenter, phase III SAR-3007 trial, trabectedin reduced the risk of disease progression by 45% versus dacarbazine in patients with advanced soft tissue sarcoma. There was also a slight survival trend with trabectedin, but the results were not significant.

The trial compared trabectedin with dacarbazine in 518 patients with liposarcoma and leiomyosarcoma who previously received an anthracycline-containing regimen followed by at least one additional line of chemotherapy. The protocol required patients to have an ECOG performance status of 0 or 1. The study was conducted at 85 sites in four different countries, but 94% of the patients were enrolled in the United States.

In an exclusive interview withTargeted Oncology, Shreyaskumar R. Patel, MD, professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and Jonathan C. Trent, MD, professor of Medicine, co-director, Musculoskeletal Center, Sarcoma Medical Research Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, discussed the use of trabectedin and the future of the treatment paradigms in soft tissue sarcoma.

What have been some of the challenges toward evidence-based treatment in soft tissue sarcoma and how is that evolving?

PATEL:One of the biggest challenges is that this is a rare group of tumors. Of the 1,650,000 or so new cancers diagnosed in the calendar year 2015, soft tissue sarcomas are just under 12,000 cases. As a group of diseases, it's rare. The added complexity is that the soft tissue sarcomas umbrella is comprised of 50 to 75 subtypes of sarcomas.

The three or four of the more common ones tend to be liposarcomas, leiomyosarcomas, and differentiated biomorphic sarcomas, but the list of entities that fall within this group of tumors that we call soft tissue sarcomas is very long. Consequently, what ends up happening is, to try to get level one evidence, you would need a large sample size in a very homogenous population. That's virtually impossible. Compare this to breast cancer, for example, where there are clearly more than 200,000 new cases in a given calendar year. The heterogeneity is a lot less than it is for soft tissue sarcomas. Consequently, it's not impractical.

As a matter of fact, it is standard practice to run between 2000 and 4000 patient clinical trials in the breast cancer population, in a uniform or homogenous population, to obtain the right answers that would constitute that level one evidence. That's virtually impossible in soft tissue sarcomas. You may run into several trials that may show a 10% difference in the primary endpoint in favor of an experimental arm versus the control arm, but theP-value may not be significant because the sample size is small. This is one of the major issues that we run into.

From a statistical standpoint, you really do want larger clinical trials and to get a large number of patients in a reasonable period of time. Of course, "reasonable" as defined by the sponsors and investigators, collectively. You then end up lumping a lot of patients together, and as I typically said, "you make a fruit salad out of the patient population." You mix apples, pears, peaches, and oranges, which makes the data that much less interpretable, if you will. To try to just test the apples, it will take a very, very long time, and that's the major limitation with soft tissue sarcomas.

Is there anything being done about it? I think over the last several years, the international community has come together. There are examples of trials that are run on both sides of the Atlantic, or even extending over to Asia, Australia, and beyond, to try to get behind a given trial that may be of interest to see if we can try to homogenize, if you will, the population as best as we can.

TRENT:The management of sarcoma patients has always been challenging in terms of an evidence-based approach. There are a number of studies, but these clinical trials and other studies tend to be small. They tend to be limited in the focus on specific types of sarcomas. This is not surprising when there"s only 10,000 to 15,000 new patients per year diagnosed with sarcoma in the United States, and there are over 50 different types of sarcoma. It can be really challenging to have robust data and large numbers of patients.

That being said, there have been a number of randomized studies recently that have asked several specific questions. For instance, there was a recent study asking whether the use of gemcitabine/docetaxel was better than using an anthracycline such as doxorubicin in frontline therapy for patients with metastatic sarcoma. The result of that study was that doxorubicin was better tolerated and probably more effective than the combination of gemcitabine/docetaxel. Another study recently led to the approval of pazopanib in the treatment of patients with soft-tissue sarcoma, including liposarcoma and GI stromal tumors. This was based on a phase III study comparing pazopanib to placebo in patients with metastatic sarcoma.

A more recent study looked at the use of trabectedin in patients with liposarcoma or leiomyosarcoma. This subset of patients had metastatic disease, and the patients were randomized to either trabectedin or dacarbazine. The result of the study was superiority of the trabectedin arm.

You can see that there are a number of studies that are enrolling a larger number of patients, some of these in specific histologies such as the trabectedin study, which looked at liposarcomas and leiomyosarcoma.

Shreyaskumar R. Patel, MD

What is the most effective method for a diagnosis and grading soft tissue sarcoma, and how important is molecular genetic testing?

PATEL:The histopathologic diagnosis part of the disease is fairly well standardized. If patients are presenting with a lump or a mass, we will get a biopsy. The tissue is, and should be, analyzed by pathologists with expertise in musculoskeletal pathology. The characteristics of each one of these 50 to 100 different subtypes, depending on how many you're lumping under the umbrella of sarcomas, is reasonably well defined. Pathologists with expertise will not have difficulty in making the diagnosis.

I think the molecular genetics portion of this particular group of sarcomas is a different story. We will slowly, but steadily, be peeling away at some of the smaller subsets. Where there are characteristic translocations, for example, there may be fusion probings that can be identified to try to help from a diagnostic standpoint, assign a specific name to that particular entity.

TRENT:Sarcomas have always been a challenging type of cancer to diagnose and grade. There are 10,000 to 15,000 new sarcoma patients per year in the United States compared with somewhere near 200,000 women diagnosed with breast cancer. This is a very rare disease. To make it more complicated, there are over 50 different types of sarcoma. In any individual type, there may only be several hundred or several thousand cases diagnosed per year in the United States. The rarity of this tumor makes it challenging for pathologists to make the diagnosis and assess the grade of the tumor.

At the University of Miami Sylvester Comprehensive Cancer Center, we have our sarcoma pathologists review all new cases in all new patients that come to our site. I think that the critical first step in understanding how to treat a patient with a sarcoma is making the right diagnosis. I generally recommend have the material reviewed at a sarcoma center by a sarcoma specialty pathologist.

In what population of patients would first-line chemotherapy be most appropriate?

PATEL:I don't think these decisions are any different for soft tissue sarcomas than most other malignancies. Soft tissue sarcomas is more common in the fifth and sixth decade of life, so most of these patients tend to have a reasonable or a very decent performance status, even when they present with metastatic disease, organ function and performance status is acceptable enough for consideration of front-line systemic therapy. This is unlike some of the other epithelial tumors that may be far more widespread, where patients, either because of organ dysfunction, poor performance status, or just personal choice, would not be candidates for any line of systemic therapy. That proportion happens to be relatively small for the group of patients with soft tissue sarcomas.

In my practice, and in my experience, I think most of these patients with metastatic soft tissue sarcomas will end up going through multiple different lines of chemotherapy, or targeted therapies, or experimental trials, simply because they do tend to maintain and preserve their performance status and organ function for quite a long time.

TRENT:Frontline chemotherapy is used in a variety of different situations in patients diagnosed with sarcoma. A patient is diagnosed with a primary tumor if the metastatic potential is high such as rhabdomyosarcoma, Ewing"s Sarcoma, desmoplastic small-round-cell tumor, osteosarcoma, these are patients that we initiate on chemotherapy as their frontline surgery, generally even before surgery or radiation therapy. In the metastatic setting, chemotherapy is the mainstay of treatment. These patients may get surgery or radiation at some point in the future, but in the setting of metastatic disease, the primary goal is to use systemic therapy to really control, shrink, hopefully even induce a complete remission for patients with metastatic sarcoma.

Who would be the right patient to receive trabectedin?

PATEL:Trabectedin recently got approved for patients with metastatic or advanced leiomyosarcomas and liposarcomas. This was based on the way the clinical trial was designed. If you follow the prescribing information, then this would be appropriate for patients with leiomyosarcomas and liposarcomas who have metastatic disease, have advanced incurable disease, and who have failed at least one prior line of therapy that included anthracycline. This is the eligibility criteria for the clinical trial that led to the approval of this drug.

Certain subsets like a patient with myxoid liposarcoma are supposed to have exquisite sensitivity to this drug trabectedin, and if there were issues or contraindications to conventional anthracycline-based therapy, this [trabectedin] certainly can be moved up front in the line of therapy for that particular patient population.

TRENT:Trabectedin is a new agent that we"re using to treat patients with metastatic or advanced sarcomas, specifically liposarcoma and leiomyosarcoma. Patients with liposarcoma and leiomyosarcoma generally present with primary disease, although many patients present with metastatic disease. Patients who do present with metastatic disease are often treated with an anthracycline combination therapy such as doxorubicin plus dacarbazine or doxorubicin plus ifosfamide. That"s standard frontline therapy for patients with metastatic sarcoma for most types. There are certainly caveats and certainly situations where that"s not the case, but that is the usual course of action.

After an anthracycline-based therapy, patients with metastatic sarcoma are treated with second-line therapy. In the setting of a diagnosis of liposarcoma or leiomyosarcoma, those options are gemcitabine/docetaxel for leiomyosarcoma or trabectedin, which has activity and is now FDA approved for leiomyosarcoma but also for liposarcoma, including dedifferentiated and myxoid liposarcomas.

What important developments have occurred toward improving treatments in leiomyosarcoma?

PATEL:Leiomyosarcoma, one of the more common subsets of soft tissue sarcomas, has been a focus of attention of at least two large phase III randomized trials recently completed, presented, and to be published soon. One of them would be the Yondelis trabectedin approval for patients with leiomyosarcoma. The other one is a drug called eribulin. Eribulin, similar to trabectedin, was tested in a randomized phase III trial against dacarbazine and the data presented at ASCO last year showed improvement in overall survival. The drug is not yet approved for this indication, but certainly the hope would be that that becomes part of the therapeutic armamentarium for patients specifically with leiomyosarcomas.

TRENT:Patients diagnosed with metastatic leiomyosarcoma have been difficult to treat over the years. Standard regimens include a combination of an anthracycline such as doxorubicin plus dacarbazine, occasionally doxorubicin plus ifosfamide. Second-line therapy that has been used in the United States includes gemcitabine/docetaxel, and now we have a new agent, trabectedin, that has been proven to be effective in second- and third-line therapy for patients with leiomyosarcoma. This is based on a phase III study where patients with metastatic leiomyosarcoma and liposarcoma were randomized to either trabectedin or a comparator arm of dacarbazine. Trabectedin was found to be superior.

What important developments have occurred toward improving treatment in liposarcoma?

PATEL:I think both the phase III trials that we just mentioned included patients with liposarcomas and leiomyosarcomas. Yondelis is now approved for use in the United States, as it was for many other parts of the world. Eribulin data, like I said, was presented at ASCO and showed survival advantage, but is not yet approved by the FDA for this indication.

TRENT: