The Next Generation of Treatments for Advanced Soft Tissue Sarcomas Jointly provided by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC This activity is supported by educational grants from EMD Serono and Lilly. Image: Rido/Copyright©2016 Shutterstock Images LLC. All Rights Reserved

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Faculty William Tap, MD Chief, Sarcoma Medical Oncology Service Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York William Tap, MD, has disclosed that he has received consulting fees from Daiichi Sankyo, Eli Lilly, EMD Serono, Novartis, and Plexxikon.

Agenda  Soft tissue sarcoma: characteristics and stratification  Best practices for using established and novel approved agents to treat advanced soft tissue sarcoma  Promising investigational agents for treating advanced soft tissue sarcoma  Targeting specific soft tissue sarcoma subtypes Slide credit: clinicaloptions.comclinicaloptions.com

Soft Tissue Sarcoma  Heterogeneous collection of rare, solid tumors –Mesenchymal origin, arise in soft tissues/bones  NCCN subdivides into 5 categories –Soft tissue sarcoma of extremity, superficial/trunk, head/neck –Retroperitoneal/intra-abdominal soft tissue sarcoma –Gastrointestinal stromal tumors –Desmoid tumors –Rhabdomyosarcoma Slide credit: clinicaloptions.comclinicaloptions.com NCCN. Clinical practice guidelines in oncology: soft tissue sarcoma. v

Soft Tissue Sarcoma: Survival  12,310 new cases, 4990 deaths projected in US for 2016 [1]  5-yr relative survival: localized disease, 81.4%; metastatic disease, 17.3% [2]  EORTC [3] : adults pts with locally advanced, unresectable, or metastatic high-grade STS (N = 455) randomized to DOX + IFO or DOX –Median OS: mos; 2-yr OS: 28% to 31%  Trial in which pts younger than 30 yrs of age with primary bone tumors (N = 518) randomized to standard CT with DOX/VINC/CYC/DACT or experimental CT with above regimen alternating with IFO/ETO [4] –Mean 5-yr EFS, nonmetastatic disease: 54% to 69% –Mean 5-yr EFS, metastatic disease: 22% Slide credit: clinicaloptions.comclinicaloptions.com 1. Siegel RL, et al. CA Cancer J Clin. 2016;66: SEER Statistics. Soft tissue Judson I, et al. Lancet Oncol. 2014;15: Grier HE, et al. N Engl J Med. 2003;348:

Sarcomas Stratified by Genetic Abnormalities Characteristic Sarcomas With Specific Genetic Alterations* Sarcomas With Nonspecific Genetic Alterations † Karyotypes  Translocations Often simple Reciprocal, simple Usually complex Nonspecific Average age at diagnosis, yrs2757 Prevalence of p53 pathway alterations  Prognostic impact of p53 pathway alterations Relatively low Strong High Weak to moderate Incidence in:  p53 mutant/KO mice  Bilateral retinoblastoma/Li-Fraumeni syndrome  Radiation-induced sarcomas Rare, if ever Rare Common Slide credit: clinicaloptions.comclinicaloptions.com Borden EC, et al. Clin Cancer Res. 2003;9: *ASPS, DFSP, Ewing sarcoma, GISTs, myxoid liposarcoma, rhabdomyosarcoma, synovial sarcoma. † Angiosarcoma, chondrosarcoma, adult fibrosarcoma, leiomyosarcoma, liposarcoma, myxofibrosarcoma, osteosarcoma.

What Guides Treatment Decisions for Pts With Advanced Disease?  Various-sized phase II and III trials with multiple soft tissue sarcoma subgroups –Chemotherapy sensitive vs resistant –Varied dosing schedules –Locally advanced vs unresectable/metastatic –Different endpoints: OS, ORR, CBR Slide credit: clinicaloptions.comclinicaloptions.com

Lack of Subtype Definition in Older Trials  1997 meta-analysis examined DOX-based adjuvant CT for pts with STS in 14 randomized, controlled trials (N = 1568) –Overall RFS improved with adjuvant CT (25% risk reduction; P =.0001) vs control; OS not significantly different for adjuvant CT vs control –Histology unclear in ~ 69% of pts Slide credit: clinicaloptions.comclinicaloptions.com HistologyPts, % Leiomyosarcoma12 Liposarcoma9 Malignant fibrous histiocytoma20 Synovial10 Other (no AIDS-related tumors)31 Not available18 SMAC. Lancet. 1997;350:

NCCN: Therapeutic Options for Selected Advanced Soft Tissue Sarcomas Slide credit: clinicaloptions.comclinicaloptions.com SubtypeCombinationSingle Agent Nonspecific Histology*  DOX-based (+ DACA or IFO + MES ± DACA)  GEM-based (+ DOC or VINO ‡ or DAC)  IFO + EPI + MES  DOX, IFO, EPI, GEM, DACA, liposomal DOX, TMZ, ‡ VINO, ‡ PAZO, ‡ ERIB, ‡ TRAB ‡ GIST  IMA, SUN, REG, SOR, † NIL, † DAS, † PAZO † Desmoid  TAM + SUL  MTX + VINB or VINO  DOX-based regimens  SUL (or other NSAIDs), IMA, SOR, liposomal DOX, TAM, TOR, low-dose IFN Non- Pleomorphic Rhabdo- myosarcoma  VINC + CYC-based (+ DACT or DOX ± IFO/ETO)  VINC + DACT or IRI ± TMZ  DOX + IFO ± VINC  CYC + TOP  ETO + IFO or CAR  VINO ‡ + low-dose CYC  DOX, IRI, TOP, VINO, ‡ high- dose MTX, TRAB ‡ All recommendations category 2A. *Anthracycline-based regimens preferred in neoadjuvant/adjuvant setting. † Agents for use after disease progression with IMA, SUN, or REG. ‡ Recommended only for palliative therapy. NCCN. Clinical practice guidelines in oncology: soft tissue sarcoma. v

Agents Assessed in Recent Clinical Trials in Pts With Advanced Non-GIST STS  Established agents –Doxorubicin + ifosfamide (EORTC 62012) –Gemcitabine + docetaxel (GeDDiS)  Novel therapeutics –Pazopanib (PALETTE) –Eribulin –Trabectedin –Olaratumab + doxorubicin –Aldoxorubicin –Evofosfamide + doxorubicin (SARC021) –Palifosfamide (PICASSO III) Slide credit: clinicaloptions.comclinicaloptions.com

Established and Novel Approved Agents

EORTC 62012: DOX ± IFO for Advanced/ Unresectable Soft Tissue Sarcoma  Randomized, controlled phase III trial in 38 international centers  Primary endpoint: OS  Secondary endpoints: PFS, best OR, toxicity Pts aged yrs with locally advanced, unresectable, or metastatic, high-grade STS; WHO PS 0-1 (N = 455) Treatment repeated Q3W (max of 6 cycles) until PD or unacceptable toxicity Doxorubicin 25 mg/m 2 QD Days Ifosfamide 2.5 g/m 2 QD Days 1-4 (n = 227) Doxorubicin 75 mg/m 2 IV bolus Day 1 or 72-hr CIVI (n = 228) Slide credit: clinicaloptions.comclinicaloptions.com Judson I, et al. Lancet Oncol. 2014;15: Stratified by center, WHO PS, age, liver metastases, histopathologic grade

EORTC 62012: Efficacy  DOX + IFO vs DOX: –Median follow-up: 59 vs 56 mos –1-year OS: 60% vs 51% –2-year OS: 31% vs 28% –ORR: 26% vs 14%; P =.0006  Pts in DOX + IFO group more likely to experience grade 3/4 AEs, reduce dose, interrupt/ discontinue treatment vs pts in DOX group  Pts in DOX arm more likely to receive postprotocol IFO Slide credit: clinicaloptions.comclinicaloptions.com Judson I, et al. Lancet Oncol. 2014;15: OS (%) PFS (%) Mos Median PFS, Mos DOX + IFO DOX HR: 0.74 (95% CI: ; P =.003) Median OS, Mos DOX + IFO DOX HR: 0.83 (95% CI: ; P =.076)

 Randomized, controlled phase III trial at 1 Swiss/24 UK sites  Primary endpoint: PFS at 24 wks post randomization  Secondary endpoints: PFS at 12 wks post randomization, median PFS, OS, ORR, AEs, QoL Pts aged 13 yrs or older with previously untreated locally advanced or metastatic STS; WHO PS ≤ 2; evidence of PD (N = 257) Treatment repeated Q3W (max of 6 cycles), then followed bimonthly until PD or death Gemcitabine 675 mg/m 2 IV Days 1,8 + Docetaxel 75 mg/m 2 IV Day 8 Q3W (n = 128) Doxorubicin 75 mg/m 2 IV Day 1 Q3W (n = 129) Slide credit: clinicaloptions.comclinicaloptions.com Seddon BM, et al. ASCO Abstract GeDDiS: GEM + DOC vs DOX for Advanced Soft Tissue Sarcoma Stratified by age, histologic subtype

Slide credit: clinicaloptions.comclinicaloptions.com Seddon BM, et al. ASCO Abstract GeDDiS: Efficacy GEM + DOC (n = 128) DOX (n = 129) HR (95% CI) P Value Median PFS, mos ( ) wk PFS, % Median OS, mos ( ) wk OS, %  Subgroup analysis, PFS HR (95% CI), GEM + DOC vs DOX Interaction P Value Leiomyosarcoma (n = 118)1.12 ( ).326 Nonleiomyosarcoma (n = 139)1.46 ( )

Slide credit: clinicaloptions.comclinicaloptions.com Seddon BM, et al. ASCO Abstract GeDDiS: Safety Grade 3 or 4 AE, % GEM + DOC (n = 126) DOX (n = 128) P Value Any Anemia Leukopenia Neutropenia Febrile neutropenia Diarrhea Fatigue Mucositis (oral) Pain Thromboembolic event  Withdrawals during treatment: GEM + DOC = 63%; DOX = 47% –For unacceptable tox: GEM + DOC, 13/80 (16%); DOX = 1/60 (2%)

Slide credit: clinicaloptions.comclinicaloptions.com Pazopanib  Multi–tyrosine kinase inhibitor with antiangiogenic properties –Targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFRα, PDGFRβ, FGFR-1, FGFR-3, Kit, Itk, Lck, c-Fms  FDA indications –Pts with advanced STS having previously received chemotherapy –Efficacy for adipocytic STS/GIST has not been demonstrated –Pts with advanced renal cell carcinoma Pazopanib [package insert] Kasper B, et al. Future Oncol. 2011;7:

 International, randomized, double-blind, placebo- controlled phase III trial Pts aged 18 yrs or older with angiogenesis inhibitor-naive, metastatic STS and PD despite ≤ 4 prior systemic therapies; WHO PS = 0-1 (N = 369) Treatment continued until PD, unacceptable toxicity, withdrawal of consent, or death; no crossover allowed Placebo PO QD (n = 123) Slide credit: clinicaloptions.comclinicaloptions.com van der Graaf WT, et al. Lancet. 2012;379: PALETTE: Pazopanib for Treating Metastatic Soft Tissue Sarcoma Stratified by number of previous lines of therapy, WHO PS  Primary endpoint: PFS  Secondary endpoints: OS, RR, safety, QoL Pazopanib 800 mg PO QD (n = 246)

PALETTE: Efficacy Slide credit: clinicaloptions.comclinicaloptions.com van der Graaf WTA, et al. Lancet. 2012;379: Toxicity Pazopanib (n = 239) Placebo (n = 123) Any-grade AE,* % Fatigue6549 Diarrhea5816 Nausea5428 Weight loss4820 Hypertension417 Anorexia4020 Hair hypopig382 Vomiting3311 Increased liver enzymes, % ALT103 AST82 Total bilirubin22 *Incidence > 30% in any group Mos OS (%) PFS (%) Median PFS, Mos (95% CI) PAZO PBO 4.6 ( ) 1.6 ( ) HR: 0.31 (95% CI: ; P <.0001) Median OS, Mos (95% CI) PAZO PBO 12.5 ( ) 10.7 ( ) HR: 0.86 (95% CI: ; P =.2514)

Slide credit: clinicaloptions.comclinicaloptions.com Eribulin Mesylate  Microtubule dynamics inhibitor that sequesters tubulin, disrupts mitotic spindles, and leads to apoptosis  FDA indications –Pts with unresectable or metastatic liposarcoma previously treated with anthracycline-based regimen –Pts with metastatic breast cancer previously treated with ≥ 2 chemotherapy regimens Eribulin [package insert]

Eribulin vs Dacarbazine for Advanced Leiomyosarcoma and Liposarcoma  Randomized, open-label, multicenter, active- controlled, phase III trial  Primary endpoint: OS  Secondary endpoints: PFS, PFS rate at Wk 12, safety Pts aged 18 yrs or older with locally recurrent/advanced or metastatic LMS or LPS and ≥ 2 prior systemic therapies; ECOG PS 0-2 (N = 452) Treatment continued until PD Eribulin 1.4 mg/m 2 IV Day 1, 8 Q3W (n = 228) Dacarbazine mg/m 2 IV Day 1 Q3W (n = 224) Slide credit: clinicaloptions.comclinicaloptions.com Schöffski P, et al. Lancet. 2016;[Epub ahead of print].

Eribulin vs Dacarbazine: Key Results Outcomes, Mos Eribulin (n = 228) Dacarbazine (n = 224) HR (95% CI) P Value Median OS ( ).0169 Median PFS ( ).2287 Slide credit: clinicaloptions.comclinicaloptions.com  Rate of grade ≥ 3 TEAEs higher with eribulin vs dacarbazine (67% vs 56%)  Subgroup analysis showed activity of eribulin in liposarcoma Median OS by Histologic Subgroup, Mos (Events/Pts) EribulinDacarbazineHR (95% CI) Liposarcoma15.6 (52/71)8.4 (63/72)0.51 ( ) Leiomyosarcoma12.7 (124/157)13 (118/152)0.93 ( ) Schöffski P, et al. Lancet. 2016;[Epub ahead of print].

Slide credit: clinicaloptions.comclinicaloptions.com Trabectedin  Alkylating agent that bends the DNA helix via minor groove guanine binding; affects DNA-binding proteins, perturbs cell cycle, induces cell death  FDA indications –Pts with unresectable/metastatic liposarcoma or leiomyosarcoma, previously treated with anthracycline- containing regimen Trabectedin [package insert]

 International, randomized, open-label, active- controlled, parallel-group phase III trial  Primary endpoint: OS  Secondary endpoints: PFS, TTP, ORR, DoR, safety Slide credit: clinicaloptions.comclinicaloptions.com Pts aged 15 yrs or older with unresectable locally advanced or metastatic liposarcoma or leiomyosarcoma despite prior anthracycline therapy; ECOG PS 0-1 (N = 518) Treatment repeated Q3W until PD or unacceptable toxicity Trabectedin* 1.5 mg/m 2 IV Day 1 (n = 345) Dacarbazine 1.0 g/m 2 IV Day 1 (n = 173) Trabectedin vs Dacarbazine for Advanced Liposarcoma or Leiomyosarcoma *Administered after premedication with dexamethasone 20 mg IV. Demetri GD, et al. J Clin Oncol. 2016;34:

Trabectedin vs Dacarbazine: Efficacy Endpoint Trabectedin (n = 345) Dacarbazine (n = 173) HR (95% CI)P Value Median OS, mos* Median PFS, mos ( ) <.001 TTP, mos ( ) <.001 ORR, n (%)34 (10)12 (7) 1.47 ( ).33 DoR, mos ( ).14 Slide credit: clinicaloptions.comclinicaloptions.com Demetri GD, et al. J Clin Oncol. 2016;34: *Interim analysis, 64% censored.

Trabectedin vs Dacarbazine: PFS by Histologic Subtype Histologic SubtypeTrabectedin, Median PFS, Mos (Events/Pts) Dacarbazine, Median PFS, Mos (Events/Pts) HR (95% CI) Leiomyosarcoma4.3 (154/252)1.6 (85/126)0.55 ( )  Nonuterine4.9 (70/118)1.6 (28/48)0.58 ( )  Uterine4.0 (84/134)1.5 (57/78)0.58 ( ) Liposarcoma3.0 (63/93)1.5 (27/47)0.55 ( )  Dedifferentiated2.2 (35/45)1.9 (16/25)0.68 ( )  Myxoid ± round cell5.6 (21/38)1.5 (8/19)0.41 ( )  Pleomorphic1.5 (7/10)1.4 (3/3)0.33 ( ) Slide credit: clinicaloptions.comclinicaloptions.com Demetri GD, et al. J Clin Oncol. 2016;34:

Trabectedin vs Dacarbazine: Safety Adverse Event, % Trabectedin (n = 340)Dacarbazine (n = 155) Grade 3Grade 4Grade 3Grade 4 Nausea5020 Fatigue6011 Neutropenia ALT increase25110 AST increase12100 Vomiting5010 Anemia Thrombocytopenia89108 Slide credit: clinicaloptions.comclinicaloptions.com Grade 3/4 adverse events occurring with ≥ 5% frequency. Demetri GD, et al. J Clin Oncol. 2016;34:

Investigational Agents

Slide credit: clinicaloptions.comclinicaloptions.com Olaratumab (IMC-3G3)  Investigational monoclonal antibody that binds to PDGFRα –Inhibits PDGF ligand binding and cellular signaling that may lead to cell proliferation, angiogenesis, and recruitment of stromal-derived fibroblasts  FDA breakthrough therapy designation for soft tissue sarcoma Shah GD, et al. Cancer. 2010;116:

Doxorubicin ± Olaratumab for Treating Metastatic/Unresectable STS  Open-label, multicenter, randomized phase Ib/II trial  Primary endpoint: PFS (target HR: 0.67)  Secondary endpoints: OS, ORR, PFS at 3 mos Slide credit: clinicaloptions.comclinicaloptions.com Tap WD, et al. ASCO Abstract Pts aged 18 yrs or older with unresectable or metastatic STS (N = 133) Olaratumab until PD Olaratumab 15 mg/kg IV Days 1,8 + Doxorubicin 75 mg/m 2 IV Day 1 x 8 cycles* (n = 66) Doxorubicin 75 mg/m 2 IV Day 1 x 8 cycles* (n = 67) Optional olaratumab after PD *Pts received dexrazoxane 750 mg/m 2 IV, at investigator’s discretion, on Day 1 of cycles 5-8 to prevent cardiotoxicity. Stratified by PDGFRα IHC, prior lines of therapy, ECOG PS, and histology

Doxorubicin ± Olaratumab: Efficacy  No statistical difference in ORR between groups –OLA + DOX: 18.2% (95% CI: 9.8% to 29.6%); DOX: 11.9% (95% CI: 5.3% to 22.2%) Slide credit: clinicaloptions.comclinicaloptions.com Tap WD, et al. ASCO Abstract Mos PFS Proportion OS Proportion Mos Median PFS, Mos (95% CI) OLA + DOX DOX 6.6 ( ) 4.1 ( ) HR: 0.67 (95% CI: ; P =.0615) Median OS, Mos (95% CI) OLA + DOX DOX 26.5 ( ) 14.7 ( ) HR: 0.46 (95% CI: ; P =.0003)

Doxorubicin ± Olaratumab: Safety Grade ≥ 3 AEs, % OLA + DOX (n = 64) DOX (n = 65) Treatment-related SAEs2225 Neutropenia Febrile neutropenia Anemia Fatigue Thrombocytopenia Infections Slide credit: clinicaloptions.comclinicaloptions.com Grade 3 AEs occurring with ≥ 5% frequency. Tap WD, et al. ASCO Abstract  AEs leading to discontinuation: OLA + DOX, 13%; DOX, 22%

Slide credit: clinicaloptions.comclinicaloptions.com Aldoxorubicin  Prodrug of doxorubicin  Binds to albumin in bloodstream via acid-sensitive linker  Albumin collects in tumor; acidic tumor environment induces cleavage of linker, freeing doxorubicin Chawla SP, et al. JAMA Oncol. 2015;1:

Slide credit: clinicaloptions.comclinicaloptions.com Aldoxorubicin vs Doxorubicin for Treating Advanced/Unresectable STS  International, open-label, prospective, randomized phase IIb trial  Primary endpoint: PFS  Secondary endpoints: PFS at 6 mos, OS, tumor response rate, safety Pts aged yrs with previously untreated locally advanced, unresectable, and/or metastatic STS; ECOG PS 0-2 (N = 126) Treatment repeated, max of 6 cycles Doxorubicin 75 mg/m 2 Q3W (n = 40) Aldoxorubicin 350 mg/m 2 IV Day 1 Q3W (n = 86)

Chawla SP, et al. JAMA Oncol. 2015;1: Slide credit: clinicaloptions.comclinicaloptions.com Aldoxorubicin vs Doxorubicin: Key Results  Aldoxorubicin vs doxorubicin –Median PFS: 8.3 vs 4.6 mos (P <.001) –Median OS: 15.8 vs 14.3 mos (P =.21) –ORR: 23% vs 5% Grade 3/4 TEAEs, %Aldoxorubicin (n = 83)Doxorubicin (n = 40) Any Neutropenia Febrile neutropenia Anemia Leukopenia Thrombocytopenia Stomatitis Grade 3/4 TEAEs occurring with ≥ 5% frequency.

Evofosfamide + Doxorubicin for Treating Advanced Soft Tissue Sarcoma  Evofosfamide: prodrug of alkylating agent bromo- isophosphoramide mustard; activated under hypoxic conditions  Single-arm, multicenter, open-label phase II trial –Evofosfamide + doxorubicin* for pts aged 18 yrs or older with first-line locally advanced unresectable or metastatic soft tissue sarcoma (N = 91) –6-mo PFS † : 58% (95% CI: 46-68); median PFS: 6.5 mos (95% CI: ) –Median OS: 21.5 mos (95% CI: ) –ORR: 36% Chawla SP, et al. J Clin Oncol. 2014;32: Slide credit: clinicaloptions.comclinicaloptions.com *Evofosfamide 300 mg/m 2 IV Days 1, 8 + doxorubicin 75 mg/m 2 d1 Q3W x 6 cycles. † Primary endpoint.

SARC021: Evofosfamide ± Doxorubicin for Treating Advanced STS  Randomized, open-label, multicenter phase III trial [1]  Primary endpoint: OS; secondary endpoints: safety, pharmacokinetics  Study did not meet primary endpoint (results not yet published) [2] 1. ClinicalTrials.gov. NCT Threshold Pharmaceuticals press release. December 7, Slide credit: clinicaloptions.comclinicaloptions.com Pts aged 15 yrs or older with locally advanced unresectable or metastatic STS; ECOG PS 0-1 (N = 450) Evaluate at end of cycles 2, 4, 6 until PD; eligible for evofosfamide monotherapy after cycle 6 DOX 75 mg/m 2 Day 1 Q3W EVO 300 mg/m 2 IV Days 1, 8 + DOX 75 mg/m 2 Day 1 + G-CSF Day 8 or 9 Q3W Evaluate at end of cycles 2, 4, 6 until PD

Doxorubicin ± Palifosfamide for Metastatic Soft Tissue Sarcoma  Palifosfamide: bifunctional DNA alkylator; active metabolite of ifosfamide  PICASSO III: international, multicenter, randomized, double-blind, placebo-controlled phase III trial –Pts aged 18 yrs or older with chemotherapy-naive metastatic STS (N = 447) randomized to palifosfamide + doxorubicin* or doxorubicin alone –Study did not meet primary endpoint (PFS) Ryan CW, et al. ESMO Abstract Slide credit: clinicaloptions.comclinicaloptions.com *Palifosfamide 150 mg/m 2 IV Days 1-3; doxorubicin 75 mg/m 2 Day 1 Q3W x 6 cycles. Outcome, MosPALI + DOX (n = 226) PBO + DOX (n = 221) HR (95% CI)P Value Median PFS ( ).1831 Median OS ( ).7423

Summary: Novel Therapeutics for Advanced Soft Tissue Sarcoma TherapeuticMechanism of ActionSarcoma Indications/ Clinical Trial Stage Pazopanib [1] Multi–tyrosine kinase inhibitorAdvanced STS*, previous CT Eribulin [2] Microtubule inhibitor Unresectable/metastatic liposarcoma, previous anthracycline-based treatment Trabectedin [3] DNA alkylator Unresectable/metastatic liposarcoma or leiomyosarcoma, previous anthracycline- based treatment Olaratumab [4] Monoclonal Ab to PDGFRα FDA breakthrough therapy designation; phase III trial ongoing (ANNOUNCE) Aldoxorubicin [5] Prodrug of doxorubicinPhase III trials ongoing Evofosfamide [6] Prodrug of alkylating agent Br-IPM; hypoxia activated Phase III SARC021 did not meet primary endpoint Palifosfamide [7] DNA alkylator Phase III PICASSO III did not meet primary endpoint Slide credit: clinicaloptions.comclinicaloptions.com *Efficacy for treating pts with adipocytic STS or GIST not demonstrated.

Targeting Specific Soft Tissue Sarcoma Subtypes

Subtype: Well-Differentiated/ Dedifferentiated Liposarcoma  Frequently have complex karyotypes, chromosome 12q13- q15 amplifications (including MDM2 and CDK4 amplification) [1]  Open-label phase II trial [2] –Adult pts* with CDK4-amplified well-differentiated or dedifferentiated liposarcoma treated with palbociclib † (N = 30) –Palbociclib: inhibitor of CDK4/CDK6 activity –12-wk PFS: 66% (90% CI: 51% to 100%) –Median PFS: 17.9 wks 1. Tap WD, et al. Genes Chromosomes Cancer. 2011;50: Dickson MA, et al. J Clin Oncol. 2013;31: *Pts aged 18 yrs or older who had experienced PD despite ≥ 1 systemic therapy. † 200 mg PO QD for 14 days Q3W; also known as PD Slide credit: clinicaloptions.comclinicaloptions.com

Subtype: Tenosynovial Giant Cell Tumor/ Pigmented Villonodular Synovitis  Locally aggressive synovial malignancies with elevated morbidity and common postresection recurrence  Diagnosis commonly occurs at yrs with ~ 600 annual cases in US  Clinical presentation: swelling, pain, hemathrosis, joint stiffness, decreased range of motion or functional impairment, bone erosions  Characterized by overexpression of CSF1, which can lead to recruitment/proliferation of CSF1R-expressing inflammatory cells Brahmi M, et al. Curr Treat Options Oncol. 2016;17:10. Lucas DR. Arch Pathol Lab Med. 2012;136: Ottaviani S, et al. Semin Arthritis Rheum. 2011;40: West RB, et al. PNAS. 2006;103: Slide credit: clinicaloptions.comclinicaloptions.com

Imatinib Mesylate for TGCT/PVNS  Multicenter, retrospective study of adult pts with locally advanced (93%) or metastatic (7%) TGCT/ PVNS who received imatinib mesylate, a CSF1R inhibitor (N = 29)  Median follow-up: 10.8 mos  Median PFS: 20.9 mos Cassier PA, et al. Cancer. 2012;118: Best Response, n (%)Imatinib Mesylate (n = 27) CR1 (4) PR4 (15) SD20 (74) PD2 (8) Slide credit: clinicaloptions.comclinicaloptions.com

Tap WD, et al. N Engl J Med. 2015;373: PLX3397 for Treating Progressive TGCT  Multicenter, 2-part phase I study of adult pts with progressive TGCT –Part 1: PLX3397 dose- escalation study (N = 41); part 2: extension study at chosen PLX3397 dose (N = 23) –PLX3397: potent, specific CSF1R inhibitor  Extension study results –83% of pts achieved a PR (n = 12, 52%) or SD (n = 7, 30%). Slide credit: clinicaloptions.comclinicaloptions.com Mos Extension Study Pts Continued in study Discontinued study RECIST PR Duration of Treatment

Summary  Soft tissue sarcoma consists of a diverse group of malignancies  Understand the biology underlying individual subtypes may allow more effective treatment strategies  The individual must be considered when treating advanced soft tissue sarcoma –Subtype is important and can dictate choice of treatment  Pts with advanced sarcoma are best served in consultation with tertiary care centers with sarcoma- specific expertise Slide credit: clinicaloptions.comclinicaloptions.com

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