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Multiple Molecular Subtypes of Sarcoma Allow for Orphan Drug Development

Brian A. Van Tine, MD, PhD
Published Online: Nov 18,2016


The treatment of sarcomas is complicated by the fact that we have historically treated them as 1 single disease entity. Presently, the term sarcoma represents over 100 separate diseases, each with multiple molecular subtypes and underlying biology. Under the rubric of orphan drug development, each molecular subtype, whether by biomarker or gene signature, may allow for targeted drug development. As we biologically subdivide the sarcomas, more clinical trials are needed to advance the treatment of rare cancers. The sarcoma field has matured in the last 5 years to become a clinical trialist community that is well organized to perform rapid phase III clinical trials. The field is also able to conduct trials in rare or focused subgroups in an efficient fashion using collaborative group mechanisms such as the Sarcoma Alliance for Research and Collaboration (SARC). In this review, we will examine the most attractive molecular targets in sarcoma and the current state of drug development.


Sarcoma is a group of well over 100 different diseases that only have their mesenchymal origin in common.1,2,3,4 This is a family of tumors that arise from fat, muscle, bone and cartilage.5 Although it is often categorized as one disease, in reality it is an aggregate of many molecular and pathologic separate subtypes of sarcoma.3,4

It is interesting that the parallel to sarcoma is carcinoma. Our colleagues who treat carcinomas are not referred to as carcinoma doctors; instead they refer to themselves as breast cancer, lung cancer, colon cancer, etc. oncologists. As sarcoma doctors, we take over 100 different diseases with their individual subtypes and often lump them into 1 group. This does a great disservice to a disease whose biological diversity and well-known underlying genetics are therapeutic opportunities for drug development. In addition, it has likely been this all-inclusive approach to sarcoma that has led to the lack of positive phase III trials in all-comer sarcoma trials.

One of the things that makes sarcomas different from carcinomas is that they have a propensity fibrosis, as opposed to shrinking and disappearing, when there is a chemotherapy response.6 Though the propensity to fibrose is variable, some histologies, such as synovial sarcomas in some patients do respond, this may be related to the amount of matrix associated with each tumor. As such, trials looking at response rate (RR), which counts only complete and partial responses, instead of clinical benefit rate (CBR), which also includes stable disease, are hindered by a lack of appreciation for mesenchymal biology. The appreciation of fibrosis has changed the metric for drug approval in sarcoma,7,8,9 as progression-free survival (PFS) and overall survival (OS) metrics are better measures of trial outcomes for sarcoma patients.

In the last 5 years, there have been many phase III clinical trials for soft tissue sarcomas.7,8,9,10 The most important of which may be the clinical trial using ridaforlimus (Taltorvic) for maintenance therapy after chemotherapy in soft tissue sarcoma.10 Of interest, this clinical trial was able to demonstrate a statistically significant 3-week OS compared to placebo. While this may be a clinically meaningless result, the reason for the OS benefit was never explained, because there was no correlative biomarker work explored in this clinical trial. What makes this trial so important is that it was a 711-patient trial that accrued in approximately 2 years, which demonstrated clearly that the sarcoma community could conduct large trials efficiently. This was followed by 2 other rapidly accruing clinical trials, ZIO-201 (palifosfamide) and TH302 (evofosfamide). While both of these rapidly accrued, they did not demonstrate PFS or OS. Next, a large phase III trial was performed in Europe using pazopanib for the treatment of non-liposarcoma soft tissue sarcoma (STS) that led to the FDA approval based on PFS, but not OS. The broad spectrum of tyrosine kinase inhibition of pazopanib (Votrient) may explain why there was a positive PFS amongst a large selection of multiple subtypes of sarcomas.7 More recently, another large phase III clinical trial of aldoxirubicin also rapidly accrued, most likely due to patient selection and trial design, but failed to demonstrate the predetermined trial endpoints at this time.11 These trials were all complicated by the all-comer study design.

Two other drugs have been recently approved by the FDA based on phase III trials, but these trials were histology focused. The first trial was of trabectedin, which was a phase III trial in leiomyosarcoma (LMS) and liposarcoma, and was granted FDA approval based on its secondary aim of PFS.9 Though this drug is used to treat many types of high-grade sarcomas, the investigators tailored this trial to 2 well-known responding histologies for approval in the USA. Even with this approach, the study failed to meet its primary objective, which was OS. In parallel, eribulin (Halaven) was also studied in a phase III trial in the same patient population.8 While it was found to be no better than dacarbazine in terms of PFS, it was found to have an OS driven by the liposarcoma arm of the trial, and as such was approved for liposarcoma by the FDA. Neither of these studies truly accounted for the molecular heterogeneity of LMS or the 5 separate subtypes of liposarcoma which all have diverse underlying molecular biology.

As will be discussed below, the underlying molecular knowledge of the sarcoma subtypes represents an extensive literature, which when exploited, can be used for orphan-drug development. In this review, we will look at the most promising therapeutic targets found in the sarcoma subtypes. We will also look at current clinical trials and clinical trial opportunities that are promising in the rare tumor field.

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Multiple Molecular Subtypes of Sarcoma Allow for Orphan Drug Development
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