Soft Tissue Sarcomas: Emerging and Novel Concepts

Karen Fritchie, MD

Mayo Clinic, Department of Laboratory Medicine and Pathology

200 First Street SW

Rochester, MN 55905

fritchie.karen@mayo.edu

Scott H. Okuno, MD

Mayo Clinic, Division of Medical Oncology

200 First Street SW

Rochester, MN 55905

Okuno.Scott@mayo.edu

Steven I. Robinson, MBBS

Mayo Clinic, Division of Medical Oncology

200 First Street SW

Rochester, MN 55905

robinson.steven@mayo.edu

Abstract

Soft tissue sarcomas are a rare and challenging group of malignancies of mesenchymal origin that have historically been treated with similar approaches. Improvements in molecular techniques and understanding of tumor biology, however, have paved the way for more selective treatment of distinct subtypes. Broad-based approaches through targeting angiogenesis and the use of novel cytotoxic approaches are still applicable across multiple histologies. Appropriate selection of sarcoma subtypes that may benefit from a given treatment and clinical trial design that takes into account the mechanism of action of the agent involved may potentially improve clinical trial results.

Soft tissue sarcomas are a heterogeneous group of malignancies that account for approximately 1% of all malignancies in adult patients.^1,2This rarity, coupled with their variety, creates a difficult environment for treating physicians and investigators alike. In the first part (June, 2014) of this 2-part series, we explored currently accepted treatment options and available agents in the therapeutic arsenal for soft tissue sarcomas. We reviewed management strategies, including targeted approaches, to unique subtypes of soft tissue sarcomas, such as anaplastic lymphoma kinase (ALK) and inflammatory myofibroblastic tumor. In the present review, we will explore emerging agents and concepts. An exhaustive review of these agents is beyond the scope of this and arguably any single manuscript. Rather, we will survey the rationale behind the selection of these drugs, exploring any relevant pitfalls that may have led to a realization or perception of inactivity, and offer our thoughts on potential treatment directions.

Clinical Trial Endpoints in Soft Tissue Sarcomas

Efforts to overcome the heterogeneity of soft tissue sarcomas may involve approaching the disease group in a broad-based manner or in an individualized way. A broad-based approach involves targeting the environment that is believed to be common to all the subtypes, using cytotoxic agents that act irrespective of the histology, or adopting an immunebased approach. Conversely, an individualized approach focuses on individual histologies or pathways that transcend individual subtypes. Regardless of the philosophy of the investigator, it is of paramount importance that the development of drugs with potential activity in soft tissue sarcomas is not hampered by poor clinical trial design.Clinical trial endpoints in both bone sarcomas and soft tissue sarcomas are unique and have shaped the development of new trials in sarcomas. For primary bone sarcomas, the percentage of necrosis rate is a useful clinical endpoint for patients undergoing neoadjuvant chemotherapy, but it has not been as useful for soft tissue sarcomas. In the era of cytoxic chemotherapy, the primary endpoint for many trials, including those for sarcomas, was response rate (RR), as outlined in the Response Evaluation Criteria in Solid Tumors (RECIST), which has certain limitations.^3,4To determine an appropriate endpoint for STS for noncytotoxic drugs, the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) reviewed 11 investigational agents and determined that, in first-line therapy, a 6-month progressionfree rate (PFR) of ≥30% to 56% is a good reference to suggest activity of a drug. In second-line therapy, a 3-month PFR of ≥40% suggests activity, while PFR ≤20% suggests inactivity.⁵Hence, PFR (the proportion of patients without evidence of progression at a fixed time point) and progression-free survival (PFS) are considered the new primary endpoints for trial designs rather than those from RECIST.

For gastrointestinal stromal tumors (GIST), the novel agents imatinib, sunitinib, and regorafenib have been shown to be active, but in many instances the size of the lesion is not reduced; rather, a cystic lesion remains after the solid GIST has been treated.^6-10Choi criteria were developed for GIST to account for not only the change in size of the tumors, but also the decrease in tumor density.¹¹Clinical trials for GIST often use Choi criteria as their primary endpoint. Several studies in other soft tissue sarcomas have also tried to use the Choi criteria, but this endpoint in sarcomas is best studied in GIST histology.¹²

Receptor Tyrosine Kinase Inhibitors and Angiogenesis

Clinical trials in soft tissue sarcomas continue to use PFR, PFS, and RECIST as primary endpoints. The success or failure of a new drug or combination regimen often depends on the primary endpoint that the investigators select. When designing such trials, it has been proposed that the biologic activity of the agent being investigated be taken into question, such as growth inhibition with targeted agents, and the historic progression arrest rate for distinct subtypes be garnered through retrospective review of large cooperative study databases.¹³Regardless of the endpoint chosen, the clinical benefit has to be meaningful for the patient. In this review, we will explore novel targets and emerging drugs in soft tissue sarcomas, with emphasis on the rationale for the drug, the endpoints selected, and how that might impact further studies with these agents.Proangiogenic factors, such as VEGF, platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), have been documented in soft tissue sarcomas.14-17 The behavior of soft tissue sarcomas has also been linked to the density of the microvasculature and level of VEGF expression.18 Thus, inhibiting angiogenesis has been an attractive treatment approach for this heterogenous family of tumors. Unfortunately, among the plethora of oral receptor tyrosine kinase (RTK) inhibitors tested, only pazopanib has thus far gained US Food and Drug Administration (FDA) approval, albeit limited to non-GIST and non-lipocytic soft tissue sarcomas.

Semaxanib (SU5416), a small molecule inhibitor of VEGF2 and KIT, was studied in soft tissue sarcomas in 2 separate phase II trials. A trial conducted by Kuenen and colleagues accrued 26 evaluable patients in a 3-armed study (renal cell carcinoma, melanoma, and soft tissue sarcomas). The median PFS was 2 months. Six of 26 patients (23%) met the prescribed endpoint of stable disease at 3 months, including 2 patients with leiomyosarcomas.¹⁹Conversely, Heymach et al noted no responses, with a median PFS of 1.8 months and 3-month PFR of 8%, in their single-arm study of 13 patients with sarcomas. Production of semaxanib subsequently ceased.²⁰

Imatinib mesylate, the oral RTK inhibitor of c-ABL, BCR-ABL, KIT, and PDGFR, failed to demonstrate efficacy in non-GIST soft tissue sarcomas (NGSTS) in 3 separate phase II multicenter clinical trials. Verweij et al reported the results of the EORTC trial that accrued 51 patients, including 24 NGSTS (liposarcoma, leiomyosarcoma, fibrosarcoma, synovial sarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma [MFH/UPS], and others). There were no treatment responses, and the median time to progression was 58 days.²¹

The Sarcoma Alliance for Research Collaboration (SARC) evaluated imatinib in 10 soft tissue sarcoma subtypes: angiosarcoma, Ewing’s sarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, MFH/UPS, osteosarcoma, MPNST, rhabdomyosarcoma, and synovial sarcoma. They utilized a hierarchical Bayesian statistical model in an attempt to continue accrual in only those subtypes that met the criteria for efficacy; namely, a clinical benefit response (complete or partial responses within 16 weeks and stable disease within at least 16 weeks) of at least 30%. They accrued 185 assessable patients with a response rate of 2.2% (1 complete response, 3 partial responses) and a clinical benefit response of 15.1%. No subtypes met the desired endpoint, with the closest subtypes, liposarcoma and leiomyosarcoma, achieving clinical benefit response rates of only 24.1% and 21.4%, respectively.²²

Similarly, Sugiura and colleagues attempted a tailored approach, studying imatinib in NGSTS that were either KIT-positive or PDGFR-positive, across 9 Japanese centers. Only 1 partial response was seen in 22 of 25 assessable patients.²³Sunitinib, the multitargeted inhibitor of pan-VEGF, PDGFR, FLT3, and RET-encoded tyrosine kinase, like imatinib, failed to meet the primary endpoints in the reported clinical trials. George et al utilized a continuing dosing approach of 37.5 mg daily in their multicenter phase II trial. The primary endpoint was response rate, with PFR rates at 16 and 24 weeks and metabolic response via positron emission tomography (PET) as secondary endpoints. Arm A (historic responses to RTK inhibition) included patients with leiomyosarcoma, solitary fibrous tumor/hemangiopericytoma, angiosarcoma, desmoid tumors, and intimal sarcoma. No partial responses were seen and only 2 of 18 patients remained progression-free at weeks 16 and 24.

Arm B was comprised of patients that had no prior history of RTK inhibitor response, with subtypes including UPS, synovial sarcoma, carcinosarcoma, desmoplastic small round cell tumor (DSRCT), liposarcoma, alveolar soft part sarcoma, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and giant cell tumor of bone. One partial response was seen in the patient with DSRCT. The progressionfree rates were 19% and 14%, respectively, at 16 and 24 weeks, with durable stability seen in solitary fibrous tumor and in the patient with the giant cell tumor subtype.²⁴

In their open-label, single-institution phase II study, Mahmood and colleagues utilized the more standard 50-mg daily dosing of sunitinib for 4 weeks with 2 weeks off in 3 cohorts of patients (those with liposarcoma, leiomyosarcoma, and MFH/UPS). The primary endpoint was RR, with only 1 of 43 patients (a patient with leiomyosarcoma) meeting the criteria. The median PFS rates were 3.9 months, 4.2 months, and 2.5 months for liposarcoma, leiomyosarcoma, and MFH/UPS, respectively. The retrospective PFR at 3 months exceeded 40%.²⁵

Recognizing that antiangiogenic therapy may not yield RECIST responses, Hensley and colleagues used both RR and progression-free rate at 6 months (PFR-6) as coprimary endpoints in the Gynecology Oncology Group (GOG) study of sunitinib in patients with leiomyosarcoma who had failed prior therapy. Of 23 evaluable patients, only 2 responses were seen (8.7%). With only 4 of 23 patients remaining progression-free at 6 months (17.4%), the study failed to meet the mandated 5 patients at the interim analysis required to proceed to the second stage of the study.²⁶

Like sunitinib, sorafenib is a small molecule RTK inhibitor of VEGF receptor 1-3, FLT3, and c-kit, and it also inhibits PDGF-B and Raf. Maki and colleagues conducted a multicenter, phase II study of sorafenib in soft tissue sarcomas. Assuming the biology within the subtypes would be different, they had 6 separate Simon 2-stage arms (leiomyosarcoma, malignant peripheral nerve sheath tumor [MPNST], synovial sarcoma, vascular sarcomas, UPS, and an “other” arm). Only 2 arms, leiomyosarcoma and the vascular sarcomas, had responses in the initial 12 patients and accrued an additional 25 patients. There were 6 total responses (1 complete response and 5 partial responses), with 5 occurring in the 37 patients with angiosarcoma; RR 14%. The median PFS was 3.2 months, best exhibited in angiosarcoma (3.8 months), other (3.6 months), and leiomyosarcoma (3.2 months).²⁷

The intergroup, open-label, multicenter phase II trial, S0505, conducted through the Southwest Oncology Group (SWOG), evaluated sorafenib in 3 cohorts of advanced soft tissue sarcomas: vascular sarcomas (angiosarcoma and solitary fibrous tumor), leiomyosarcoma, and liposarcoma (dedifferentiated and myxoid/round cell). These groups historically expressed VEGF and PDGF. As with several trials in this class, RR was the desired endpoint, which the trial failed to meet at the analysis of the first of the planned 2 stages of enrollment, with no confirmed responses noted. Of note, 32% of patients in this trial were progression-free at 6 months. The median PFS was 3 months in patients with angiosarcomas and leiomyosarcomas, and superior PFS was seen, with 5 and 3 months respectively compared with the 2 months in the liposarcoma cohort. There were 2 long-term responders, 18 cycles (leiomyosarcoma), and 25 cycles (solitary fibrous tumor).²⁸

Pazopanib, the VEGF receptor 1-3, PDGF-A and -B, c-kit and FGF receptor-1 blocker, is FDA approved for the treatment of nonadipocytic soft tissue sarcomas. The EORTC Soft Tissue and Bone Sarcoma Group enrolled 142 patients across 4 strata (adipocytic, leiomyosarcoma, and other STS types) in a Simon 2-stage design for each stratum, with an endpoint of PFR at 12 weeks (PFR-12) of 40% deemed active. Three of the 4 cohorts were deemed favorable at conclusion of the first stage: leiomyosarcoma (44% PFR), synovial sarcoma (49% PFR), and other soft tissue sarcoma (39% PFR). The adipocytic arm was closed, with only 5 of 19 patients (26%) progressionfree after stage 1.²⁹

Accordingly, the subsequent phase III study (PALETTE) did not include patients with adipocytic tumors. A total of 369 patients were randomized to receive pazopanib versus placebo in a 2:1 fashion. Pazopanib exhibited superior PFS versus placebo, 4.6 months (95% CI: 3.7-4.8) versus 1.6 months (95% CI: 0.9-1.8). No crossover was allowed. Overall survival was not significantly improved in the patients receiving pazopanib versus placebo, 12.5 months (10.6-14.8) versus 10.7 months (8.7-12.8), respectively.³⁰

In a subsequent analysis of pooled data from both the phase II and phase III studies (EORTC 62043 and 62072), over 30% of patients who were treated with pazopanib had a prolonged PFS and overall survival beyond 6 months and 18 months, respectively. Good performance status, low-grade or intermediate-grade tumors, and normal baseline hemoglobin at study entry were deemed advantageous for the fewer than 4% of patients who were progression-free beyond 2 years.³¹

Several clinical trials that are presently open or in development are investigating pazopanib in combination with cytotoxic agents in soft tissue sarcomas (gemcitabine, NCT01532687; gemcitabine and docetaxel, NCT01418001), or in combination with targeted therapies (MET inhibitor, NCT01468922; MEK inhibitor, NCT01438554; Endoglin antibody, NCT01975519). Given the heterogeneity within adipocytic soft tissue sarcoma, pazopanib is also being explored in high-grade liposarcomas (NCT01506596).

The broadly active multiple RTK inhibitor of VEGFR, PDGF, RET, MAP kinase, and FGF1, among others, regorafenib demonstrated its efficacy in the treatment of patients refractory to imatinib and sunitinib.^8,10It is presently being explored in the arsenal of antiangiogenic RTK therapy for soft tissue sarcomas (STS REGO SARC, NCT01900743) and angiosarcoma (NCT02048722).

Emerging Cytotoxic Agents

While the place of pazopanib in soft tissue sarcomas is clear, one could debate that the results in the clinical trials of the overlapping agents with both VEGF and PDGF blockade, sunitinib and particularly sorafenib, could have been interpreted differently with PFR as the endpoints akin to EORTC 62043. It is thus of paramount importance that investigators consider pairing suitable endpoints and agents when designing clinical trials. Similarly, it is increasingly clear that there is a place for adaptive designs when studying these agents within heterogenous tumor groups, such as soft tissue sarcomas.Cytotoxic therapy theoretically enables broad subtypes to be treated effectively, negating the need to differentiate between subtypes of STS. We know this is not the case in soft tissue sarcomas as demonstrated in the exploratory analysis of prior EORTC Soft Tissue and Bone Sarcoma Group trials.³²As the field has progressed toward molecular characterization and targeted therapies, less focus has been placed on conventional cytotoxic therapy. There is still a need for such options; hence, we will now review what we consider to be the most exciting chemotherapeutic agents.

Aldoxorubicin

Doxorubicin has been the mainstay and backbone for first-line therapy for many bone sarcomas (Ewing’s sarcoma and osteosarcoma) as well as soft tissue sarcomas, whether as a single agent or in combination. Unfortunately, its use is limited by a dose-dependent cardiomyopathy beyond a cumulative dose of 500 mg/m2.33 Reported risk factors include advanced age (>70 years), preexisting heart disease, hypertension, mediastinal radiotherapy, and use of combination chemotherapy.³³Cardiomyopathy is estimated to occur in 10% of patients and may occur beyond 10 years from the last doxorubicin exposure. It is thought to be mediated through oxidative stress.³⁴

Aldoxorubicin, also known as INNO-206, is a doxorubicin prodrug (DOXO-EMCH, 6-maleimidocaproyl hydrazone derivative of doxorubicin). It utilizes a method of coupling in which DOXO-EMCH binds to albumin at the Cys position when given intravenously,³⁴and is released by the acid-sensitive hydrazone linker in the acidic environment found in most tumors.³⁵Preclinical studies demonstrated its superiority compared with doxorubicin in minimizing cardiotoxicity and mitochondrial injury.^36,37

In the phase I study of 41 patients (including 4 sarcomas), myelosuppression and mucositis were the dose-limiting adverse effects at 340 mg/m2, with no evidence of decreased heart function sonographically or clinically with a mean doxorubicin cumulative equivalent dose of approximately 1650 mg/m2.³⁸In the phase Ib/II study in 25 patients with soft tissue sarcomas, the maximum tolerated dose of aldoxorubicin was determined to be 350 mg/m2. There were no cases of cardiotoxicity, with cumulative doxorubicin-equivalent doses of 2000 mg/m2 achieved.³⁹

At the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO), Sant Chawla presented the results of the multinational randomized phase IIb study comparing first-line treatment with aldoxorubicin versus doxorubicin in patients with soft tissue sarcomas. One hundred and twentythree patients were randomized in a 2:1 fashion at 31 sites. Upon independent blinded review, both the median PFS (5.7 months vs 2.8 months) and PFS 46.8% vs 23.7%) were double at 6 months in favor of the experimental arm.⁴⁰

Aldoxorubicin is arguably the most exciting emerging cytotoxic treatment option for soft tissue sarcomas. A randomized phase III study is currently comparing aldoxorubicin with physician’s choice in patients with advanced soft tissue sarcomas (NCT02049905). Additionally, it is being studied in a phase I/II fashion in combination with ifosfamide (NCT02235701).

Eribulin

Eribulin mesylate is a synthetic halichondrin that acts via a novel tubulin-binding mechanism that results in inhibition of microtubulin polymerization, forming abnormal mitotic spindles that arrest the cell cycle at the metaphase/anaphase checkpoint.⁴¹It is presently FDA-approved for the treatment of metastatic breast cancer following the results of the open-label phase III EMBRACE trial in heavily pretreated patients who received prior therapy including anthracyclines and a taxane.⁴²

In EORTC 62052, eribulin, at 1.4 mg/m2 given on days 1 and 8 every 3 weeks, was studied in 4 strata of patients with soft tissue sarcomas with at least one but no more than 2 prior therapies: adipocytic sarcoma, leiomyosarcoma, synovial sarcoma, and other soft tissue sarcoma (excluding Ewing family of tumors, DFSP, GIST, and IMT). The primary endpoint of PFS at 12 weeks was met by the adipocytic sarcoma (46.9%) and leiomyosarcoma (31.6%) cohorts.⁴³

The open-label phase III study of eribulin and dacarbazine in patients with liposarcoma (dedifferentiated, myxoid, round cell) and leiomyosarcoma who have received 2 prior therapies, including an anthracycline, is expected to be completed in March 2015 (NCT01327885). The results of this trial are eagerly awaited.

TH-302

Tumor hypoxia is said to induce a more aggressive phenotype and to convey resistance to many cytotoxic therapies.⁴⁴Under hypoxic conditions, the prodrug TH-302 releases its active metabolite bromoisophosphoramide mustard (Br-IPM), a DNA crosslinking agent. It has demonstrated enhanced activity across 32 human cancer cell lines and in human xenograft models, affecting both the hypoxic tumor regions and adjacent normoxic cells (bystander effect).^45,46It has also been shown to enhance the cytotoxic effect when given in conjunction with chemotherapy.⁴⁷

TH-302 was evaluated in 2 phase I studies. In the phase I study of solid tumors, TH-302 was evaluated in 2 different dosing schedules. The maximum tolerated dose was determined to be 575 mg/m2 when given weekly for 3 weeks every 28 days and 670 mg/ m2 at 3-week dosing intervals. Dose-limiting toxicities were skin and mucosal.⁴⁸

TH-302 was also combined with doxorubicin in 16 patients with soft tissue sarcoma. TH-302 was given on day 1 (2 hours after doxorubicin 75 mg/m2) and day 8 every 3 weeks. The maximum tolerated dose was 300 mg/m2, limited by neutropenia associated infection and grade 4 thrombocytopenia. Partial responses were seen in 5 of 15 evaluable patients.⁴⁹The subsequent open label phase II study enrolled 91 patients. Maintenance therapy with TH-302 on days 1 and 8 every 3 weeks was continued for patients with stable or responding disease, following 6 cycles of the combination with doxorubicin. The primary endpoint was 6-month PFS, 58% with a median PFS of 6.5 months and median PFS following maintenance therapy was 3.7 months. The overall RR was 36% (2 complete responses and 30 partial responses). Among the different histologies, leiomyosarcoma had the longest median PFS of 6.9 months (5.8-7.8 months).⁵⁰

Emerging Targets in Soft Tissue Sarcomas

A randomized phase III study of doxorubicin with TH-302 versus doxorubicin (NCT01440088), which is being conducted by the Sarcoma Alliance for Research Collaboration (SARC), has completed accrual, and results are expected in 2015.Current understanding of molecular biology and advances in detection techniques has facilitated identification of multiple molecular aberrations in varied tumor types. In this section, we will highlight several of the new and emerging targets that may serve to increase the therapeutic armamentarium and facilitate a tailored approach to the STS subtypes.

Mammalian Target of Rapamycin

Mammalian target of rapamycin (mTOR) is a serine/ threonine kinase that affects cell cycle, cellular proliferation, and metabolism.⁵¹Sarcomas that have activated PI3K, Akt, and PTEN would be targets for mTOR inhibition.^52,53The rapamycin analogs temsirolimus and everolimus are used clinically in oncology.^54,55Although studied in sarcomas, ridaforolimus is not approved for treatment of sarcomas.⁵⁶Despite the promising rationale for mTOR inhibition, clinical studies failed to show clinical activity with ridaforolimus.

Temsirolimus was studied in patients with advanced soft tissue sarcomas, with the primary endpoint of confirmed tumor response (response lasting at least 4 weeks).⁵⁷This study had 40 evaluable patients of various sarcoma histologies; only 1 patient had a confirmed partial response. The median time to progression was 2 months, with median time to death of 7.6 months.

Ridaforolimus was studied in a larger phase II trial with 4 separate cohorts (bone sarcoma, leiomyosarcoma, liposarcoma, and other soft tissue sarcomas, excluding GIST). The primary endpoint was a clinical benefit response of PFS of at least 16 weeks among more than 25% of the study patients. All cohorts essentially met that endpoint.⁵⁸

That trial and its positive outcomes led to the SUCCEED (Sarcoma Multi-Center Clinical Evaluation of Efficacy of Ridaforolimus) study.⁵⁶SUCCEED assessed the efficacy of maintenance ridaforolimus versus placebo in patients with bone sarcomas and soft tissue sarcomas who were responding to or stable after chemotherapy; the primary endpoint was PFS. Despite demonstrating a modest improvement in PFS of 7.7 weeks, this was not considered clinically significant and the FDA did not approve this drug.

Is there a role for mTOR inhibitors in soft tissue sarcomas? Given that there are over 50 different histologies of soft tissue sarcomas and most of the studies were limited in testing a specific histology, there very well might be activity that was missed. One such histology is perivascular epithelioid cell tumor (PEComa), a rare histology of soft tissue sarcomas caused by mutations of theTSC1orTSC2genes that are involved with the mTOR pathways, in which activity with mTOR inhibitors has been shown.^59,60

Cyclin Dependent Kinase 4

Cyclin dependent kinase 4 (CDK4) is involved with phosphorylation of Rb and the cell cycle.⁶¹It is overexpressed in over 90% of well-differentiated (WD) and dedifferentiated (DD) liposarcomas.⁶²A phase II study of the oral CDK4 inhibitor PD0332991 showed limited response rates, but a PFR of 66% at 12 weeks.⁶³The study required progressive disease on systemic therapy and, retrospectively, the growth of tumors over 10 weeks was 25% (17% WD, 83% DD). The PFR of 66% with PD0332991 is promising and needs further study.

MDM2 Inhibitors

MDM2 is involved with the regulation of p53 and is highly expressed in well-differentiated (WD) and dedifferentiated (DD) liposarcomas.⁶⁴Treatment-naïve patients with resectable WD/DD liposarcomas (n = 11 and 9, respectively) were treated neoadjuvantly with RG7112, a nutlin small molecule inhibitor that blocks MDM2-p53 binding.⁶⁵This study showed that there was downregulation of the MDM2 pathway and upregulation of p53, but there was only one partial response. However, 14 of 20 patients had stable disease. Unfortunately, significant hematologic and gastrointestinal toxicities were reported. Alternative MDM2 inhibitors are currently being studied in this population.

Histone Deacetylase

Histones are proteins that are acetylated and deacetylated and are involved with regulation of gene expression.⁶⁶Histone deacetylase (HDAC) inhibitors, in addition to its other substrates such as p53, HSP90, and tubulins, are good agents to target cancers. Panobinostat, a pan-HDAC inhibitor, was studied in patients with soft tissue sarcomas who had progressed on prior chemotherapy per RECIST.⁶⁷The PFR at 3 months was only 20% with no responses. The histologies that had prolonged PFS were the nontranslocated sarcomas (WD liposarcoma, solitary fibrous tumor, and leiomyosarcoma).

Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) gene rearrangement on chromosome 2p23 is present in about 50% of patients with inflammatory myofibroblastic tumor (IMT).⁶⁸The use of the MET and ALK inhibitor crizotinib has been shown to have significant activity in ALK+ IMT.^69,70The EORTC is currently sponsoring the CREATE (Cross-tumoral phase II With Crizotinib) study evaluating the efficacy of tumors expressing activation of ALK and/or MET, including clear cell sarcoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, and IMT in addition to anaplastic large cell lymphoma and papillary renal cell carcinoma type 1 (NCT01524926).

Clinical Pearls

• Targeting angiogenesis is a useful approach to soft tissue sarcomas that may overcome the heterogeneity of the group.
• In the era of targeted therapy, there is still a role for cytotoxic agents.
• Failure to recognize the mechanism of action of the drug being tested in a clinical trial, as well as selection of inappropriate endpoints, may result in a negative clinical trial and halt development of a potentially active drug for sarcomas.

Colony Stimulating Factor-1

Immune-Based Therapies

Pigmented villonodular synovitis (PVNS), also called tenosynovial giant cell tumor, is a rare neoplastic disease arising from the synovium of joints, bursae, and tendon sheaths, driven by at(1;2)translocation that results in fusion of collagen typeVIa3(COL6A3) and M-CSF genes encoding for colony stimulating factor-1 (CSF-1). The use of imatinib and nilotinib in this setting has shown complete responses through their activity against the CSF-1 receptor.^71,72More recently, RG7155, a monoclonal antibody that potently inhibits the dimerization of CSF1 receptor, and PLX3397, a tyrosine kinase inhibitor of CSF- 1, have been assessed with PVNS/TGCT and have shown clinical activity based on metabolic activity (FDG-PET), MRI size reduction, and symptomatic improvement. Further studies are being planned to confirm this activity.^73,74The history of the immune system and sarcoma dates back to Coley when he described a response to small cell sarcoma after a skin infection.⁷⁵New approaches to sarcomas involving the use of immune checkpoint blockade (CTLA-4) and PD-1 blockade similar to that used in melanoma^76,77are being explored in sarcomas.^78,79Immunologic approach to sarcomas are being directed toward immunogenic self-proteins called cancer testis antigens (CT antigens) that are expressed in cancers and germs cells, but not in other adult tissues.^80,81There are over 70 CT gene families. The first described CT antigen in sarcoma was NY-ESO-1 in synovial sarcoma.⁸²Other CT antigens have been described, including LAGE-1, PRAME, MAGE-1, MAGE-A3, MAGE-A4, MAGE-A9, and SSX-2, and are expressed in other sarcomas, such as leiomyosarcoma, pleomorphic sarcoma, and myxoid round cell liposarcoma.

Conclusion

Several clinical trials are presently recruiting patients for treatment with autologous NY-ESO-1 specific CD8+ T cells, specifically targeting patients with sarcoma (NCT01343043, NCT02059850, NCT01477021) or solid tumors including sarcomas (NCT01522820, NCT01697527). Sarcomas have Tcell tumor infiltrations and the amount of T cells has been associated with shorter disease-specific survival, supporting the role of checkpoint inhibition in soft tissue sarcomas.⁸³PD-L1 expression is seen in a variety of soft tissue sarcomas and provides additional rationale for PD-L1 inhibition.⁸⁴The continued recognition of the importance of separating the soft tissue sarcomas into their histologic subtypes and the selection of those subtypes that will most likely benefit from a specific drug in phase III testing will aid in successful drug development. Improvements in molecular testing and advances in the understanding of tumor biology will similarly provide us with the ability to tailor treatment for this heterogenous group of tumors. Emphasis must be placed on validating biomarkers and targets, preferably demonstrating proof of concept prior to embarking on expensive and potentially flawed clinical trials. Clearly, there is still a role for cytotoxic therapy, however, and drugs such as aldoxorubicin and TH-302 demonstrate how novel approaches can maximize the efficacy of proven beneficial drugs.

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