This document provides a summary of established and emerging targeted agents for the treatment of soft tissue sarcomas (STS). It discusses approved agents such as olaratumab and pazopanib which target PDGFRα and multiple receptor tyrosine kinases respectively. Emerging agents targeting EZH2, XPO1, ALK, ROS1, NTRK1-3, and MET are discussed including their mechanisms of action and current clinical trial statuses. The identification of gene fusions such as NTRK fusions is also summarized, highlighting the potential for next-generation sequencing to efficiently detect these drivers across cancer types.

1. ALK: anaplastic lymphoma kinase; EWSR1: Ewing sarcoma breakpoint region 1; EZH2: enhancer of zeste homolog 2; GIST: gastrointestinal stromal tumor; INI1: integrase interactor 1; NTRK1/2/3: neurotrophic receptor tyrosine kinase 1/2/3; MET: mesenchymal epidermal transition;
PD: progressive disease; PDGFRα: platelet-derived growth factor receptor α; pts: patients; STS: soft tissue sarcoma; TKI: tyrosine kinase inhibitor; XPO1: exportin 1.
1. Lartruvo (olaratumab). Prescribing Information. http:// http://pi.lilly.com/us/lartruvo-uspi.pdf. Accessed October 25, 2018. 2. Votrient (pazopanib). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022465s020lbl.pdf. Accessed October 25, 2018.
3. Gounder MM et al. American Society Clinical Oncology 2017Annual Meeting (ASCO 2017). Abstract 11058. 4. https://www.onclive.com/web-exclusives/fda-lifts-partial-clinical-hold-on-tazemetostat-trials. Accessed October 25, 2018. 5. Malone ER et al. ASCO 2018. Abstract 11562.
6. Gounder MM et al. ASCO 2018. Abstract 11512. 7. Schöffski P et L. Ann Oncol. 2017;28:3000-3008. 8. https://www.asco.org/research-progress/clinical-trials/clinical-trial-resources/clinical-trial-design-and-methodology. Accessed May 11, 2018. 9. http://www.clinicaltrials.gov.
Accessed May 11, 2018.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Summary of the STS Treatment Landscape
Focus on Established and Emerging Targeted Agents
PRACTICE AID
Access the activity,“The Promise of New Concepts and Innovative Therapy in Advanced Sarcoma: From Established Targets to TRK Inhibition and Beyond”at
www.peerview.com/RZF40.
DRUG STATUS
MECHANISM OF
ACTION
DOSE
Emerging Agents
Approved
First line, in combination with
doxorubicin for STS subtypes
where anthracycline is appropriate
Anti-PDGFRα
antibody
15 mg/kg IV over 60 min, day 1 and 8 of each 21-day cycle
until PD or unacceptable toxicity; for first 8 cycles, administer
with doxorubicin; premediate with diphenhydramine and
dexamethasone prior to administration on day 1 of cycle 1
Olaratumab1
Approved
Advanced STS (except liposarcoma or
GIST) after prior chemotherapy
TKI
800 mg orally once daily without food (≥1 h before or ≥2 h
after a meal); for baseline moderate hepatic impairment,
200 mg once daily (not recommended in patients with
severe hepatic impairment)
Pazopanib2
Phase 1: Pts 6 mo to 21 y with synovial
sarcoma or INI1-negative tumors
Phase 2: Adults with advanced disease
epithelioid sarcoma whose tumors harbor loss
of INI1 expression.
Phase 1: 7 dose levels, ranging from 240 to 1200 mg/m2
Phase 2: 800 mg orally twice daily
EZH2 inhibitorTazemetostat3,4
Selinexor5,6
Phase 1b: Combination with doxorubicin
in pts with STS
Phase 2: Pts with advanced unresectable
dedifferentiated liposarcoma
Phase 1: 60-80 mg weekly
Phase 2: 60 mg twice weekly
XPO1 inhibitor
Crizotinib7
Phase 2
Pts with clear cell sarcoma with MET+ disease
with documented rearrangement of EWSR1
ROS1 and
ALK inhibitor
250 mg twice daily
Entrectinib8
Phase 2
Pts with NTRK1/2/3, ROS1, or ALK gene
fusions across tumor types, including STS
TRK,
ROS1, and
ALK inhibitor
600 mg orally daily on a 28-day cycle
Larotrectinib9
Phase 2: Pts with NTRK1/2/3 gene fusion,
including STS
TRK
inhibitor 100 mg orally twice daily on a 28-day cycle

2. Tools for Capturing Gene Fusions in Cancer
and Implications for Sarcoma Management
PRACTICE AID
Although multiple diagnostic
tests (eg, IHC, FISH) may be
used to capture TRK fusions,
NGS may be the most efficient
method
q Particularly useful in
settings where pretest
probability is low
q Potential for multiplexed
testing
q Less depletion of tissue
What Are TRK Fusions and How do They Occur?
q TRK fusion proteins are constitutively active
oncogenic drivers across tumor types in pediatric
and adult patients1,2
q TRK gene fusions occur when an NTRK gene
(eg, NTRK1, NTRK2, NTRK3) is joined with
an unrelated gene
NTRK1 LMNA NTRK1–LMNA
Fusion
+ >
What Is the Incidence of TRK Fusions in Sarcoma?
Infantile fibrosarcoma3,4
Thyroid cancer2,5
High-grade gliomas (pediatric)6
Lung2,7
Colon cancer2
Sarcoma2
Glioblastoma8
Head and neck squamous
cell carcinoma2
91%-100%
2%-12%
10%
0.2%-3%
1%
1%
1%
0.5%
TRK fusions appear
across cancer
histologies
with different
frequencies
Next-Generation Sequencing for Identification of TRK Fusions
Current Gene List
Entire coding sequence (base substitutions, indels, copy number alterations)
Select
rearrangements
ABL1 ABL2 ACVR1B AKT1 AKT2 AKT3 ALK AMER1(FAM123B) APC ALK
AR ARAF ARFRP1 ARID14 ARID1B ARID2 ASXL1 ATM ATR BCL2
ATRX AURKA AURKB AXIN1 AXL BAP1 BARD1 BCL2 BCL2L1 BCR
BCL2L2 BCL6 BCOR BCORL1 BLM BRAF BRCA1 BRCA2 BRD4 BRAF
BRIP1 BTG1 BTK
C11orf30
(EMSY) CARD11 CBFB CBL CCND1 CCND2 BRAC1
CCND3 CCNE1 CD274 (PD-L1) CD79A CD79B CDC73 CDH1 CDK12 CDK4 BRCA2
CDK6 CDK8 CDKN1A CDKN1B CDKN2A CDKN2B CDKN2C CEBPA CHD2 BRD4
CHD4 CHEK1 CHEK2 CIC CREBBP CRKL CRLF2 CSF1R CTCF EGFR
CTNNA1 CTNNB1 CUL3 CYLD DAXX DDR2 DICER1 DNMT3A DOT1L ETV1
EGFR EP300 EPHA3 EPHA5 EPHA7 EPHB1 ERBB2 ERBB3 ERBB4 ETV4
ERG ERRFI1 ESR1 EZH2 FAM46C FANCA FANCC FANCD2 FANCE ETV5
FANCF FANCG FANCL FAS FAT1 FBXW7 FGF10 FGF14 FGF19 ETV6
FGF23 FGF3 FGR4 FGF6 FGFR1 FGFR2 FGFR3 FGFR4 FH FGFR1
FLCN FLT1 FLT3 FLT4 FOXL2 FOXP1 FRS2 FUBP1 GABRA6 FGFR2
GATA1 GATA2 GATA3 GATA4 GATA6 GID4 (C17orf39) GLI1 GNA11 GNA13 FGFR3
GNAQ GNAS GPR124 GRIN2A GRM3 GSK3B H3F3A HGF HNF1A KIT
HRAS HSD3B1 HSP90AA1 IDH1 IDH2 IGF1R IGF2 IKBKE IKZF1 MSH2
IL7R INHBA INPP4B IRF2 IRF4 IRS2 JAK1 JAK2 JAK3 MYB
JUN KAT6A (MYST3) KDM5A KDM5C KDM6A KDR KEAP1 KEL KIT MYC
KLHL6 KMT2A (MLL) KMT2C (MLL3) KMT2D (MLL2) KRAS LMO1 LRP1B LYN LZTR1 NOTCH2
MAGI2 MAP2K1 (MEK1) MAP2K2 (MEK2) MAP2K4 MAP3K1 MCL1 MDM2 MDM4 MED12 NTRK1
MEF2B MEN1 MET MITF MLH1 MPL MRE11A MSH2 MSH6 NTRK2
MTOR MUTYH MYC MYCL (MYCL1) MYCN MYD88 NF1 NF2 NFE2L2 PDGFRA
NFKBIA NKX2-1 NOTCH1 NOTCH2 NOTCH3 NPM1 NRAS NSD1 NTRK1 RAF1
NTRK2 NTRK3 NUP93 PAK3 PALB2 PARK2 PAX5 PBRM1
PDCD1LG2
(PD-L2) RARA
PDGFRA PDGFRB PDK1 PIK3C2B PIK3CA PIK3CB PIK3CG PIK3R1 PIK3R2 RET
PLCG2 PMS2 POLD1 POLE PPP2R1A PRDM1 PREX2 PRKAR1A PRKCI
TMPRSS2PRKDC PRSS8 PTCH1 PTEN PTPN11 QKI RAC1 RAD50 RAD51
RAF1 RANBP2 RARA RB1 RBM10 RET RICTOR RNF43 ROS1
RPTOR RUNX1 RUNX1T1 SDHA SDHB SDHC SDHD SETD2 SF3B1
SLIT2 SMAD2 SMAD3 SMAD4 SMARCA4 SMARCB1 SMO SNCAIP SOCS1
SOX10 SOX2 SOX9 SPEN SPOP SPTA1 SRC STAG2 STAT3
STAT4 STK11 SUFU SYK TAF1 TBX3 TERC
TERT (Promoter
only) TET2
TGFBR2 TNFAIP3 TNFRSF14 TOP1 TOP2A TP53 TSC1 TSC2 TSHR
U2AF1 VEGFA VHL WISP3 WT1 XPO1 ZBTB2 ZNF217 ZNF703
Example of Gene Panel via NGS
ROS1

3. CGP: comprehensive genomic profiling; DAPI: 4',6-diamidino-2-phenylindole; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; LMNA: lamin A/C; NTRK1: neurotrophic receptor tyrosine kinase 1;
RT-PCR: reverse transcription polymerase chain reaction; SHC1: SHC-transforming protein 1; STS: soft tissue sarcoma; TRK: tyrosine receptor kinase.
1. Amatu A et al. ESMO Open. 2016;1:e000023. 2. Stransky N et al. Nat Commun. 2014;5:4846. doi:10.1038/ncomms5846. 3. Bourgeois JM et al. Am J Surg Pathol. 2000;24:937-946. 4. Rubin BP et al. Am J Pathol. 1998;
153:1451-1458. 5. Brzeziańska E et al. Mutat Res. 2006;599:26-35. 6. Wu G et al. Nat Genet. 2014;46:444-450. 7. Vaishnavi A et al. Nat Med. 2013;19:1469-1472. 8. Kim J et al. PLoS One. 2014;19;9:e91940. doi:10.1371/journal.
pone.0091940. 9. Doebele RC et al. Cancer Discov. 2015;5:1049-1057.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice.
Tools for Capturing Gene Fusions in Cancer
and Implications for Sarcoma Management
PRACTICE AID
Access the activity,“The Promise of New Concepts and Innovative Therapy in Advanced Sarcoma: From Established
Targets to TRK Inhibition and Beyond”at www.peerview.com/RZF40.
LMNA–NTRK1 gene fusion was identified by CGP panel, joining the first two exons of LMNA (NM_170707) with exons 11 to 17 of NTRK1 (NM_002529)
Example of Multimodal Testing Demonstrating the Presence of LMNA–NTRK1 Gene Fusion in STS9
Genomic, Transcriptional, and Functional Evidence
A
B
D E
C
A
NTRK1 break-apart FISH demonstrating both paired green (5' NTRK1)
and red (3' NTRK1) signals corresponding to the normal NTRK1 gene
(yellow arrow); isolated red signals (red arrows) are observed in tumor
nuclei (stained blue with DAPI), indicative of a chromosomal deletion
leading to an NTRK1 gene fusion
B
Chromatograph of DNA sequencing of RT-PCR product using LMNA
(5') and NTRK1 (3') primers indicating the fusion breakpoint
between exon 2 of LMNA and exon 11 of NTRK1
C
TRK–SHC1 proximity ligation assay demonstrates robust signaling in
the tumor cells but weak signaling in the thick-walled blood vessel
D
Adjacent tumor tissue section stained with hematoxylin and eosin,
indicating a thick-walled blood vessel (within partial ellipse
indicated by dotted white line) and flanking tumor nuclei
E