Systemic Treatments for Soft-Tissue Sarcoma

Victoria Wytiaz, MD

Rashmi Chugh, MD

Dr. Chugh or an immediate family member has received research or institutional support from SpringWorks Therapeutics and serves as a board member, owner, officer, or committee member of SpringWorks Therapeutics and Deciphera Pharmaceuticals. Neither Dr. Wytiaz nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

This chapter is adapted from Chow WA, Uche AN: Systemic treatments for soft tissue sarcoma, in Biermann JS, Siegel GW, eds: Orthopaedic Knowledge Update^®: Musculoskeletal Tumors 4. American Academy of Orthopaedic Surgeons, 2021, pp 67-81.

ABSTRACT

Sarcoma represents a rare and heterogeneous group of solid tumors that accounts for less than 1% of all adult malignancies. Soft-tissue sarcomas comprise more than 70 different histologic subtypes. Systemic therapy remains the principal treatment for advanced and metastatic disease, although local therapies are still used frequently with both palliative and, at times, curative intent. In the past several decades, the expanding understanding of cancer biology has revealed distinct molecular alterations responsible for the pathogenesis of different subtypes of sarcoma and has allowed for the increased use of targeted therapies. Comprehensive systemic therapy options include cytotoxic chemotherapy as well as newer treatment strategies.

INTRODUCTION

Sarcomas are rare, malignant mesenchymal neoplasms that account for less than 1% of all human malignancies. They comprise approximately 15% of all pediatric malignancies and are the fifth most common malignancy in young adults age 20 to 39 years. Sarcomas are a heterogenous group of tumors that includes soft-tissue sarcomas (STSs), which comprise more than 70 histologic subtypes. Osseous sarcomas occur at an incidence of approximately 10% of STSs. The wide variety of subtypes leads to distinct clinical profiles and highlights the need for histology-driven treatment approaches. Herein, both cytotoxic chemotherapy and newer treatment agents for STSs are reviewed, with a particular focus on histologic indications for each outlined therapy.

CYTOTOXIC CHEMOTHERAPY

Cytotoxic chemotherapy remains an important form of systemic therapy for both osseous sarcoma and many STS subtypes. It is important to review common regimens relevant to certain histologies based on the chemotherapy backbone (Table 1).

Table 1 Targeted Therapies in Sarcoma

Agent	Target	Sarcoma Subtypes
Imatinib	BCR-ABL1, KIT, PDGFRα/β	GIST,^a desmoid, DFSP^a
Sunitinib	KIT, PDGFRα/β, VEGFR 1-3, FLT3, RET	GIST,^a ASPS, angiosarcoma, solitary fibrous tumor
Regorafenib	c-Kit, PDGFRα/β, VEGFR 2 and 3, B-raf, RET	GIST;^a advanced nonadipocytic STS
Ripretinib	KIT, PDGFRα	GIST^a
Avapritinib	KIT, PDGFRα (high potency for PDGFRα exon 18 mutations)	GIST with PDGFRα exon 18 mutations^a
Pazopanib	c-Kit, PDGFRα/β, VEGFR 1-3	Anthracycline-refractory or ineligible STS (other than liposarcoma)^a and desmoid
Sorafenib	KIT, PDGFRα/β, VEGFR 1-3, FLT3	Desmoid; GIST, solitary fibrous tumor
Trabectedin	Binds to minor groove of DNA to alter transcription factor binding, alkylating agent	Liposarcoma and leiomyosarcoma
Tazemetostat	EZH2	Epithelioid sarcoma^a
Palbociclib, abemaciclib	CDK4/CDK6	Liposarcoma
Pembrolizumab	PD-1	TMB-H;^a myxofibrosarcoma, cutaneous angiosarcoma, UPS, undifferentiated sarcomas; MSI-H^a or dMMR^a tumors; ASPS
Ipilimumab	CTLA-4	TMB-H;^a myxofibrosarcoma, cutaneous angiosarcoma, UPS, undifferentiated sarcomas
Nivolumab	PD-1	TMB-H;^a myxofibrosarcoma, cutaneous angiosarcoma, UPS, undifferentiated sarcomas
Selpercatinib	RET	RET-fusion positive STS^a
Larotrectinib	NTRK	NTRK-fusion positive STS^a
Entrectinib	NTRK	NTRK-fusion positive STS^a
Nirogacestat	Gamma secretase	Desmoid^a
Tegavivint	Transducinlike β protein 1	Desmoid (investigational)
Denosumab	RANKL	Giant cell tumor of bone^a
Pexidartinib	CSF1 receptor	Tenosynovial giant cell tumor^a
ASPS = alveolar soft part sarcoma, B-raf = B-rapidly accelerated fibrosarcoma kinase, CDK = cyclin-dependent kinase, CSF1 = colony-stimulating factor 1, CTLA4 = cytotoxic T-lymphocyte-associated antigen 4, DFSP = dermatofibrosarcoma protuberans, dMMR = deficient mismatch repair, EZH2 = enhancer of zeste homolog 2, GIST = gastrointestinal stromal tumor, MSI-H = microsatellite instability-high, NTRK = neurotropic tyrosine receptor kinase, PD-1 = programmed cell death protein 1, PDGFR = platelet-derived growth factor receptor, alpha polypeptide, RANKL = receptor activator of nuclear factor-κ B, RET = rearranged during transfection kinase, STS = soft-tissue sarcoma, TMB-H = tumor mutational burden-high, UPS = undifferentiated pleomorphic sarcoma, VEGFR = vascular endothelial growth factor receptor
^aFDA-approved for this indication.

Anthracycline-Based Therapies

Anthracycline-based chemotherapy regimens are indicated in a wide variety of STS subtypes, including leiomyosarcoma, synovial sarcoma, liposarcoma, undifferentiated STS, and malignant peripheral nerve sheath tumor. The primary mechanism of action for anthracyclines is the ability to complex with DNA and topoisomerase II and cause double-stranded DNA breaks. Anthracyclines also can intercalate with DNA and release free radicals, which leads to further DNA damage. Trials have shown consistently higher response rates for combination regimens compared with single-agent doxorubicin, specifically doxorubicin + dacarbazine and doxorubicin + ifosfamide/mesna.¹^,² Despite this finding, combination regimens do not definitively correlate with improved overall survival in the metastatic setting and are associated with greater toxicity.³ As such, it is reasonable to consider combination regimens in fit patients who can tolerate the potential toxicity and have a high symptom burden or rapidly progressive disease for which combinations would be advantageous with their associated higher response rate. Single-agent anthracycline or clinical trials should be considered for asymptomatic patients or in those for whom combination treatment may be excessively morbid.

Gemcitabine-Based Therapies

Gemcitabine-based combinations are also common STS regimens, often in the second line or for patients who are ineligible for anthracyclines. Gemcitabine is considered a deoxycytidine analog that is incorporated into DNA as a false base pair, resulting in DNA damage. Gemcitabine also inhibits ribonucleotide reductase, thus reducing overall DNA synthesis. Gemcitabine + docetaxel has shown the highest responses in leiomyosarcoma and undifferentiated STS but is used in a variety
of histologies.⁴ Gemcitabine may also be used in combination with vinorelbine or dacarbazine.⁵^,⁶ Single-agent gemcitabine can be considered for patients unable to tolerate a combination regimen and its associated toxicities although overall there is a reduced likelihood of benefit with single agents compared with combinations.⁷^,⁸

Trabectedin

Trabectedin is a novel alkylating agent that binds to the minor groove of DNA to disrupt cell proliferation and has shown objective responses in patients with advanced STS. Results from a 2021 randomized phase III trial comparing trabectedin with best supportive care in patients with pretreated STS (T-SAR) showed a progression-free survival (PFS) benefit with a partial response rate in 13.7% of patients across multiple histologies.⁹ Trabectedin also demonstrated superior disease control when compared with dacarbazine in patients with advanced liposarcoma and leiomyosarcoma in whom prior chemotherapy had failed.¹⁰ Of note, myxoid liposarcoma is particularly sensitive to trabectedin, and this high response rate has also translated to prolonged PFS.¹¹^,¹² Finally, trabectedin in combination with doxorubicin was shown to increase PFS in patients with metastatic or unresectable leiomyosarcoma compared with doxorubicin alone in LMS-04 (a leiomyosarcoma trial), a 2022 randomized, multicenter, open-label phase III trial.¹³ The addition of trabectedin did increase toxicity, specifically grade 3 to 4 neutropenia, anemia, thrombocytopenia, and febrile netutropenia.

Dacarbazine

Dacarbazine is an alkylating agent that has a variety of indications in STS, including in combination with doxorubicin for first-line therapy for advanced or metastatic disease as well as in neoadjuvant or adjuvant therapy for leiomyosarcoma or when ifosfamide is not considered appropriate.¹^,¹⁴ Dacarbazine is also used as a subsequent line of therapy in advanced or metastatic disease and, when combined with gemcitabine, has demonstrated improved PFS and overall survival when compared with dacarbazine as a single agent. Dacarbazine in combination with doxorubicin is also used in desmoid tumors and solitary fibrous tumors.¹⁵ The combination regimen of mesna, doxorubicin, ifosfamide, and dacarbazine was previously a common front-line regimen for STS; however, it has largely been replaced by dual combinations such as doxorubicin plus ifosfamide or doxorubicin plus dacarbazine, which allow for higher doses of each agent.¹⁶

Eribulin

Eribulin is a microtubule-inhibiting agent with a novel mechanism distinct from other agents such as taxanes. In a phase II study in STS, a promising signal was seen in both adipocytic sarcoma and leiomyosarcoma.¹⁷ A subsequent phase III study evaluated eribulin versus dacarbazine in patients with advanced leiomyosarcoma and liposarcoma, with a subgroup analysis demonstrating an overall survival benefit limited to liposarcoma.¹⁸ As such, eribulin was FDA approved for liposarcoma.

TYROSINE KINASE INHIBITORS

Imatinib

The development of targeted therapy for sarcomas begun with gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract. Approximately 95% of GISTs overexpress the type 3 receptor tyrosine kinase KIT (CD117), which is detectable using immunohistochemistry. Driver mutations of KIT and the related tyrosine kinase platelet-derived growth factor receptor alpha (PDGFRα) polypeptide gene, are present in approximately 85% and 5% to 7% of GISTs, respectively.¹⁹^,²⁰ Imatinib mesylate, a small molecule inhibitor of ABL, KIT and PDGFRα, was studied in two large, international phase III trials and revealed clinical responses, leading to the approval of imatinib in 2002 for advanced and metastatic GIST.²¹^,²²^,²³

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