The Next Generation of Treatments for Advanced Soft Tissue Sarcomas This activity is supported by educational grants from EMD Serono and Lilly.

About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

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. This slide lists the faculty who were involved in the production of these slides.

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.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 NCCN. Clinical practice guidelines in oncology: soft tissue sarcoma. v.2.2016. Slide credit: clinicaloptions.com 5

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 62012[3]: adults pts with locally advanced, unresectable, or metastatic high-grade STS (N = 455) randomized to DOX + IFO or DOX Median OS: 13-14 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% CT, chemotherapy; CYC, cyclophosphamide; DACT, dactinomycin; DOX, doxorubicin; EFS, event-free survival; ETO, etoposide; IFO, ifosfamide; STS, soft tissue sarcoma; VINC, vincristine. 1. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30. 2. SEER Statistics. Soft tissue. 2016 3. Judson I, et al. Lancet Oncol. 2014;15:415-423. 4. Grier HE, et al. N Engl J Med. 2003;348:694-701. Slide credit: clinicaloptions.com 6

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, yrs 27 57 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 ASPS, alveolar soft part sarcoma; DFSP, dermatofibrosarcoma protuberans; GIST, gastrointestinal stromal tumor; KO, knockout. *ASPS, DFSP, Ewing sarcoma, GISTs, myxoid liposarcoma, rhabdomyosarcoma, synovial sarcoma. †Angiosarcoma, chondrosarcoma, adult fibrosarcoma, leiomyosarcoma, liposarcoma, myxofibrosarcoma, osteosarcoma. Slide credit: clinicaloptions.com Borden EC, et al. Clin Cancer Res. 2003;9:1941-1956. 7

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 CBR, clinical benefit rate. Slide credit: clinicaloptions.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 Histology Pts, % Leiomyosarcoma 12 Liposarcoma 9 Malignant fibrous histiocytoma 20 Synovial 10 Other (no AIDS-related tumors) 31 Not available 18 CT, chemotherapy; DOX, doxorubicin; RFS, relapse-free survival; SMAC, Sarcoma Meta-Analysis Collaboration; STS, soft tissue sarcoma. Slide credit: clinicaloptions.com SMAC. Lancet. 1997;350:1647-1654.

NCCN: Therapeutic Options for Selected Advanced Soft Tissue Sarcomas Subtype Combination Single 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‡ CAR, carboplatin; CYC, cyclophosphamide; DACA, dacarbazine; DACT, dactinomycin; DOX, doxorubicin; ERIB, eribulin; EPI, epirubicin; ETO, etoposide; GEM, gemcitabine; IFN, interferon; IFO, ifosfamide; IMA, imatinib; IRI, irinotecan; MES, mesna; MTX, methotrexate; PAZO, pazopanib; REG, regorafenib; SOR, sorafenib; SUL, sulindac; SUN, sunitinib; TAM, tamoxifen; TMZ, temozolomide; TOP, topotecan; TOR, toremifene; TRAB, trabectedin; VINB, vinblastine; VINC, vincristine; VINO, vinorelbine. 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. Slide credit: clinicaloptions.com NCCN. Clinical practice guidelines in oncology: soft tissue sarcoma. v.2.2016.

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) GIST, gastrointestinal stromal tumors; STS, soft tissue sarcoma. Slide credit: clinicaloptions.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 Stratified by center, WHO PS, age, liver metastases, histopathologic grade Treatment repeated Q3W (max of 6 cycles) until PD or unacceptable toxicity Doxorubicin 25 mg/m2 QD Days 1-3 + Ifosfamide 2.5 g/m2 QD Days 1-4 (n = 227) Pts aged 18-60 yrs with locally advanced, unresectable, or metastatic, high-grade STS; WHO PS 0-1 (N = 455) Doxorubicin 75 mg/m2 IV bolus Day 1 or 72-hr CIVI (n = 228) CIVI, CIVI, continuous intravenous infusion; DOX, doxorubicin; IFO, ifosfamide; OR, overall response; PD, progressive disease; Q3W, every 3 weeks; QD, every day; STS, soft tissue sarcoma; WHO PS, World Health Organization performance status. Slide credit: clinicaloptions.com Judson I, et al. Lancet Oncol. 2014;15:415-423.

EORTC 62012: Efficacy DOX + IFO vs DOX: 100 Median OS, Mos DOX + IFO DOX 14.3 12.8 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 80 60 HR: 0.83 (95% CI: 0.67-1.03; P = .076) OS (%) 40 20 6 12 18 24 30 36 42 48 54 60 Mos 100 Median PFS, Mos 80 DOX + IFO DOX 7.4 4.6 60 AE, adverse event; DOX, doxorubicin; IFO, ifosfamide. PFS (%) HR: 0.74 (95% CI: 0.60-0.90; P = .003) 40 20 5 10 15 20 25 30 35 40 Mos Slide credit: clinicaloptions.com Judson I, et al. Lancet Oncol. 2014;15:415-423.

GeDDiS: GEM + DOC vs DOX for Advanced Soft Tissue Sarcoma 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 Stratified by age, histologic subtype Treatment repeated Q3W (max of 6 cycles), then followed bimonthly until PD or death Pts aged 13 yrs or older with previously untreated locally advanced or metastatic STS; WHO PS ≤ 2; evidence of PD (N = 257) Gemcitabine 675 mg/m2 IV Days 1,8 + Docetaxel 75 mg/m2 IV Day 8 Q3W (n = 128) Doxorubicin 75 mg/m2 IV Day 1 Q3W (n = 129) AE, adverse event; DOC, docetaxel; DOX, doxorubicin; GEM, gemcitabine; PD, progressive disease; PS, performance status; Q3W, every 3 weeks; QD, every day; QoL, quality of life; STS, soft tissue sarcoma; WHO PS, World Health Organization performance status. Slide credit: clinicaloptions.com Seddon BM, et al. ASCO 2015. Abstract 10500.

GeDDiS: Efficacy Subgroup analysis, PFS GEM + DOC (n = 128) DOX HR (95% CI) P Value Median PFS, mos 5.5 5.4 1.28 (0.98-1.67) .07 24-wk PFS, % 46.0 46.1 Median OS, mos 14.5 16.4 1.07 (0.77-1.49) .67 24-wk OS, % 82.5 86.7 Subgroup analysis, PFS DOC, docetaxel; DOX, doxorubicin; GEM, gemcitabine. HR (95% CI), GEM + DOC vs DOX Interaction P Value Leiomyosarcoma (n = 118) 1.12 (0.75-1.66) .326 Nonleiomyosarcoma (n = 139) 1.46 (1.02-2.09) Slide credit: clinicaloptions.com Seddon BM, et al. ASCO 2015. Abstract 10500.

GeDDiS: Safety Grade 3 or 4 AE, % GEM + DOC (n = 126) DOX (n = 128) P Value Any 71.4 64.8 .26 Anemia 6.3 7.8 .65 Leukopenia 7.1 .84 Neutropenia 19.0 24.2 .32 Febrile neutropenia 11.9 20.3 .07 Diarrhea 7.9 1.6 .02 Fatigue 13.5 .05 Mucositis (oral) 12.5 .001 Pain 10.3 .49 Thromboembolic event 3.2 5.5 .37 AE, adverse event; DOC, docetaxel; DOX, doxorubicin; GEM, gemcitabine; tox, toxicity. Withdrawals during treatment: GEM + DOC = 63%; DOX = 47% For unacceptable tox: GEM + DOC, 13/80 (16%); DOX = 1/60 (2%) Slide credit: clinicaloptions.com Seddon BM, et al. ASCO 2015. Abstract 10500.

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 GIST, gastrointestinal stromal tumors; STS, soft tissue sarcoma. Pazopanib [package insert]. 2015. Kasper B, et al. Future Oncol. 2011;7:1373-1383. Slide credit: clinicaloptions.com

PALETTE: Pazopanib for Treating Metastatic Soft Tissue Sarcoma International, randomized, double-blind, placebo- controlled phase III trial Primary endpoint: PFS Secondary endpoints: OS, RR, safety, QoL Stratified by number of previous lines of therapy, WHO PS Treatment continued until PD, unacceptable toxicity, withdrawal of consent, or death; no crossover allowed 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) Pazopanib 800 mg PO QD (n = 246) Placebo PO QD (n = 123) PD, progressive disease; QD, every day; QoL, quality of life; RR, response rate; STS, soft tissue sarcoma; WHO PS, World Health Organization performance status. Slide credit: clinicaloptions.com van der Graaf WT, et al. Lancet. 2012;379:1879-1886.

PALETTE: Efficacy Toxicity Pazopanib (n = 239) Placebo (n = 123) Any-grade AE,* % Fatigue 65 49 Diarrhea 58 16 Nausea 54 28 Weight loss 48 20 Hypertension 41 7 Anorexia 40 Hair hypopig 38 2 Vomiting 33 11 Increased liver enzymes, % ALT 10 3 AST 8 Total bilirubin 100 Median PFS, Mos (95% CI) 80 PAZO PBO 4.6 (3.7-4.8) 1.6 (0.9-1.8) 60 PFS (%) HR: 0.31 (95% CI: 0.24-0.40; P < .0001) 40 20 3 6 9 12 15 18 21 24 Mos 100 Median OS, Mos (95% CI) 80 PAZO PBO 12.5 (10.6-14.8) 10.7 (8.7-12.8) 60 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; hypopig, hypopigmentation; PAZO, pazopanib; PBO, placebo. OS (%) 40 HR: 0.86 (95% CI: 0.67-1.11; P = .2514) 20 3 6 9 12 15 18 21 24 Mos *Incidence > 30% in any group. Slide credit: clinicaloptions.com van der Graaf WTA, et al. Lancet. 2012;379:1879-1886.

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 Slide credit: clinicaloptions.com Eribulin [package insert]. 2016.

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) Eribulin 1.4 mg/m2 IV Day 1, 8 Q3W (n = 228) Treatment continued until PD Dacarbazine 850-1200 mg/m2 IV Day 1 Q3W (n = 224) ECOG, Eastern Cooperative Oncology Group; LMS, leiomyosarcoma; LPS, liposarcoma; PD, progressive disease; PS, performance status; Q3W, every 3 weeks. Slide credit: clinicaloptions.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 13.5 11.5 0.77 (0.62-0.95) .0169 Median PFS 2.6 0.88 (0.71-1.09) .2287 Subgroup analysis showed activity of eribulin in liposarcoma Median OS by Histologic Subgroup, Mos (Events/Pts) Eribulin Dacarbazine HR (95% CI) Liposarcoma 15.6 (52/71) 8.4 (63/72) 0.51 (0.35-0.75) Leiomyosarcoma 12.7 (124/157) 13 (118/152) 0.93 (0.71-1.20) TEAE, treatment-emergent adverse event. Rate of grade ≥ 3 TEAEs higher with eribulin vs dacarbazine (67% vs 56%) Slide credit: clinicaloptions.com Schöffski P, et al. Lancet. 2016;[Epub ahead of print].

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 Slide credit: clinicaloptions.com Trabectedin [package insert]. 2015.

Trabectedin vs Dacarbazine for Advanced Liposarcoma or Leiomyosarcoma International, randomized, open-label, active- controlled, parallel-group phase III trial Primary endpoint: OS Secondary endpoints: PFS, TTP, ORR, DoR, safety 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) Trabectedin* 1.5 mg/m2 IV Day 1 (n = 345) Treatment repeated Q3W until PD or unacceptable toxicity Dacarbazine 1.0 g/m2 IV Day 1 (n = 173) DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; PD, progressive disease; PS, performance status; Q3W, every 3 weeks; TTP, time to progression. *Administered after premedication with dexamethasone 20 mg IV. Slide credit: clinicaloptions.com Demetri GD, et al. J Clin Oncol. 2016;34:786-793.

Trabectedin vs Dacarbazine: Efficacy Endpoint Trabectedin (n = 345) Dacarbazine (n = 173) HR (95% CI) P Value Median OS, mos* 12.4 12.9 0.87 .37 Median PFS, mos 4.2 1.5 0.55 (0.44-0.70) < .001 TTP, mos 0.52 (0.41-0.66) ORR, n (%) 34 (10) 12 (7) 1.47 (0.72-3.2) .33 DoR, mos 6.5 0.47 (0.17-1.32) .14 DoR, duration of response; ORR, overall response rate; TTP, time to progression. *Interim analysis, 64% censored. Slide credit: clinicaloptions.com Demetri GD, et al. J Clin Oncol. 2016;34:786-793.

Trabectedin vs Dacarbazine: PFS by Histologic Subtype Median PFS, Mos (Events/Pts) Dacarbazine, Median PFS, Mos (Events/Pts) HR (95% CI) Leiomyosarcoma 4.3 (154/252) 1.6 (85/126) 0.55 (0.42-0.73) Nonuterine 4.9 (70/118) 1.6 (28/48) 0.58 (0.37-0.92) Uterine 4.0 (84/134) 1.5 (57/78) 0.58 (0.41-0.81) Liposarcoma 3.0 (63/93) 1.5 (27/47) 0.55 (0.34-0.87) Dedifferentiated 2.2 (35/45) 1.9 (16/25) 0.68 (0.37-1.25) Myxoid ± round cell 5.6 (21/38) 1.5 (8/19) 0.41 (0.17-0.98) Pleomorphic 1.5 (7/10) 1.4 (3/3) 0.33 (0.07-1.64) Slide credit: clinicaloptions.com Demetri GD, et al. J Clin Oncol. 2016;34:786-793.

Trabectedin vs Dacarbazine: Safety Adverse Event, % Trabectedin (n = 340) Dacarbazine (n = 155) Grade 3 Grade 4 Nausea 5 2 Fatigue 6 1 Neutropenia 21 16 11 10 ALT increase 25 AST increase 12 Vomiting Anemia 14 Thrombocytopenia 8 9 ALT, alanine aminotransferase; AST, aspartate aminotransferase. Grade 3/4 adverse events occurring with ≥ 5% frequency. Slide credit: clinicaloptions.com Demetri GD, et al. J Clin Oncol. 2016;34:786-793.

Investigational Agents

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 Slide credit: clinicaloptions.com Shah GD, et al. Cancer. 2010;116:1018-1026.

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 Stratified by PDGFRα IHC, prior lines of therapy, ECOG PS, and histology Olaratumab 15 mg/kg IV Days 1,8 + Doxorubicin 75 mg/m2 IV Day 1 x 8 cycles* (n = 66) Olaratumab until PD Pts aged 18 yrs or older with unresectable or metastatic STS (N = 133) Doxorubicin 75 mg/m2 IV Day 1 x 8 cycles* (n = 67) Optional olaratumab after PD ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate; PD, progressive disease; STS, soft tissue sarcoma. *Pts received dexrazoxane 750 mg/m2 IV, at investigator’s discretion, on Day 1 of cycles 5-8 to prevent cardiotoxicity. Slide credit: clinicaloptions.com Tap WD, et al. ASCO 2015. Abstract 10501.

Doxorubicin ± Olaratumab: Efficacy 5/11/2018 Doxorubicin ± Olaratumab: Efficacy Median PFS, Mos (95% CI) Median OS, Mos (95% CI) OLA + DOX DOX 6.6 (4.1-8.3) 4.1 (2.8-5.4) OLA + DOX DOX 26.5 (20.9-31.7) 14.7 (9.2-17.1) HR: 0.67 (95% CI: 0.44-1.02; P = .0615) 1.0 1.0 HR: 0.46 (95% CI: 0.30-0.71; P = .0003) 0.8 0.8 0.6 0.6 PFS Proportion OS Proportion 0.4 0.4 0.2 0.2 DOX, doxorubicin; OLA, olaratumab; ORR, overall response rate. 4 8 12 16 20 24 28 4 8 12 16 20 24 28 32 36 40 44 48 Mos Mos 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.com Tap WD, et al. ASCO 2015. Abstract 10501.

Doxorubicin ± Olaratumab: Safety Grade ≥ 3 AEs, % OLA + DOX (n = 64) DOX (n = 65) Treatment-related SAEs 22 25 Neutropenia 51.5 33.8 Febrile neutropenia 12.5 13.8 Anemia 7.7 Fatigue 9.4 3.1 Thrombocytopenia Infections 6.3 10.8 AE, adverse event; DOX, doxorubicin; OLA, olaratumab; SAE, serious adverse event. Grade 3 AEs occurring with ≥ 5% frequency. AEs leading to discontinuation: OLA + DOX, 13%; DOX, 22% Slide credit: clinicaloptions.com Tap WD, et al. ASCO 2015. Abstract 10501.

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 Slide credit: clinicaloptions.com Chawla SP, et al. JAMA Oncol. 2015;1:1272-1280.

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 Aldoxorubicin 350 mg/m2 IV Day 1 Q3W (n = 86) Pts aged 15-80 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/m2 Q3W (n = 40) ECOG, Eastern Cooperative Oncology Group; PS, performance status; Q3W, every 3 weeks; STS, soft tissue sarcoma. Slide credit: clinicaloptions.com Chawla SP, et al. JAMA Oncol. 2015;1:1272-1280.

Aldoxorubicin vs Doxorubicin: Key Results 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 79.5 57.5 Neutropenia 28.9 12.5 Febrile neutropenia 14.5 17.5 Anemia 16.9 20.0 Leukopenia 9.6 5.0 Thrombocytopenia 8.4 Stomatitis 6.0 2.5 ORR, overall response rate; TEAE, treatment-emergent adverse event. Grade 3/4 TEAEs occurring with ≥ 5% frequency. Slide credit: clinicaloptions.com Chawla SP, et al. JAMA Oncol. 2015;1:1272-1280.

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: 5.8-7.7) Median OS: 21.5 mos (95% CI: 16.0-26.2) ORR: 36% ORR, overall response rate. *Evofosfamide 300 mg/m2 IV Days 1, 8 + doxorubicin 75 mg/m2 d1 Q3W x 6 cycles. †Primary endpoint. Slide credit: clinicaloptions.com Chawla SP, et al. J Clin Oncol. 2014;32:3299-3306.

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] Evaluate at end of cycles 2, 4, 6 until PD; eligible for evofosfamide monotherapy after cycle 6 Pts aged 15 yrs or older with locally advanced unresectable or metastatic STS; ECOG PS 0-1 (N = 450) EVO 300 mg/m2 IV Days 1, 8 + DOX 75 mg/m2 Day 1 + G-CSF Day 8 or 9 Q3W DOX 75 mg/m2 Day 1 Q3W Evaluate at end of cycles 2, 4, 6 until PD ECOG, Eastern Cooperative Oncology Group; EVO, evofosfamide; DOX, doxorubicin; G-CSF, granulocyte-colony stimulating factor; PD, progressive disease; PS, performance status; Q3W, every 3 weeks; STS, soft tissue sarcoma. 1. ClinicalTrials.gov. NCT01440088. 2. Threshold Pharmaceuticals press release. December 7, 2015. Slide credit: clinicaloptions.com

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) Outcome, Mos PALI + DOX (n = 226) PBO + DOX (n = 221) HR (95% CI) P Value Median PFS 5.98 5.23 0.86 (0.68-1.08) .1831 Median OS 15.91 16.89 1.05 (0.79-1.39) .7423 DOX, doxorubicin; PALI, palifosfamide; PBO, placebo; Q3W, every 3 weeks; STS, soft tissue sarcoma. *Palifosfamide 150 mg/m2 IV Days 1-3; doxorubicin 75 mg/m2 Day 1 Q3W x 6 cycles. Slide credit: clinicaloptions.com Ryan CW, et al. ESMO 2013. Abstract 3802.

Summary: Novel Therapeutics for Advanced Soft Tissue Sarcoma Mechanism of Action Sarcoma Indications/ Clinical Trial Stage Pazopanib[1] Multi–tyrosine kinase inhibitor Advanced 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 doxorubicin Phase III trials ongoing Evofosfamide[6] Prodrug of alkylating agent Br-IPM; hypoxia activated Phase III SARC021 did not meet primary endpoint Palifosfamide[7] Phase III PICASSO III did not meet primary endpoint Ab, antibody; Br-IPM, bromo-isophosphoramide mustard; CT, chemotherapy; STS, soft tissue sarcoma. 1. Pazopanib [package insert]. 2. Eribulin [package insert]. 3. Trabectedin [package insert]. 4. ClinicalTrials.gov. NCT02451943. 5. ClinicalTrials.gov. NCT02049905. 6. ClinicalTrials.gov. NCT01440088. 7. ClinicalTrials.gov. NCT01168791. *Efficacy for treating pts with adipocytic STS or GIST not demonstrated. Slide credit: clinicaloptions.com

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 PD, progressive disease; Q3W, every 3 weeks; QD, every day. *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 PD0332991. 1. Tap WD, et al. Genes Chromosomes Cancer. 2011;50:95-112. 2. Dickson MA, et al. J Clin Oncol. 2013;31:2024-2028. Slide credit: clinicaloptions.com

Subtype: Tenosynovial Giant Cell Tumor/ Pigmented Villonodular Synovitis Locally aggressive synovial malignancies with elevated morbidity and common postresection recurrence Diagnosis commonly occurs at 20-40 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;136:901-906. Ottaviani S, et al. Semin Arthritis Rheum. 2011;40:539-546. West RB, et al. PNAS. 2006;103:690-695. Slide credit: clinicaloptions.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 Best Response, n (%) Imatinib Mesylate (n = 27) CR 1 (4) PR 4 (15) SD 20 (74) PD 2 (8) PD, progressive disease; PVNS, pigmented villonodular synovitis; SD, stable disease; TGCT, tenosynovial giant cell tumors. Slide credit: clinicaloptions.com Cassier PA, et al. Cancer. 2012;118:1649-1655.

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%). Duration of Treatment Extension Study Pts Continued in study Discontinued study RECIST PR PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TGCT, tenosynovial giant cell tumors. 2 4 6 8 10 12 14 16 18 20 22 Mos Slide credit: clinicaloptions.com Tap WD, et al. N Engl J Med. 2015;373:428-437.

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.com

Go Online for More CCO Coverage of Soft Tissue Sarcoma! CME-certified module with expert faculty commentary on all the key recommendations and data clinicaloptions.com/oncology