Molecular targeted therapy for advanced or metastatic soft tissue sarcoma

Abstract

Soft tissue sarcomas are a form of rare and heterogeneous neoplasms with high recurrence rate and mortality. Over the past decades, less progress has been achieved. Surgical management with or without adjuvant/neoadjuvant radiotherapy is still the first-line treatment for localized soft tissue sarcomas, and chemotherapy is the additional option for those with high-risk. However, not all patients with advanced or metastatic soft tissue sarcomas benefit from conventional chemotherapy, targeted therapy takes the most relevant role in the management of those resistant to or failed to conventional chemotherapy. Heterogeneous soft tissue sarcomas vary from biological behavior, genetic mutations, and clinical presentation with a low incidence, indicating the future direction of histotype-based even molecule-based personalized therapy. Furthermore, increasing preclinical studies were carried out to investigate the pathogenesis and potential therapeutic targets of soft tissue sarcomas and increasing new drugs have been developed in recent years, which had started opening new doors for clinical treatment for patients with advanced/metastatic soft tissue sarcomas. Here we sought to summarize the concise characteristics and advance in the targeted therapy for the most common subtypes of soft tissue sarcomas.

Introduction

Soft tissue sarcomas (STS) are aggressive tumors that originate from mesenchyme, accounting for 1% of all adult cancers, with over 50 recognized histological subtypes according to the World Health Organization classification. ¹ Despite the low incidence of STS, some subtypes are insensitive to traditional chemotherapy and progress rapidly with a high recurrence rate after resection, which results in the poor prognosis and high mortality. ² Moreover, the prognosis of patients with STS has not improved markedly over the past few decades. According to the latest data reported by the American Cancer Society and the Surveillance, Epidemiology, and End Results Program from 2011 to 2017, there are approximately 5350 estimated deaths of STS in the United States for 2021, with a 5-year survival rate of 65.0% in recent years.^3,4 At present, surgery with optional perioperative chemotherapy is the standard treatment modality for localized STS.^5,6 For most subtypes of STS, palliative anthracycline-based chemotherapy alone or in combination with ifosfamide, is currently the first-line treatment for patients with advanced or metastatic STS. Owing to the rarity and the heterogeneity of STS, the lack of large scale data impedes the development of therapy in specific subtypes STS. In addition, STS are aggressive and commonly infiltrate deep tissue, with a high recurrence rate of 35%. 16% of all cases are found to develop metastasis at diagnosis, which is commonly involved in the lungs. However, the median overall survival (OS) of advanced or metastatic STS patients with conventional chemotherapy was just over a year. ⁷ Given the limitations of conventional chemotherapy in advanced STS, there is an urgent need to develop novel therapeutic agents to improve patient’s prognosis.

Targeted therapy may indicate a future direction for advanced STS. Preclinical researches on genomics and the molecular mechanisms of pathogenesis strongly support the therapeutic strategies for STS (Table 1). ⁸ Currently, drugs for targeted therapy have the advantage over conventional chemotherapy especially in patients with locally advanced or metastatic STS, with high efficiency, and confirmed safety (Table 2). ⁹ Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) were demonstrated to be playing essential roles in tumor angiogenesis and growth and highly expressed in a variety of cancers.^10,11 Tyrosine kinase inhibitors (TKIs) targeting VEGFR and PDGFR were demonstrated to be effective in STS. ¹² Mechanistic target of rapamycin (mTOR) and insulin-like growth factor type 1 receptor (IGF-1R) were all elucidated to be implicated in the signaling pathways which mediate cell proliferation and apoptosis, indicating the potential antitumor activity of the molecule inhibitors targeting these enzymes or signal transducers.^13,14 Such molecules include but not limit to c-Kit, MET, and cyclin-dependent kinases 4/6 (CDK4/6), and all have been studied as therapeutic targets.^15-17 Here, we summarize the recent preclinical studies and the advances of targeted therapy by major subtypes of STS according to the incidence.

Table 1.

Targeted therapies and genomic changes for STS.

Tumor	Genomic Alterations	Gene(s) related	Drugs
Liposarcoma
Well-differentiated/dedifferentiated	12q14-15 amplification	MDM2, CDK4, HMGA2, SAS, GLI	Palbociclib Abemaciclib Sunitinib Pazopanib Anlotinib Regorafenib
Myxoid/round cell	t(12;16)(q13;p11); t(12;22)(q13;q12)	FUS-DDIT3; EWSR1-DDIT3
Pleomorphic	13q14.2-5 loss	RB/TP53 loss
Synovial sarcoma	t(X;18)(p11;q11)	SS18-SSX1 SS18-SSX2 SS18-SSX4	Pazopanib Regorafenib Sorafenib Anlotinib Apatinib Palbociclib
Leiomyosarcoma	del(10q11-21.2) del(13q14.3-21.1)	RB/PTEN loss	Pazopanib Sunitinib Sorafenib Regorafenib Anlotinib Cixutumumab+temsirolimus Ridaforolimus
Undifferentiated pleomorphic sarcoma	—	—	Pembrolizumab
Rhabdomyosarcoma
Alveolar	t(2;13)(q35;q14) t(1;13)(p36;q14) t(X;2)(q13;q35)	PAX3-FOXO1 PAX7-FOXO1 PAX3-AFX	Cixutumumab+Temsirolimus Bevacizumab or temsirolimus +chemotherapy
Embryonal	Complex alterations	MYOD1 mutation
Angiosarcoma	Complex alterations	MYC KIT TP53	Bevacizumab Sunitinib Sorafenib Pazopanib Everolimus
Solitary fibrous tumor	inv(12)(q13;q13)	NAB2 - STAT6	Sunitinib Sorafenib Bevacizumab + temozolomide Pazopanib Dasatinib
Ewing sarcoma	t(11;22)(q24;q12) t(21;22)(q22;q12) t(2;22)(q33;q12) t(7;22)(p22;q12)	EWSR1-FLI1 EWSR1-ERG EWSR1-FEV EWSR1-ETV1	Apatinib Cixutumumab + temsirolimus Cabozantinib
Alveolar soft parts sarcoma	der(17)t(X;17)(p11;q25)	ASPL-TFE3	Anlotinib Sunitibib Axitinib + pembrolizumab
Clear cell sarcoma	t(12;22)(q13;q12) t(2;22)(q33;q12)	EWSR1-ATF1 EWSR1-CREB1	Crizotinib Pazopanib Vemurafenib
Inflammatory myofibroblastic tumor	t(1;2)(q22;p23) t(2;19)(p23;p13) t(2;17)(p23;q23) t(2;2)(p23;q13) t(2;11)(p23;p15) inv(2)(p23;q35)	TPM3-ALK TPM4-ALK CLTC-ALK RANBP2-ALK CARS-ALK ATIC-ALK	Crizotinib Ceritinib
Perivascular epithelioid cell tumor		Loss of heterozygosity of TSC2	Sirolimus Everolimus Temsirolimus
Dermatofibrosarcoma protuberans	t(17;22)(q21;q13)	COL1A1-PDGFB	Imatinib
Epithetlioid sarcoma	Inactivation, deletion, or mutation of INI1 (SMARCB-1)	SMARCB-1/INI1	Tazemetostat
Malignant peripheral nerve sheath tumors		NF1, CDKN2A and EED or SUZ12	—
Desmoid tumor		CTNNB1 or APC mutation	Imatinib Sorafenib
Tenosynovial giant cell tumor/pigmented villonodular synovitis	t(1;2)(p13;q35)	CSF1	Pexidartinib Imatinib Nilotinib

Table 2.

Clinical trials about targeted therapy on STS.

Tumor	Drugs	Targets	Phase	Year	Population	Response	Clinical outcomes	NCT number
Liposarcoma (LPS)
	Palbociclib	CDK4	II	2013	Advanced CDK4-amplified WDLPS/DDLPS	PR: 1/29	PFR12 66%; mPFS 17.9w	NCT01209598
	Abemaciclib	CDK4	II	2019	Adults with advanced DDLS	PR: 1/29	PFR12 76%; mPFS 30.4w	NCT02846987
	Sunitinib	PDGFR; VEGFR; c-Kit; FLT3	II	2011	Relapsed/refractory STS	SD:14/17	PFR12 75% for the untreated; 69.2% for the pretreated; mPFS 3.4m	NCT00400569
	Pazopanib	PDGFR; VEGFR	II	2017	Advanced intermediate-/high-grade LPS	PR: 1/41 SD: 17/41	PFR12 68.3%; mPFS 4.4m; mOS 12.6m	NCT01506596
	Anlotinib	VEGFR; FGFR; PDGFR; c-Kit; Ret; Aurora-B; c-FMS; DDR1	II	2018	Refractory metastatic STS	PR: 1/13 ORR: 13%	PFR12 63%; mPFS 5.6m; mOS 13m	NCT03016819
	Regorafenib	c-Kit; PDGFR; FGFR-1; RET; BRAF; VEGFR	II	2020	Advanced/Metastatic treatment-refractory LPS	No response	mPFS 1.87m; mOS 6.4m	NCT02048371
Synovial sarcoma (SS)
	Pazopanib	VEGFR; PDGFR; c-Kit	II	2009	Relapsed/refractory advanced STS	PR: 5/37	PFR12 49%; mPFS 161d; mOS 310d	EORTC study 62043
	Pazopanib	VEGFR; PDGFR; c-Kit	III	2012	Metastatic STS	—	mPFS 4.6m; mOS 12.5m	NCT00753688
	Regorafenib	c-Kit; PDGFR; FGFR-1; RET; BRAF; VEGFR, Raf	II	2016	Advanced STS	PR: 1/13	PFR12 77%; mPFS 5.6m; mOS 13.4m	NCT01900743
	Sorafenib	BRAF; VEGFR	II	2009	Metastatic/recurrent STS	PR: 6/12 PD: 6/12	PFR12 42%	NCT00245102
	Sorafenib+dacarbazine	BRAF; VEGFR	II	2018	Advanced STS with zero to two prior lines of chemotherapy	PR: 1/11	PFR12 51%; mPFS 13.4w; mOS 13.2m*	NCT00837148
	Apatinib	VEGFR; c-Kit; PDGFR-β	R	2018	Advanced sarcoma not amenable to curative treatment	Best response PR DR:3.8m	4m-PFR 46.3%; 6m-PFR 36.5%*	—
	Apatinib	VEGFR-2	II	2019	Stage IV sarcomas failed prior chemotherapy	PR: 9/59 a SD: 25/59 a ORR:15.25% a	PFR12 74%; mPFS 7.93m; mOS 17.27m a	NCT03121846
	Cixutumumab	IGF-1R	II	2013	Previously treated advanced/metastatic STS	SD: 6/17	PFR12 21.4%; mPFS 6.4w; mOS 56.3w	NCT00668148
Leiomyosarcoma (LMS)
	Pazopanib	VEGFR; PDGFR; c-Kit	II	2009	Relapsed/refractory advanced STS	PR: 1/41	PFR12 44%; mPFS 91d; mOS 354d	EORTC study 62043
	Sunitinib	PDGFR; VEGFR; c-Kit; FLT3	II	2011	Relapsed/refractory STS	SD:12/13	PFR12: 60% for the untreated, 62.5% for the pretreated; mPFS 3.7m	NCT00400569
	Sorafenib	BRAF; VEGFR	II	2013	Advanced STS patients pretreated with anthracycline-based chemotherapy	PR: 2/35 SD: 15/35 PD: 11/35	6-month PFR 35%; mPFS 4.9m; mOS 12.5m	—
	Regorafenib	c-Kit; PDGFR; FGFR-1; RET; BRAF; VEGFR, Raf	II	2016	Advanced STS	SD: 24/28	PFR12 57%; mPFS 3.7m; mOS 21m	NCT01900743
	Sorafenib+dacarbazine	BRAF; VEGFR	II	2018	Advanced STS with zero to two prior lines of chemotherapy	PR: 1/11	PFR12 51%; mPFS 13.4w; mOS 13.2m a	NCT00837148
	Anlotinib	VEGFR; FGFR; PDGFR; c-Kit; Ret; Aurora-B; c-FMS; DDR1	II	2018	Refractory metastatic STS	PR: 2/16	PFR12 75%; mPFS 11m; mOS 15m	NCT03016819
	Ridaforolimus	mTOR	II	2011	Advanced bone sarcoma and STS	CBR: 19/57	12-month PFR 20.2%; mPFS 16.1w	—
	Temsirolimus	mTOR	II	2011	Advanced STS with no prior chemotherapy for metastatic disease	PR: 1/9	PFR12 41%; mPFS 2m; mOS 7.6m a	—
	Cixutumumab+temsirolimus	IGF-1R; mTOR	II	2013	Metastatic/locally advanced of STS and bone sarcoma	—	mPFS 11.4w; mOS 14.6m a	NCT01016015
Undifferentiated pleomorphic sarcoma (UPS)
	Anlotinib	VEGFR; FGFR; PDGFR; c-Kit; Ret; Aurora-B; c-FMS; DDR1	II	2018	Refractory metastatic STS	PR: 1/19 ORR: 5.3%	PFR12 58%; mPFS 4.1m	NCT03016819
Rhabdomyosarcoma (RMS)
	Temsirolimus	mTOR	II	2013	Children with refractory/recurrent RMS	SD: 4/16 at 12w	PFR12 7%; mPFS 39d; mOS 7.6m	NCT00106353
	Cixutumumab	IGF-1R	II	2013	Previously treated advanced/metastatic STS	SD: 4/17	PFR12 12%; mPFS 6.1w; mOS 23.6w	NCT00668148
	Cixutumumab+temsirolimus	IGF-1R; mTOR	II	2013	Metastatic/locally advanced of STS and bone sarcoma	—	mOS 18.9m	NCT01016015
	Cixutumumab+temsirolimus	IGF-1R; mTOR	II	2015	Pediatric patients and young adults with recurrent/refractory sarcomas	—	PFR12 12% a	NCT01614795
	Bevacizumab/temsirolimus +chemotherapy	VEGFR; mTOR	II	2019	Patients with RMS in first relapse with unfavorable prognosis	ORR: 28% for bevacizumab; 47% for temsirolimus	6-month EFS rate: 54.6% for bevacizumab; 69.1% for temsirolimus	NCT01222715
Angiosarcoma (AS)
	Bevacizumab	VEGFR	II	2013	AS and epithelioid hemangioendotheliomas not surgically resectable	PR: 2/23 SD: 11/23	mPFS 11.4w; mOS 14.6m a	—
	Sorafenib	BRAF; VEGFR	II	2009	Metastatic/recurrent STS	PR: 5/37 PD: 6/12	PFR12 64%	NCT00245102
	Sorafenib	BRAF; VEGFR	II	2011	Advanced/metastatic AS patients	—	mPFS 1.8m; mOS 12m	NCT00874874
	Sorafenib	BRAF; VEGFR	II	2012	Recurrent/metastatic vascular sarcomas	PR: 1/8; SD: 5/8	mPFS 3m; mOS 17m a	—
	Everolimus	mTOR	II	2013	Metastatic/recurrent STS after failure of anthracycline and ifosfamide	PR: 1/3 SD: 1/3	PFR16 67% (2/3)	NCT01830153
Solitary fibrous tumors (SFT)
	Sorafenib	BRAF; VEGFR	II	2013	Metastatic/advanced progressive SFT	No response	mOS 19.7m	NCT00874874
	Temozolomide + bevacizumab	VEGFR	R	2011	Advanced, recurrent and metastatic hemangiopericytoma and malignant SFT	—	6-month PFR 92.9%; mPFS 10.8m; mOS 24.3m	—
	Pazopanib	VEGFR; PDGFR; c-Kit	P	2015	Advanced SFT	PR: 1/11 SD: 8/11	6-month PFR 44.9%; mPFS 4.7m; mOS 13.3m	—
	Cixutumumab+temsirolimus	IGF-1R; mTOR	II	2013	Metastatic/locally advanced of STS and bone sarcoma	PR: 1/8	mPFS 89.6w for IGF-1R+	NCT01016015
	Pazopanib	VEGFR; PDGFR; c-Kit	R	2018	Recurrent/metastatic SFT	DCR: 88.95%	mPFS 6.2m	-
	Dasatinib	Src; PDGFR; c-Kit; BCR-ABL	II	2017	Advanced sarcoma including SFT	Objective tumor response: 5/25	6-month PFR 30%; mPFS 2m	NCT00464620
Ewing sarcoma (EWS)
	Cixutumumab	IGF-1R	II	2013	Previously treated advanced/metastatic STS	SD: 5/18	PFR12 11%; mPFS 6.4w; mOS 24.1w	NCT00668148
	Cixutumumab+temsirolimus	IGF-1R; mTOR	II	2013	Metastatic/locally advanced of STS and bone sarcoma	PR: 4/27	mPFS 6w; mOS 16.2m	NCT01016015
	Cabozantinib	VEGFR-2	II	2020	Advanced EWS or osteosarcoma	PR: 10/39	mPFS 4.4m; mOS 10.2m a	NCT02243605
	Apatinib	VEGFR; c-Kit; PDGFRB	R	2018	Advanced sarcoma not amenable to curative treatment	Best response PR DR: 2m	4m-PFR 46.3%; 6m-PFR 36.5% a	—
Alveolar soft part sarcoma (ASPS)
	Cediranib	VEGFR; c-Kit	II	2014	Metastatic STS	PR: 4/6	—	NCT00385203
	Cediranib	VEGFR; c-Kit	II	2019	Metastatic STS	ORR: 45.5%	12m-PFR 38.7%; 12m-OS rate 90.3%	NCT01337401
	Crizotinib	MET; ALK; ROS1	II	2018	Locally advanced/metastatic ASPS	PR: 1/40	PFR12 85%; mPFS 8m for MET+	NCT01524926
	Axitinib+pembrolizumab	VEGFR; PD-L1	II	2019	Advanced/metastatic ASPS	PR: 6/11	PFR12 65.6%; mPFS 4.7m; mOS 18.7m	NCT02636725
	Anlotinib	VEGFR; FGFR; PDGFR; c-Kit; Ret; Aurora-B; c-FMS; DDR1	II	2018	Refractory metastatic STS	PR: 6/13	PFR12 77%; mPFS 21m	NCT03016819
Clear cell sarcoma (CCS)
	Vemurafenib	BRAF	Case	2015	Soft tissue of left lumbar with lung metastases	CR	—	—
	Crizotinib	MET; ALK; ROS1	II	2017	Advanced CCS with MET alterations	PR: 1/26 SD: 17/26	mPFS 131 days; mOS: 277 days; PFR12 53.8%	NCT01524926
Inflammatory myofibroblastic tumor (IMT)
	Crizotinib	MET; ALK; ROS1	II	2017	Pediatrics of unresectable IMT	PR: 5/14; SD: 7/14	—	NCT00939770
Perivascular epithelioid cell tumor (PEComa)
	Sirolimus	mTOR	II	2020	Advanced malignant PEComa	ORR: 39%; DCR: 71%	—	NCT02494570
Dermatofibrosarcoma protuberans (DFSP)
	Imatinib	PDGFRB	II	2012	Advanced/Metastatic DFSP	PR: 7/16; SD: 4/16	—	NCT00084630
	Imatinib	PDGFRB	II	2013	Advanced/Metastatic DFSP	PR: 4/8; SD: 2/8	—	NCT00085475
Malignant peripheral nerve sheath tumor (MPNST)
	Pexidartinib+ sirolimus	CSF-1R; c-Kit; FLT3; mTOR	II	—	Unresectable MPNST	Recruiting	Recruiting	NCT02584647
	Sirolimus+Ganetespib	Mtor; Hsp90	II	2020	Unresectable/refractory MPNST	No response	No response	NCT02008877
Epithelioid sarcoma (ES)
	Tazemetostat	EZH2	II	2020	Advanced ES with loss of INI1/SMARCB-1	Objective response: 9/62	mPFS: 5.5m; mOS: 19m	NCT04204941
Desmoid Tumor (DT)
	Imatinib	PDGFRB	II	2006	Advanced DT	PR: 3/19; SD: 4/19	—	—
	Imatinib	PDGFRB	II	2010	Progressive and recurrent aggressive DT	CR: 1/35; PR: 3/35	PFR12 91%; 2-year PFR 55%	—
	Sorafenib	BRAF; VEGFR	R	2012	DT patients	PR: 6/24; SD: 17/24	—	—
	Sorafenib	BRAF; VEGFR	III	2019	Progressive, symptomatic/recurrent DT	ORR: 33%	2-year PFR 81%	NCT02066181
Tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS)
	Imatinib	PDGFRB; CSF1	R	2011	Advanced and/or metastatic TGCT/PVNS	CR: 1/27; PR: 4/27	mPFS: 20.9m	—
	Nilotinib	CSF1; PDGFR; ABL	II	2018	Advanced TGCT/PVNS	PR: 3/51; SD: 46/51	PFR12: 92·6%	NCT01261429
	Pexidartinib	CSF-1R; c-Kit; FLT3	III	2020	Advanced TGCT	ORR: 53%	—	NCT02371369

SD, stable disease; PR, partial response; PD, progression disease; CBR, clinical benefit response; ORR, objective response rate; DR, duration of response; PFS, progression-free survival; PFR12, progression-free survival rate at 12 weeks; 6-month PFR, progression-free survival rate at 6 months, similarly 4-month, 12-month PFR; OS, overall survival; mPFS, median progression-free survival; mOS, median overall survival; R: retrospective study; P: prospective study.

^aMeans that the results were obtained from analysis of the whole cohort of multiple subtypes.

Liposarcoma

Liposarcoma (LPS) is the most common histotype of STS, accounting for 20% of all STS and including 5 subtypes. ¹⁸ Well differentiated LPS (WDLPS) together with dedifferentiated LPS (DDLPS) account for the majority of LPS. Generally, liposarcoma exhibits relatively low malignancy compared to other subtypes of sarcomas. Advanced or metastatic patients with liposarcoma can reach a median OS of 15.6 months with eribulin, and median progression-free survival (PFS) of 4.2 months with trabectetin.^19,20 However, WDLPS/DDLPS presents indolent nature to chemotherapy. Specifically, these two subtypes were confirmed to be involved in CDK4 protein overexpression, resulting in cell cycle aberrations.^15,21,22 Locally advanced or metastatic WDLPS/DDLPS patients with CDK4 amplification and RB expression have a 12-week PFS (PFR12) of 66% (median PFS = 17.9 weeks) with CDK4 inhibitor palbociclib. ²³ 57.2% PFS at 12 weeks (median PFS = 17.9 weeks) was observed in another clinical trial of palbociclib in patients with advanced WD/DDLPS. ²⁴ More favorable PFR12 of 76% and median PFS of 30 weeks were observed with CDK4 inhibitor abemaciclib treatment in advanced progressive DDLPS. ²⁵ Additionally, LPS responses to antiangiogenic therapy. Mahmood et al ²⁶ reported that 82% patients with relapsed or refractory LPS with VEGFR and PDGFR inhibitor sunitinib malate achieved stable disease (SD) at 6 weeks, with a median PFS of 3.4 months, and PFR12 of 75% in the unpretreated LPS patient. 68.3% patients with unresectable or metastatic LPS remained progression-free at 12 weeks of 74.1% for DDLPS and 66.7% for myxoid/round cell liposarcoma (MRCLPS), with pazopanib targeting VEGFR, PDGFR, and KDR. ²⁷ Anlotinib has been explored in patients with metastatic STS, and a PFR12 of 63% and a median PFS of 5.6 months were observed in LPS cohort. ⁹ However, similar multitargeted TKI regorafenib with targets including VEGFR-1, VEGFR-2, VEGFR3, c-Kit, and PDGFR, showed no improvement on PFS in treatment-refractory LPS. ²⁸

Though sensitive to chemotherapy and relatively low malignancy, it is also indispensable to investigate the potential targets of MRCLPSfor therapy. Recent study reported that JAK1/2 inhibitor combined with doxorubicin targeted both proliferating cells as well as cells with cancer stem cells features to circumvent chemotherapy resistance in treatment of myxoid cell liposarcoma. ²⁹ Several drugs targeting receptor tyrosine kinases are under exploring for treating LPS, including sitravatinib (NCT02978859), lenvatinib (NCT03526679), and itacitinib (NCT03670069). Furthermore, continued exploration is encouraged due to the revealed specific amplification of CDK4 in WDLPS/DDLPS.

Synovial sarcoma

Synovial sarcoma (SS), characterized by a t (X; 18) reciprocal chromosomal translocation, is a rare, aggressive malignancy with high recurrent and metastatic rate. ³⁰ About 50% patients with synovial sarcoma will develop metastasis, with a 5-year survival rate of 14.4%. ³¹ High-dose of ifosfamide has long been used to treat advanced synovial sarcoma for the relative sensitivity, with a best median PFS of 7.4 months. ⁷ However, more effective and less toxic agent is urgently needed. A phase 2 study of pazopanib treatment on patients with high- or intermediate-grade unresectable advanced STS reported a PFR12 of 49% and a median PFS of 161 days with treatment of pazopanib in SS cohort. ³² Later in a phase 3 study, pazopanib was observed to improve PFS notably in metastatic STS patients for most histologic types including SS. ³³ Some other TKIs also achieved promising effect on SS. Olivier et al reported a phase 2 study of regorafenib in advanced and inoperable STS patients with intolerance or failure to first-line chemotherapy. They showed a significant longer median PFS (5.6 months) and a median duration (3.4 months) of treatment with regorafenib compared with placebo (1.0 month and 1.4 months, respectively), but there was no difference in OS. ³⁴ The effect of BRAF and VEGFR inhibitor sorafenib on metastatic and/or locally advanced SS was reported to be limited. ³⁵ A subsequent prospective research showed a patient affected by advanced SS who failed more than two regimens of chemotherapy achieved partial response (PR) with 6 months of time to progression and an OS of 11 months with sorafenib. ³⁶ A phase 2 clinical trial reported that encouraging results were observed on patients with sorafenib plus dacarbazine. ³⁷ Comfortingly, Chi et al ⁹ reported that patients affected by refractory metastatic SS in treatment with anlotinib achieved the PFR12, median PFS, and OS of 75%, 7.7, and 12 months, respectively. A retrospective study of apatinib on patients with advanced sarcoma including SS conducted by Xie showed the 4-month and 6-month PFS rates were 46.3 and 36.5% for whole cohort, respectively, and 5.2 months for median duration of response (DR). ³⁸ Another phase 2 trial of apatinib for metastatic sarcoma reported a PFR12 of 74% for the whole cohort, patients of whom with SS account for 9.4%. ³⁹

Yet some efforts did not lead to satisfactory results. Cixutumumab, an IGF-1R inhibitor, was reported to have unsatisfactory effect on patients with unresectable or relapsed/metastatic SS in a phase 2 study. ⁴⁰ Therefore, researchers should put focus on preclinical studies to provide the basis for clinical trials. Continued SS18-SSX fusion genes induces the pathogenesis of SS. Preclinically, integrase interactor 1 (INI-1) deficiency was confirmed to allow Enhancer of Zeste Homologue 2 (EZH2) to become an oncogenic driver and specifically link to the presence of SS18-SSX1 fusion gene.^41,42 Thus, targeting SS18-SSX and related oncogenic pathways provides new direction for drug discovery,^43,44 and the clinical trials of EZH2 inhibitor tazemetostat in synovial sarcoma are already at the status of recruiting (NCT01897571; NCT02601950). Moreover, CDK4 inhibitor palbociclib was found to inhibit Rb-phosphorylation, inducing G1 arrest and proliferation block, which indicates palbociclib to be a potential agent for SS. ⁴⁵

Leiomyosarcoma

Leiomyosarcoma (LMS) arises from several locations, including the uterus, retroperitoneum, gastrointestinal tract, and vasculature, with an overall incidence ranging between 10% and 20% of all STS. ⁴⁶ In an aforementioned study, PFR12 was 44% with median PFS of 91 days in the LMS cohort treated with pazopanib, and PR occurred in one patient with LMS. ³² Subsequent research of sunitinib on relapsed or refractory STS was carried out, reporting a median PFS and median OS of 3.7 and 9.2 months in LMS patients, respectively. ²⁶ In another phase 2 study on patients with advanced STS after anthracycline-based regimens, the 6-month PFR was 35% with sorafenib in LMS group with the median PFS and OS of 4.9 and 12.5 months, respectively. ⁴⁷ Moreover, sorafenib and dacarbazine combination present certain efficacy on pretreated STSs including LMS. ³⁶ A significant longer median PFS of 3.7 months was achieved in LMS group with regorafenib in a placebo-controlled phase 2 trial. ³⁴ In a phase 2 study of anlotinib on patients with refractory metastatic STS conducted by Chi et al, the PFR12 and median PFS was 75% and 11 months for LMS cohort. ⁹

Leiomyosarcoma was characterized by the changes of losses in chromosomes 10q11 to 21.2 and 13q14.3 to q21.1, which leads to the deletion of tumor suppressor genes PTEN and the hyperactivation of phosphatidylinositol 3 kinase (PI3K)/AKT. ⁴⁶ Preclinically, mTOR activation was seen in mice with PTEN-deficiency in the smooth cell muscle lineage, showing a critical role of AKT-mTOR pathway in LMS genesis. ⁴⁸ Although mTOR inhibitor showed a significant effect on LMS preclinically, the clinical trials of single-agent temsirolimus or ridaforolimus on LMS was not inspiring.^49,50 Moreover, it is disappointing that the combination of an mTOR inhibitor with an IGF-1R inhibitor only showed effects mainly on bone sarcomas, with no significant activity in LMS. ⁵¹ Due to the complex and unbalanced karyotype of LMS, more efforts will be required to elucidate the underlying genetic mechanisms to guide targeted therapy.

Undifferentiated pleomorphic sarcoma

Undifferentiated pleomorphic sarcoma (UPS), previously classified as malignant fibrous histiocytoma (MFH), is a group of STS arising from fibroblasts. Although UPS accounts for one of the most common subtypes of STS, there are a few studies evaluating chemotherapy in patients with UPS. Anthracycline-based regimens are still the preferred regimens for UPS. However, the clinical outcomes of patients with advanced UPS were worst with the median OS of only 11 months. ⁵² Chi et al reported a PFR12 and median PFS of 58% and 4.1 months with anlotinib, respectively, in patients with refractory metastatic UPS. ⁹ In addition, pembrolizumab exhibited meaningful clinical activity in UPS, with an objective response rate (ORR) of 40%. ⁵³

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS), a malignant tumor of striated muscle origin, is the third most common extracranial solid tumor of childhood after Wilms tumor and neuroblastoma, accounting for approximately 4.5% of all childhood cancer.^54,55 There are three major subtypes of RMS, embryonal RMS (ERMS), alveolar RMS (ARMS), and pleomorphic RMS (PRMS). Adults are more likely to have PRMS which exhibits relative resistance to chemotherapy compared to ERMS and ARMS. Standard chemotherapy treatment is widely considered as the combination of vincristine, actinomycin D, and cyclophosphamide/ifosfamide. Localized RMS patients with integrated multidisciplinary treatment achieve a 5-year survival rate of 70%, whereas the prognosis of those with metastatic or recurrent RMS still remains poor. ⁵⁴ Receptor tyrosine kinases, including the IGF-1R, anaplastic lymphoma kinase (ALK), PDGFR α and β, VEGFR, epidermal growth factor receptor (EGFR), and the fibroblast growth factor receptor 4 (FGFR4) have been demonstrated to be potential targets for therapy in RMS. ⁵⁶ Increasing studies reported that only a small portion of patients with RMS benefit from single-agent targeted therapy. In a phase 2 study, mTOR inhibitor temsirolimus showed a poor efficacy in children with refractory or recurrent RMS. ⁵⁷ Unsatisfactory result was also observed in patients with advanced or metastatic RMS with anti-IGF-1R antibody cixutumumab, with a PFR12 of 12% and median PFS of 6.1 weeks. ⁴⁰ In contrast, Gary et al ⁵¹ reported that the combination of cixutumumab and temsirolimus had certain efficacy on patients with sarcoma, but clinical outcome of patients after treatment with this combination cannot be predicted by IGF-1R expression. However, another study reported that there was no improvement of activity but increased toxicity of this combination in pediatric patients and young adults with recurrent or refractory sarcoma including RMS. ⁵⁸ Subsequently, a study of bevacizumab or temsirolimus in combination with chemotherapy demonstrated that RMS patients with temsirolimus had a superior event-free survival (EFS) compared with bevacizumab. ⁵⁹ Till now, there are still not many suggested molecular targeted drugs for advanced or metastatic RMS. More efforts should be taken to reveal the pathogenesis and improve the outcome of advanced PRMS, and currently the targeted therapy for PRMS is hindered by two main factors, the rarity of PRMS with deficient clinical information and the undiscovered targets.

Angiosarcoma

Angiosarcoma (AS) is rare malignant endothelial-cell tumor of vascular or lymphatic origin, accounting for only 1% of all sarcomas. ⁶⁰ For antiangiogenic therapy, Koontz et al ⁶¹ reported two pathological-complete response (CR) cases with nasal angiosarcomas with treatment of bevacizumab plus preoperative radiotherapy. Subsequently, single-agent bevacizumab showed significant activity in advanced AS patients with 2 PR and 11 SD observed in 32 patients. ⁶² Moreover, two successfully treated cases report of retroperitoneum and breast AS patients with sunitinib treatment indicated potential efficacy for further investigation.^63,64 The activity against AS was also seen with antiangiogenic molecule sorafenib, with PR rate of 14% and median PFS of 3.2 months. ³⁵ However, sorafenib was reported to have limited antitumor activity in pretreated AS patients, and no response was seen in chemotherapy-naïve patients. ⁶⁵ Similar results of limited efficacy of sorafenib were seen in vascular sarcoma patients including AS and solitary fibrous tumor in another trial. ⁶⁶ Several retrospective studies analyzed the AS patients with pazopanib, and modest benefit was observed.^67-69 There is a multicenter phase 2 trial of mTOR inhibitor everolimus on patients with AS, reporting a highest PFR at 16 weeks of 67% (2/3) in previously anthracycline- and ifosfamide-containing chemotherapy treated AS patients. ⁷⁰

FLT4 gene co-amplification or KDR mutation was elucidated to be related to tumor genesis, and may play a critical role in therapeutic targeting.^71,72 Isabelle et al ⁶⁵ reported that limited efficacy of sorafenib in AS patients may be implicated in the absence of KDR gene mutations. A case with advanced AS achieved a PR for three months with VEGFR-2 inhibitor apatinib, which may be attributable to KDR gene amplification. ⁷³ All the demonstrations indicate the essential role of KDR in the targeted therapy for AS.

Solitary fibrous tumor

Solitary fibrous tumor (SFT), arising from submesothelial origin, is a rare mesenchymal malignancy that poorly responds to conventional chemotherapy. ⁷⁴ Although SFT is rare, it is classified into three clinical-pathologic types: typical SFT, malignant SFT, and dedifferentiated SFT. Solitary fibrous tumor was long recognized to the rich vascular characteristics. Case reports showed IFN-α and/or thalidomide had certain efficacy in advanced SFT.^75,76 For potential targets, immunohistochemistry examination showed that upregulation of endothelial growth factors and receptors was implicated in the genesis of SFT. ⁷⁷ Later, the efficacy of sunitinib on SFT was retrospectively confirmed, with 14 out of 29 patients achieved PR by Choi criteria. ⁷⁸ Valentin et al reported a PFS of 9 months was observed in 2 out of 5 patients with progressive malignant SFT in treatment with sorafenib. ⁷⁹ The efficacy of bevacizumab was retrospectively analyzed in advanced malignant SFT patients in combination with temozolomide, with an estimated PFS of 9.7 months and 6-month PFR of 78.6%. ⁸⁰ Alice et al ⁸¹ reported that advanced SFT patients with sunitinib or pazopanib as 2nd, 3rd, or 4th line achieved median PFS of 5.1 months and 5 SD in 10 patients. Pazopanib also showed some activity as first-line treatment in patients with advanced SFT in a single-institution. ⁸² A median PFS of 6.2 months achieved in 9 recurrent or metastatic SFT patients retrospectively in another study, demonstrating an effective treatment of pazopanib in both first- and second-line settings. ⁸³ However, limited results were observed with another TKI dasatinib, indicating dasatinib not suggested for standard treatment. ⁸⁴ Additionally, in an aforementioned study, 4 out of 8 patients with IGF-1R-positive SFT achieved a median PFS of 89.6 weeks and 16.1 weeks for those IGF-1R-negative, with the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus. ⁵¹ Since SFT can arise from anywhere in the body, and many studies did not have the specific subtypes as eligibility criteria, which may make the demonstration lack of precision.

Ewing sarcoma

Ewing sarcoma (EWS) is highly malignant small round cell mesenchymal sarcoma commonly with EWSR1-FLI1 fusion, accounting for less than 1% of all subtypes of STS. ⁸⁵ Through decades probing, well-standardized treatment protocols was formed based on multidisciplinary care incorporating, with a reported long-term survival rates of 70%.^86,87 However, nearly 30% patients develops distant metastases, with 5-year survival rates of approximately 20%–30%. ⁸⁸ Due to the high sensitivity to chemotherapy, several combinations of chemotherapy drugs exhibited promising responses in a variety of studies.^89-93 Of note, whether the benefit of the efficacy of these combinational agents overweighs toxicity is still under debate. Thus, new strategies for combining targeted therapy with chemotherapy is indispensable. The pathogenesis was demonstrated to be related to IGF-1, mTOR, and angiogenesis. ⁸⁵ Cixutumumab showed an unsatisfactory result in patients with EWS, but showed a significant beneficial efficacy in combination with temsirolimus, and the expression of IGF-1R may indicate the clinical benefit.^40,51,94 Apatinib was reported to have an objective response rate(ORR) of 70% in Ewing sarcoma, with median duration of response of 2 months. ³⁸ Moreover, antitumor effect of VEGFR-2 inhibitor cabozantinib has been confirmed in another study recently. ⁹⁵ Recently Guenther et al demonstrated that dual targeting IGF-1R and CDK4/6 in vitro and in vivo promoted a synergistic response, suggesting further clinical investigation is warranted. ⁹⁶

Although EWS oncogenesis driven by EWS-FLI1 has long been proven, it is still difficult to use EWS-FLI1 protein as a therapeutic target. Novel peptide targeting EWS-FLI1 interaction with RNA helicase A was demonstrated to reduce the transcriptional activity of EWS-FLI1 with disruption of cell cycle kinetics in vitro. ⁹⁷ Some other agents targeting Poly (ADP-ribose) polymerase 1, protein kinase C, RANKL, GD2, and CD99 also showed certain effects in EWS. In a word, new therapeutics are required to improve the clinical outcomes and prognosis of relapsed or metastatic EWS patients, mainly through developing new molecular targeted agents and new strategies with reduced toxicity.

Alveolar soft part sarcoma

Alveolar soft part sarcoma (ASPS) is a rare neoplasm representing < 1% of all STS, and usually presents early with metastases. Alveolar soft part sarcoma is highly angiogenic, typically insensitive to standard chemotherapy and radiotherapy, thus targeted therapy is urgent for the treatment of advanced/metastatic or unresectable ASPS. ⁹⁸ Shivaani et al ⁹⁹ reported metastatic ASPS patients with VEGFR-1, -2, and -3 inhibitor cediranib had a disease control rate (DCR) (PR+SD) of 84% at 24 weeks, and confirmed PR was observed in four of six patients with ASPS in another study. ¹⁰⁰ Additionally, a recent study demonstrated an effective result of cediranib in ASPS patients with a median PFS of 10.1 months. ¹⁰¹ Clinical efficacy of sunitinib in patients with advanced ASPS was confirmed with a median PFS of 17 months. ¹⁰² The activity of crizotinib, MET, ALK, and ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) inhibitor, was confirmed to have inspiring DCR and PFR in ASPS patients. ¹⁰³ VEGFR inhibitor axitinib plus pembrolizumab were demonstrated to have preliminary activity in advanced ASPS patients, with a PFR12 of 72.7%. ¹⁰⁴ Notably, ASPS patients benefit from anlotinib significantly with a median PFS of 21 months. ⁹ ASPSCR1-TFE3 in the MET signaling pathway has long been demonstrated to promote proliferation and angiogenesis in ASPS, with a confirmed activity of crizotinib reported in TFE3 rearranged ASPS MET+ patients.^103,105,106 All these findings indicate the angiogenesis molecules and MET kinase inhibitors to be the promising drugs for ASPS.

Clear cell sarcoma

Clear cell sarcoma (CCS), an extremely rare and aggressive form of sarcomas, approximately comprises 1% of all sarcomas. ¹⁰⁷ The hallmark of CCS is the genetic aberration of t (12; 22) (q13; q12) translocation, leading to the creation of EWSR1-ATF1 fusion gene. ¹⁰⁸ Chemotherapy is poorly effective for CCS, as a result, there is still no recognized treatment standards for advanced or metastatic CCS. ¹⁰⁹ Another characteristic of CCS is the morphological and immunohistochemical profile of melanocytic differentiation. However, Yang et al ¹¹⁰ found that none of the 16 CCS harbored BRAF mutations, with a significantly higher IGF-1R expression in CCS compared to melanoma. Afterward, Protsenko et al ¹¹¹ reported a metastatic relapse of BRAF-mutated CCS achieved CR in lung lesions with BRAF kinase inhibitor vemurafenib. No more studies of IGF-1R or BRAF inhibitors on CCS were carried out. Preclinically, the essential role of MET was confirmed for the viability and motility of CCS. ¹¹² And then a phase 2 trial was carried out and demonstrated a beneficial effect of crizotinib on locally advanced or metastatic MET-positive CCS, with a median PFS of 131 days which was similar to the results achieved with pazopanib in previously treated sarcoma patients. ¹¹³ These aforementioned targets are all worth to further investigate.

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm characterized by myofibroblastic and fibroblastic spindle cell proliferation with inflammatory infiltration. Inflammatory myofibroblastic tumor was considered as intermediate malignancies and rarely metastasizing by the World Health Organization, and half of all diagnosed cases were mutated with the presence of an ALK rearrangement. ¹¹⁴ Moreover, it is reported that ROS1 fusions were discovered in ALK‐negative IMTs. ¹¹⁵ Crizotinib, an potent ALK and ROS1 inhibitor, showed an active antitumor effect on ALK‐positive or ROS1‐positive IMT even in adolescents, with no response to the ALK‐negative IMT.^116,117 A literature review analyzed 30 crizotinib-treated patients with IMT and showed 12 out of 30 patients achieved CR or PR. ¹¹⁸ Although explorative data is promising, there is not many prospective studies about evaluating the efficacy of crizotinib on ALK-positive unresectable IMT. Of note, the clinical activity of crizotinib in pediatric IMT has been documented, with an ORR of 86%. ¹¹⁹

Perivascular epithelioid cell tumors

Perivascular epithelioid cell tumor (PEComa) represents a family of rare mesenchymal tumors composed of distinctive perivascular epithelioid cells with expression of myo-melanocytic markers. ¹²⁰ Only a small subset of PEComas behave as malignancies. The characteristic genetic alteration is the loss of heterozygosity of TSC2 gene or more rarely of TSC1 gene which negatively regulates the mTOR complex 1, leading to the activation of the mTOR pathway. In recent years, a variety of case reports showed the activity of mTOR inhibitors in PEComas.^121-123 A most recent retrospective study aimed to clarify the activity of chemotherapy, and molecular targeted agents in advanced or metastatic PEComas showed a durable benefit of mTOR inhibitors. ¹²⁴ Due to the promising efficacy of mTOR inhibitors observed in advanced PEComas, prospective studies are warranted. Recently, nab-sirolimus, nanoparticle albumin-bound mTOR inhibitor, was reported to be effective in advanced malignant PEComa with manageable toxicities, with an ORR and DCR of 39% and 71%, respectively, representing an important novel treatment option. ¹²⁵

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP), the most common dermal neoplasm, is a malignant fibroblastic tumor with a high rate of local recurrence and a low risk of metastasis. ¹²⁶ The first option for localized DFSP is wide surgical resection or Mohs micrographic surgery (MMS), and the recurrence rates by MMS have been reported at 0% to 8.3%. ¹²⁷ Conventional chemotherapy was ineffective in DFSP. ¹²⁸ Hence, better treatment option is needed for those metastatic DFSP. The PDGFRB inhibitor imatinib showed a significant antitumor activity in locally advanced or metastatic DFSP.^129,130 A pooled analysis of two phase II clinical trials demonstrated that 11 of 24 DFSP patients with imatinib (45.9%) achieved PR, with median time to progression of 1.7 years. ¹³¹ Moreover, it was reported that a patient without t (17; 22) translocation did not respond to imatinib. Imatinib was approved as first-line therapy for advanced or metastatic DFSP, although primary resistance and secondary resistance could occur. Thus, more efforts should be taken to explore the resistance mechanisms and develop new therapeutic strategies for imatinib-resistant DFSP.

Malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumor (MPNST) is a rare neoplasm arising associated in a peripheral nerve or preexisting plexiform neurofibromas, accounting for approximately 5%–10% of all sarcomas. ¹³² Half of all MPNSTs are developed in patients with neurofibromatosis type 1 (NF1), with mutations of Neurofibromin 1 gene and TP53. ¹³³ Kroep et al reported a response rate of 21%, with a median PFS and OS of 17 weeks and 48 weeks, respectively, in unresectable or metastatic MPNSTs with chemotherapy, which was similar with the outcomes of other histological subtype STSs. ¹³⁴ Based on the preclinical findings that mTOR activation can be induced by NF1 inactivation, several mTOR inhibitors for MPNST has entered clinical trials and is currently ongoing (NCT02584647). Moreover, the antitumor effect of erlotinib on MPNST has been proven in vivo and in vitro, but there is no clinical activity observed (NCT00068367).^135,136 Despite promising preclinical activity of sirolimus in combination with ganetespib on MPNST, no responses were observed. ¹³⁷ It is confusing that the clinical activity of mTOR inhibitors on MPNST did match the preclinical results, there is much more to discover potential targets.

Epithelioid sarcoma

Epithelioid sarcoma (ES) is a high-grade and highly aggressive STS of unknown histogenesis, displaying multidirectional differentiation that is predominantly epithelial. ¹³⁸ Epithelioid sarcoma is prospectively treated with systemic therapy, and it was reported that the median PFS and OS for ES patients were lower as compared with STSs, indicating a poorer prognosis of ES than other STSs although the response to treatment was equivalent. ¹³⁹ It was demonstrated that the interaction between inactivation of INI-1 and upregulation of EZH2 leads to ES tumorigenesis. ¹⁴⁰ Tazemetostat, an oral selective inhibitor of the histone methyltransferase enhancer of EZH2, achieved a median PFS and median OS of 5.5 months and 19 months, respectively, in advanced epithelioid sarcoma with loss of INI-1/SMARCB-1. ¹⁴¹ Now, tazemetostat was approved as the first-line treatment for ES and identified to potentially enhance immune checkpoint inhibition in combination preclinically.^142,143 Such combination is worthy of thorough exploring and investigation.

Desmoid tumor

Desmoid tumor (DT), also known as aggressive desmoid-type fibromatosis, is an invasive, non-metastasizing STS derived from mesenchymal progenitor cells. ¹⁴⁴ There are two major types of DT based on etiology, sporadic DT and familial adenomatous polyposis-associated DT. Although the prognosis is relatively good, the clinical behavior of DT is highly variable, which requires constant multidisciplinary management. Imatinib was the first TKI utilized for treating progressive DT and showed a favorable result with an ORR of 10%–15% and a DCR of up to 70% at 6 months, especially effective on patients with S45F mutation of CTNNB1.^145,146 Sorafenib has a better efficacy than imatinib, with a response rate of 25% reported by a retrospective study of 26 DT patients. ¹⁴⁷ More convinced results were observed in a double-blind phase 3 trial, reporting a 2-year PFR of 81% and ORR of 33%. ¹⁴⁸ Given that DT is specifically driven by Wnt/β-catenin pathways, the inhibitors tegavivint are believed to be the expected therapeutic strategies, and the phase 1 trial currently is active (NCT03459469). Moreover, Notch-signaling pathway was also elucidated to be an essential regulator of embryonic development, and several Gamma-secretase inhibitors (GSIs) targeting Notch showed inspiring results in patients with DT.^149,150

Tenosynovial giant cell tumor/pigmented villonodular synovitis

Tenosynovial giant cell tumor (TGCT), characterized by rearrangements of the macrophage colony-stimulating factor 1 (CSF1) gene, is a locally aggressive tumor arising from synovium of joints, bursae, or tendon sheaths. ¹⁵¹ Pigmented villonodular synovitis (PVNS), also known as diffuse type of this disease, is a synonym for the intra-articular form, and the extra-articular, localized variant is commonly called giant cell tumor of tendon sheath. Imatinib was reported to induce CRs in a relapsing PVNS/TGCT, providing a therapeutic option for advanced or unresectable PVNS/TGCT. ¹⁵² Another multicenter study of imatinib with 27 eligible advanced and/or metastatic TGCT/PVNS patients showed stable disease in 74% of patients, with one CR and 4 PRs. ¹⁵³ Moreover, imatinib also showed an activity on patients with nilotinib-resistant PVNS. ¹⁵⁴ In 2018, a phase 2, single-arm study with 51 advanced PVNS patients reported that 92.6% patients achieved stable disease with 12 week-treatment nilotinib. ¹⁵⁵ Pexidartinib is a novel TKI targeting CSF1 receptor, and recently showed an overall response rate of 53% with a robust tumor response in advanced TGCT. ¹⁵⁶ Although the mixed and cholestatic hepatotoxicity of pexidartinib was identified, it is manageable, and pexidartinib is the preferred regimens for TGCT/PVNS according to the latest NCCN guidelines for soft tissue sarcoma.

Future directions and conclusions

For the rarity and heterogeneities, the best treatment option for most subtypes of advanced sarcomas is still not clearly defined, and less attention was paid by researchers in this area. Thus, more efforts are required on the preclinical and clinical research for specific subtypes of STSs to investigate the appropriate treatment options. The inspiring results of targeted therapy in other solid tumors expand the studies utilizing this therapy for STS. Some TKIs for other disease indications were empirically tested in STS further in subtypes from basic research to clinical trials and achieved inspiring results, such as pazopanib and anlotinib which were used for treatment of renal cell carcinoma and non-small cell lung cancer, respectively. For this reason, the efficacy of some drugs for other indications were encouraged to be investigated in STS. An increasing body of researches reveal the pathogenesis and drug targets of STS, which strongly promote the investigation of drugs for targeted therapy. A great part of STS is involved in histotype-specific genetic or chromosome alterations, and their downstream molecules are mostly transcriptional factors which are difficult to be developed as therapeutic targets.

Furthermore, some molecule inhibitors in combination with chemotherapy or immunotherapy showed an enhanced efficacy in patients with STS compared to a single-agent therapy. In theory, targeted agents function on inducing rapid cancer cell death and the subsequent release of neoantigens, which in turn affects immune pathways and enhances the efficacy of checkpoint inhibitor treatment. ¹⁵⁷ As the primary agents for targeted therapy, antiangiogenic agents improve the responsiveness with normalization of the abnormal vasculature and the increase of infiltration of immune effector cells, and then transform the immunosuppressive tumor microenvironment into the immunosupportive. ¹⁵⁸ Moreover, pruning of vessels with antiangiogenic agents may worsen hypoxia, with the tumor progression via increased migration and inflammation, partially owing to the reduced delivery and efficacy of agents.^159,160 Thus, judicious dose of antiangiogenic agents can lead to the reduced vascular permeability, interstitial fluid pressure, and improved tumor perfusion, resulting in the enhanced antitumor immunity.^159-162 Recently, two combinations, nivolumab plus sunitinib and axitinib plus pembrolizumab, both showed an inspiring ORR in several subtype of advanced STS.^104,163 And now, combined targeted therapy with immunotherapy is the most promising treatment strategy. But most of all, the indications, standard protocol, time-window and appropriate dose of antiangiogenic agents for each type of STS still remain to be explored.

Aside from the combinational therapy, presurgical targeted therapy appears to be feasible. TKI was the most studied targeted agent for presurgical targeted therapy and applied in the treatment of renal cell carcinoma and breast cancer.^164-168 Favorable results were demonstrated by these case reports and retrospective studies, including tumor or thrombus shrinkage and lower recurrence rates, with deceased surgical difficulty. Of note, in the aforementioned studies, presurgical targeted therapy was mostly utilized in the treatment of patients with advanced cancer, which was believed to be beneficial for both primary tumorectomy and metastasectomy. As for breast cancer, a systematic review illuminated that patients with HER2-positive breast cancer and HER2-negative breast cancer had significant increased pathologic and clinical CR, overall response with neoadjuvant treatment of trastuzumab and bevacizumab, respectively. ¹⁶⁸ However, there is no obvious increase of breast conserving surgery rates was observed. Additionally, the risk for specific wound-related complications was reported to be increased but not severe complications. There are few studies about presurgical targeted therapy applied in sarcomas. Much remains to be explored, though, including but not limited to, about standardizing indications, protocols, the time-window for treatment.

In summary, targeted therapy in treatment of STS has achieved successes in a variety of subtypes. However, the clinical benefits are limited in some sarcomas with no specific therapeutic targets. Moreover, treatment resistance is still difficult to overcome, thus combinational therapy is a new approach to manage. The focal point should be on the investigation of critical molecules and driver oncogenes for the tumorigenesis to develop novel agents and guide therapy. Additionally, due to the difference of gene mutations between primary and metastatic lesions, more efforts should be made to clarify the mechanisms to guide therapy. Prospective and multicenter studies are required for the specific subtypes of STS for its important instruction significance. The targeted therapy currently cannot answer the expectations for the treatment of STS, there is much left to explore, both preclinically and clinically.

ORCID iDs

Xiaoyang Li https://orcid.org/0000-0001-8316-3013

Shengji Yu https://orcid.org/0000-0002-8994-0562