Evolving Paradigms in Soft Tissue Sarcoma: Current and Emerging Targets

November 17, 2015
Evolving Paradigms, Soft Tissue Sarcoma, Volume 2, Issue 1

This section covers the Emerging Cytotoxic Agents, Current and Emerging Targets, and Emerging Therapies For Specific Histologies sections of the current Evolving Paradigms in Soft Tissue Sarcoma issue.

Emerging Cytotoxic Agents

Several emerging agents are being investigated in STS. Eribulin, like trabectedin, is derived from a marine compound.49Eribulin stops cell proliferation by inhibiting the movement of microtubules, and has also demonstrated improved efficacy in liposarcoma and leiomyosarcoma when compared with other forms of STS. In a phase II study, Schöffski et al evaluated 128 patients with either adipocytic sarcoma, leiomyosarcoma, synovial sarcoma, or other sarcomas treated with eribulin 1.4 mg/m2 on days 1 and 8 every 3 weeks. The adipocytic sarcoma and leiomyosarcoma groups met the primary endpoint, and the 12-week PFS was 46.9% and 31.6%, respectively. Common grade 3 to 4 AEs included neutropenia and leucopenia.49

Aldoxorubicin is a prodrug of doxorubicin.50When administered intravenously, aldoxorubicin binds to albumin, which accumulates at solid tumors due to their high metabolic rate. In the acidic environment of the tumor, aldoxorubicin becomes the active drug, doxorubicin. This mechanism of delivery reduces the risk for cardiotoxicity, which is associated with doxorubicin. In the phase IIb trial, Chawla et al randomly assigned 83 patients with unresectable STS to receive aldoxorubicin 350 mg/m2 every 3 weeks and 40 patients to receive doxorubicin 75 mg/m2 every 3 weeks.51 PFS was significantly longer with aldoxorubicin than doxorubicin (5.7 vs 2.8 months; P = .018). Common AEs included neutropenia, anemia, nausea, and mucositis. Aldoxorubicin was not associated with reduced left ventricular ejection fraction.

Evofosfamide, a DNA-alkylating agents also known as TH-302, is a prodrug that is activated in hypoxic environments. Because solid tumors have hypoxic regions, evofosfamide is more selective for tumor cells.52In a phase II study, 91 patients with advanced STS received evofosfamide 300 mg/m2 on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 of each 21-day cycle.53Chawla et al found that PFS was 6.5 months. OS was 21.5 months, and 34% of patients had partial response. The study authors concluded that outcomes compared favorably with historical outcomes. In an ongoing phase III study, evofosfamide is being compared with doxorubicin alone for STS (NCT01440088).54

Current and Emerging Targets

Targets of therapy with activity in soft tissue sarcoma are depicted inFIGURE 5.55

Tyrosine Kinase Receptors

STS express factors for angiogenesis, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).56Such factors are required for the development of sarcomas. Activation of proto-oncogenes also aid in the development of sarcomas. The inhibition of tyrosine kinase receptors disrupts cell signaling and has demonstrated clinical benefit in gastrointestinal stromal tumors (GIST) with imatinib and sunitinib and in STS with pazopanib. Although imatinib and sunitinib are effective in GIST, they have not demonstrated activity in STS as a whole.57-59Sorafenib, an inhibitor of VEGF, is also not effective for STS.56,60

Pazopanib, a second-line therapy, is an oral multitargeted tyrosine kinase receptor inhibitor and is approved to treat patients with non-adipocytic and non-gastrointestinal stromal tumor STS.61Specifically, pazopanib targets VEGF 1-3, fibroblast growth factor receptor 1 and 3, PDGF a and b, and KIT selectivity. In the phase III PALETTE trial, van der Graaf et al randomized 369 patients with advanced STS to receive pazopanib or placebo.62Pazopanib significantly improved PFS compared with placebo (4.6 vs 1.6 months, respectively; P <.0001). No differences in OS were found, and the majority of patients had stable disease. Only 6% of patients had partial response. In the same group of patients, Coens et al found that pazopanib did not improve or worsen health-related quality of life.63

Using data from the PALETTE trial and a phase II trial, Kasper et al determined that 22% of patients were long-term responders and survivors with pazopanib.64This was defined as PFS,3of 6 months and OS,3of 18 months. A total of 12 patients (3.5%) were treated with pazopanib for >2 years, and favorable prognostic factors included good performance status, low or intermediate tumor grading, and normal hemoglobin level at baseline.

Regorafenib is a multikinase inhibitor, and in a phase II study, Mir et al found that regorafenib may have antitumor activity in STS.65In 57 patients with leiomyosarcoma and 53 patients with other STS, regorafenib significantly improved PFS compared with placebo (4.0 vs 1.9 months, P = .017; 4.6 vs 1.0 months, P= .002, respectively). At 6 months, rates of OS were better with regorafenib than placebo among patients with leiomyosarcoma (87% vs 75.9%, respectively; P = .013).

Mammalian Target of Rapamycin

Mammalian target of rapamycin (mTOR), a kinase, participates in a pathway often deregulated in cancers.66Ridaforolimus, temsirolimus, and sirolimus inhibit mTOR, but benefits with therapy have been limited. In a phase II study, clinical benefit response rate with ridaforolimus was 28.8% among 212 patients with advanced STS or bone sarcomas. Median OS was 40 weeks and PFS was 15.3 weeks. AEs included stomatitis, mouth ulceration, rash, and fatigue. Researchers concluded that ridaforolimus has favorable survival benefits compared with historic metrics. In a phase III trial, ridaforolimus significantly improved PFS compared with placebo (17.7 vs 14.6 weeks), but OS with ridaforolimus was similar to placebo.67With temsirolimus, 39 out of 41 patients had disease progression and only 2 patients had a confirmed partial response.68Median time to progression was 2 months. Radiographic response to sirolimus was observed in 3 patients with perivascular epithelioid cell tumors.69

Similar to many tyrosine kinase receptor inhibitors, many monoclonal antibodies can target angiogenic factors. Bevacizumab, a recombinant human monoclonal antibody, binds VEGF. D’Adamo et al evaluated the activity of bevacizumab with doxorubicin in 17 patients with metastatic STS.70They found that response rate (12%) with combination therapy was not higher than response rates with doxorubicin alone, but they did find that more than half of patients had stable disease for ≥4 cycles.

Cixutumumab, a fully human monoclonal antibody, inhibits growth factor type 1 receptor and may be active in adipocytic sarcoma.71In a phase II study, patients with STS or Ewing family tumors received cixutumumab. At 12 weeks, rate of PFS was greatest with adipocytic sarcoma compared with other STS. Ontuxizumab targets endosialin, which aids in the growth of tumor blood vessels.72Endosialin is usually expressed only by tumor cells. In an ongoing phase II study, researchers are evaluating the combination of ontuxizumab with gemcitabine and docetaxel in patients with metastatic STS.

Emerging Therapies for Specific Histiologies


Lesions of leiomyosarcoma have smooth muscle features and mainly occur in the retroperitoneum.1Some may occur in the large blood vessels. Along with liposarcoma, leiomyosarcoma is on of the most common STS subtypes, and response of leiomyosarcoma to cytotoxic therapy varies, especially in regards to tumor location. Uterine leiomyosarcoma has demonstrated response to gemcitabine with or without docetaxel.73,74In the TAXOGEM study, Pautier et al assigned 90 patients to receive either gemcitabine alone or with docetaxel. ORRs were 19% with gemcitabine and 20% with combination therapy among patients with uterine leiomyosarcomas. For nonuterine leiomyosarcomas, ORRs were 14% and 5%, respectively. The 3-month PFS rate was 40% for uterine and nonuterine leiomyosarcomas.74Criticisms of the study suggest that comparisons cannot be made between the study groups because the study is not appropriately powered.75The combination of temozolomide, bevacizumab, and cabozantinib (an inhibitor of MET and VEGF) demonstrated synergistic effects among 20 patients with heavily pretreated uterine leiomyosarcoma.76


Liposarcomas are adipocytic tumors.1The most common liposarcoma is atypical lipomatous tumor/well (ALT/WD) differentiated liposarcoma. ALT/WD liposarcoma usually occurs in the deep tissue of the extremities, especially the thigh and is characterized by ring and giant rod chromosomes. Myxoid liposarcoma is the second most common liposarcoma and is composed of oval shaped cells. They usually occur in the extremities, and >90% of cases present with the translocation t(12;16)(q13;p11), which results in the fusion of FUSDDIT3.1

Although exact mechanisms are unclear, trabectedin promotes the differentiation of myxoid tumors by interacting with FUSDDIT3.77This interaction may explain the response myxoid tumors have with trabectedin. Among 51 patients with myxoid liposarcoma, overall response to trabectedin was 51%, PFS rate was 88% at 6 months, and PFS was 14 months.78Grosso et al found similar results, with a 50% response rate per RECIST and a 17-month PFS.79As noted, trabectedin has recently been approved by the FDA for the treatment of both liposarcoma and leiomyosarcoma on the basis of phase III trial results.46

Eribulin has been compared with dacarbazine in 452 patients with liposarcoma and leiomyosarcoma. Patients receiving eribulin had an OS of 13.5 months compared with dacarbazine (11.5 months), but the difference was not significant (P = .017). PFS was also not significantly different between the 2 groups.80

Alveolar Soft Part Sarcomas

Alveolar soft part sarcomas (ASPS) are composed of large epithelioid cells organized in nests that are separated by thin blood vessels.1They mainly occur in the extremities and account for <1% of all soft tissue sarcomas.1,81Although diagnosis can occur at any age, median age of diagnosis is 30, which is younger than the age of diagnosis for STS in general. ASPS is associated with low rates of local and distant recurrence, and when metastasized, usually spreads to the lungs. It is also associated with brain metasteses.81,82Reported 5-year OS rates range from 50% to 85%.81

Because ASPS is a rare condition, there are no standard guidelines for its management, and unlike other STS, ASPS does not respond to cytotoxic therapy.81,83,84Targeted therapies, especially antiangiogenic therapies, may be more appropriate for ASPS treatment. ASPS expresses the translocation der(17)t(x;17)(p11;q25), which fuses ASPL-TFE3.85This fusion increases the expression of proteins involved in angiogenesis, metastasis, and myogenic differentiation. Specifically, the fusion of ASPL-TFE3 increases the transcription and activation of MET, which promotes angiogenesis.

Sunitinib, the multitargeted tyrosine kinase inhibitor (TKI), has antiangiogenic activity. It targets VEGF2 and PDGFRB and has demonstrated activity in ASPS.86Stacchiotti et al found that 5 of 9 patients with ASPS had partial response to sunitinib 37.5 mg/day, and that median PFS with sunitinib was 17 months. They also concluded that sunitinib reduces MET activity by inhibiting RET. Cediranib targets VEGF1, VEGF2, and VEGF3 and has also demonstrated activity in ASPS.86 In a phase II study, Kummar et al evaluated cediranib 30 mg/day in 28-day cycles among 43 patients with metastatic, unresectable disease. At 24 weeks, ORR and disease control rate were 35% and 84%, respectively. In a recent phase I study, cediranib with bevacizumab, a monoclonal antibody that targets VEGF, demonstrated activity in ASPS, but dosing had to be limited for toxicity.87


Angiosarcoma is also a rare form of STS.1Often occurring in the deep muscles of the lower extremities, angiosarcoma is recognized as an aggressive tumor, and about half of patients with metastatic disease die within 1 year of diagnsosis.1,88Unlike ASPS, cytotoxic therapies are active in angiosarcoma.89In a retrospective study, Fury et al determined that PFS was 4, 3.7, 4.2, and 5.4 among 125 patients receiving paclitaxel, doxorubicin, liposomal doxorubicin, or doxorubicin with ifosfamide, respectively. PFS was shorter with gemcitabine or ifosfamide alone (2.2 and 1.6 months, respectively).90By contrast, Stacchiotti et al found that gemcitabine as a single agent was associated with a PFS of 7 months among 25 patients.91Gemcitabine was dosed at 1000 mg/m2 every week for 3 weeks for a total of 4 doses.

Paclitaxel has also demonstrated efficacy as a single agent for the treatment of angiosarcomas.92 In the phase II ANGIOTAX study, Penel et al evaluated paclitaxel dosed at 80 mg/m2 on days 1, 8, and 15 of a 4-week cycle in 30 patients with metastatic or unresectable angiosarcoma. Median time to progression was 4 months and median OS was 8 months. Among 117 patients with metastatic angiosarcoma, weekly paclitaxel also demonstrated similar efficacy to doxorubicin. Cutaneous angiosarcomas especially received benefit from paclitaxel.93

Sorafenib and bevacizumab are targeted therapies that have been evaluated for the treatment of angiosarcoma. Sorafenib, a TKI, targets BRAF and VEGF receptors. In a phase II study, Ray-Coquard et al found that sorafenib only had antitumor therapy in patients pretreated with conventional chemotherapy.94PFS with sorafenib was 1.8 months in superficial angiosarcoma and 3.8 months in visceral angiosarcoma, and OS was 12.0 months and 9.0 months, respectively. Bevacizumab maintained stable disease in 15 out of 32 patients and elicited a partial response in 4 patients in a small phase II study.95

Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans (DFSP) occurs in fibrous tissue and is rare, with an incidence rate of 4.2 to 4.5 cases per 1 million individuals per year.96In DFSP, the translocation between chromosomes 17 and 22 causes the overexpression of PGDFRB. Metastatic disease occurs in about 5% of cases, and it is unclear if mitotic rate and tumor change are prognostic factors. Local recurrence occurs at higher rates, from 10% to 60%.96

As with other STS, initial treatment for DFSP is surgical resection.96Imatinib is active in DFSP, and the FDA has approved its use in unresectable, recurrent, and metastatic disease. In a pooled analysis of two phase II trials, Rutkowski et al found that 46% of patients with unresectable DFSP had partial response with imatinib and a 1-year OS rate was 87.5%.97Imatinib may also be beneficial as a neoadjuvant therapy. In a phase II study, 25 patients with primary or recurrent DFSP received imatinib for up to 2 months before surgery.98Nine patients had clinical response and tumors decreased in size by 20%. Ugurel et al also found benefit with neoadjuvant imatinib therapy.99In this study, tumor size decreased by 31.5% and 7.1% of patients had complete response. Half of patients had partial response.

Inflammatory Myofibroblastic Tumors

Inflammatory myofibroblastic tumors (IMT) is usually a pediatric cancer with a median diagnosis age of 9 years.1Lesions are composed of myofibroblasts and inflammatory cells. They rarely metastasize (<5% of cases). ALK rearrangement is a common genetic aberration found with IMT. Rearrangements of ALK often result in its activation and increased expression. Crizotinib inhibits ALK and MET tyrosine kinases and has demonstrated antitumor activity in case reports and a phase I study.100,101In the phase I study, 3 of the 7 patients with IMT had partial responses. The other 4 patients had stable disease. At the time of study, 1 patient had received crizotinib for 2 years. Antiinflammatory therapies, such as corticosteroids and nonsteroidal antiinflammatory drugs, have also demonstrated antitumor activity in case reports.102-105

Solitary Fibrous Tumors

Solitary fibrous tumors (SFT) refers to a group of benign and malignant spindle-cell tumors.106They can be further described by their primary location — pleural, meningeal, and extrathoracic soft tissue — and do not respond well to chemotherapies, although one study supported the activity of dacarbazine.107-110Antiangiogenic therapies may have activity in SFT. With the combination of bevacizumab and temozolomide, 11 of 14 patients had partial response per Choi, and PFS was 9.7 months.109With sunitinib, a multitargeted TKI, PFS per RECIST was 6 months among 35 patients.111

Synovial Tumors

Synovial sarcoma varies in epithelial differentiation and despite the name, is not associated with the synovium, although it often occurs near the joints.1It is associated with the translocation t(x;18) (p11;q11), which can result in the fusion of SYT-SXX. Synovial sarcoma responds well to ifosfamide. In a 1993 study, better response was observed with ifosfamide plus doxorubicin when compared with other doxorubicin combinations.112When ifosfamide was evaluated as a single agent, 33% of patients receiving high-dose ifosfamide had partial response, and OS was 12 months.113Although ifosfamide may have activity as a single agent, Spurrell et al found that response rate with the combination of doxorubicin and ifosfamide was higher than either agent alone.114