after Prior Chemotherapy: A Subgroup Analysis Martee L. Hensley 1* , - - PowerPoint PPT Presentation

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Efficacy and Safety of Trabectedin or Dacarbazine for Treatment of Patients with Uterine Leiomyosarcoma after Prior Chemotherapy: A Subgroup Analysis

Martee L. Hensley1*, Shreyaskumar R. Patel2, Margaret von Mehren3, Kristen Ganjoo4, Robin L Jones5, Arthur Staddon6, Daniel Rushing7, Mohammed Milhem8, Bradley Monk9, George Wang10, Sharon McCarthy10, Roland

• E. Knoblauch10, Trilok V. Parekh10, Robert G. Maki11, George D. Demetri12

*Presenting author

1MSK Cancer Center, New York, NY; 2The University of Texas M.D. Anderson Cancer Center, Houston, TX; 3Fox Chase Cancer Center, Philadelphia, PA; 4Stanford

Hospital and Clinics, Stanford, CA; 5Seattle Cancer Care Alliance, Seattle, WA; 6Arthur James Cancer Center, Columbus, OH; 7Indiana University, Simon Cancer Center, Indianapolis, IN; 8University of Iowa Hospitals and Clinics, Iowa City, IA; 9St. Joseph's Hospital & Medical Center, Phoenix, AZ; 10Janssen Research & Development LLC Raritan, NJ; 11Mount Sinai School of Medicine New York, NY; 12Dana-Farber Cancer Institute and Ludwig Center at Harvard, Boston, MA

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• Consulting or Advisory Role: Janssen Pharmaceuticals
• Research Funding: Janssen Research & Development, LLC
• Other: Spouse employed by Sanofi

Disclosures for Presenter: Dr. Martee L. Hensley

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Background

Trabectedin mechanisms of action1

Impacts DNA Binding and Repair:

• Distorts DNA structure resulting in the initiation of DNA repair

mechanisms

• Binds and inhibits repair mechanisms thereby activating apoptosis

Inhibits Transcriptional Activation:

• Inhibits activated transcription process
• Induces degradation of RNA polymerase II
• Detachment of fusion chimeras from their target promoters

Modifies Tumor Microenvironment:

• Decreases IL-6 and CCL2 production
• Decreases macrophage and monocyte recruitment
• Decreases angiogenesis

A B C

1D’Incalci and Galmarini, Mol Cancer Therapeutics. 2010, 9(8): 2157-63

Trabectedin (ET743)

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ET743-SAR-3007 Study: Background

• Largest phase-3 study in soft-tissue sarcoma
• Trabectedin demonstrated statistically significant improvement in PFS as compared

to treatment with dacarbazine

• 4.2 months vs. 1.5 months, HR=0.55 P<0.0011
• Results led to FDA approval of trabectedin for treatment of patients with

leiomyosarcoma (LMS) or liposarcoma (LPS), after prior anthracycline therapy

• Previously reported subgroup analysis demonstrated equivalent PFS benefit in

patients with either LMS (HR=0.56) or LPS (HR=0.55)2

• The majority of patient population (73%) had LMS
• Uterine=40%
• Non-uterine= 33%
• 1. Demetri et al, JCO, September 2015, doi: 10.1200/JCO.2015.62.4734
• 2. Demetri et al, Presented at ESMO 2015

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Key Eligibility Criteria:

• Histologically proven LPS or LMS
• Previously treated with an anthracycline and ifosfamide

containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen

• Adequate bone marrow, renal and hepatic function

Stratified By:

• Prior lines chemotherapy (1 vs 2+)
• ECOG PS (0 vs 1)
• Sarcoma subtype (LPS vs LMS)

Randomization

2:1 N=577

pretreated with Dexamethasone 20 mg IV

Trabectedin 1.5 mg/m² 24h infusion q3wks (N=384) Dacarbazine 1 g/m2 20-120 min infusion q3wks (N=193)

• Conducted at 90 sites in 4 different countries (US, Australia, Brazil, New Zealand)
• Majority of patients were treated at US sites (94%)
• Final analysis of OS: After 381 death events (66% of all randomized patients)
• Investigator reported histology and disease site prospectively collected

Primary Endpoint Secondary Endpoints Overall Survival (OS) Progression-free survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), Safety, Patient-Reported Outcomes (PRO)

ET743-SAR-3007 Study Design and Methods

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Patient Disposition at Final Analysis

Total Patients Randomized (N=577) Trabectedin (N=384) Dacarbazine (N=193) Subgroup Analysis of Patients with Uterine LMS Randomized (N=144) Treated (n=140) Randomized (N=88) Treated (n=81)

Discontinued (n=138) Disease progression (n=108) Adverse event (n=20) Physician decision (n=1) Withdrew consent (n=5) Other (n=1) Death (n=2) Subsequent therapy (n=1) Discontinued (n=80) Disease progression (n=69) Adverse event (n=6) Physician decision (n=1) Withdrew consent (n=4)

Ongoing (n=2) Ongoing (n=1)

Untreated (n=7) Withdrew consent (n=7) Untreated (n=4) Withdrew consent (n=3) Adverse event (n=1)

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Patient Demographics and Disease Characteristics: Uterine LMS Subset

Dacarbazine N=88 Trabectedin N=144 Age, n (%) 18-< 65 75 (85.2) 122 (84.7) 65-<75 11 (12.5) 18 (12.5) ≥75 2 (2.3) 4 (2.8) Baseline ECOG performance status, n (%) 41 (46.6) 69 (47.9) 1 47 (53.4) 75 (52.1) Prior surgery, n (%) 85 (96.6) 140 (97.2) Time from last disease progression to randomization, months median (range) 0.99 (0.1; 8.7) 0.76 (0.0; 13.7)

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Dacarbazine N=88 Trabectedin N=144 Lines of prior chemotherapy, n (%) 1 3 (3.4) 4 (2.8) 2 34 (38.6) 66 (45.8) 3 32 (36.4) 46 (31.9) ≥4 19 (21.6) 28 (19.4) Common Prior chemotherapies Anthracycline 88 (100) 143 (99.3) Doxorubicin 79 (89.8) 127 (88.2) Gemcitabine –Docetaxel 84 (95.5) 132 (91.7)

Prior Treatment Information: Uterine LMS Subset

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Dacarbazine (N=81) n (%) Trabectedin (N=140) n (%) Treatment-emergent adverse events 81 (100.0) 140 (100.0) Drug-related 74 (91.4) 136 (97.1) Grade 3-4 TEAEs 48 (59.3) 114 (81.4) Drug-related 34 (42.0) 97 (69.3) Serious TEAEs 28 (34.6) 63 (45.0) Drug-related 9 (11.1) 29 (20.7) Grade 3-4 26 (32.1) 57 (40.7) TEAE leading to treatment termination 24 (29.6) 32 (22.9) Drug-related 7 (8.6) 18 (12.9) Deaths within 30 days of last dose 2 (2.5) 8 (5.7) Due to progressive disease 2 (2.5) 6 (4.3) Due to TEAE 2 (1.4) Death within 60 days of initiation of study drug 6 (7.4) 10 (7.1)

Safety Profile: Uterine LMS Population

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Adverse Events (≥20% Frequency)

Dacarbazine (N=81) Trabectedin (N=140)

All Grades, % Grade 3, % Grade 4 ,% All Grades, % Grade 3, % Grade 4, % Nausea 44.4 2.5 74.3 8.6 Fatigue 50.6 1.2 65.7 8.6 ALT increased 7.4 1.2 49.3 32.9 0.7 Vomiting 22.2 1.2 48.6 7.1 Anemia 32.1 13.6 47.1 19.3 0.7 Neutropenia# 29.6 16.0 6.2 46.4 20.7 15.7 Constipation 39.5 35.0 Decreased appetite 19.8 1.2 33.6 1.4 Diarrhea 29.6 32.9 1.4 Leukopenia 16 9.9 3.7 32.1 20.7 5 AST increased 7.4 31.4 14.3 0.7 Thrombocytopenia 27.2 9.9 6.2 26.4 5 10 Headache 18.5 26.4 0.7 Edema peripheral 9.9 1.2 25.7 0.7 Abdominal pain 22.2 7.4 24.3 8.6 Dyspnea 17.3 1.2 24.3 4.3 Cough 21.0 22.9 Pyrexia 14.8 20.7 0.7

#Febrile neutropenia: Trabectedin (4.8%) and Dacarbazine (1.7%)

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Dacarbazine N=81 Trabectedin N=140 Number of treatment cycles, median 2 4 Cumulative treatment cycles, n (%) ≥ 6 15 (18.5) 55 (39.3) ≥ 9 9 (11.1) 33 (23.6) ≥ 12 4 (4.9) 22 (15.7) Maximum number of cycles 30 44 Relative dose intensity median (range) 0.99 (0.5; 1.0) 0.89 (0.6; 1.0)

Study Treatment Exposure

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Dacarbazine N=81 Trabectedin N=140 Total number of patients with at least 2 cycles, n (%) 64 (79.0) 124 (88.6) Cycle delays Yes 31 (38.3) 84 (60.0) No 33 (40.7) 40 (28.6) Dose reduction Yes 5 (6.2) 55 (39.3) No 59 (72.8) 69 (49.3) Number of dose reductions 1 5 (6.2) 38 (27.1) 2 17 (12.1)

Dose Modifications

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Progression-Free Survival : ET743-SAR-3007

Total Population1

HR (95% CI)=0.55 (0.44, 0.70) p<0.0001

PFS events 329 Median PFS Trabectedin 4.2 months Median PFS Dacarbazine 1.5 months

HR (95% CI)=0.57 (0.41, 0.81) p=0.0012

Uterine Leiomyosarcoma Population

PFS events 141 Median PFS Trabectedin 4.0 months Median PFS Dacarbazine 1.5 months

1Demetri et al, JCO, September 2015, doi: 10.1200/JCO.2015.62.4734

• ET743-SAR-3007 PFS results confirmed through independent radiological audit of 60% of study patients1

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Dacarbazine (N=78) Trabectedin (N=134) Odds ratio (95%CI) p-value Overall Response Rate (all PR) 7 (9.0%) 15 (11.2%) 1.279 (0.463 - 3.888) 0.816 Clinical Benefit Rate* 14 (17.9%) 41 (30.6%) 2.015 (0.976 - 4.332) 0.051

*Clinical benefit defined as PR, CR, or SD ≥ 18 weeks [6 cycles] (Statistical Analysis Plan-defined endpoint)

Additional Secondary Endpoints1

Dacarbazine (N=7) Trabectedin (N=15) Hazard Ratio (95% CI) p-value Median Time to Response, Months (range) 2.79 (1.3; 8.3) 3.22 (1.2; 10.4) Median Duration of Response, Months (95% CI) 4.07 (2.14, 4.17) 6.47 (1.12, 7.62) 0.463 (0.099, 2.156) 0.316

1Analysis of secondary efficacy endpoints performed at the time of the interim analysis of OS

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Overall Survival: ET743-SAR-3007

HR (95% CI)=0.89 (0.65, 1.24) p=0.5107

Uterine Leiomyosarcoma Population

OS events 161 Median OS Trabectedin 13.4 months Median OS Dacarbazine 12.9 months

Total Population1

HR (95%CI)=0.92 (0.75, 1.15) p=0.4920

OS events 381 Median OS Trabectedin 13.7 months Median OS Dacarbazine 13.1 months

1Patel et al, Presented at ESMO 2015

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2.3% 2.3% 2.3% 10.2% 11.4% 13.6% 10.2% 9.1% 19.3% 21.6% 8.0% 45.5% 0.0% 4.2% 5.6% 5.6% 5.6% 7.6% 8.3% 10.4% 14.6% 16.0% 22.9% 34.7% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 45.0% 50.0%

Trabectedin Eribulin Doxorubicin Vinorelbine Ifosfamide Docetaxel Surgery Temozolomide Radiation Gemcitabine Dacarbazine Pazopanib Trabectedin Dacarbazine

Subsequent Anticancer Therapy

• Reported in 75.0% patients in dacarbazine group and 75.7% patients in trabectedin group

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Conclusions

• In patients with uterine LMS, trabectedin significantly improved PFS

compared to treatment with dacarbazine

• Median PFS: 4.01 months vs.1.54 months
• HR: 0.57; 95% CI: 0.41–0.81; p=0.0012
• Overall survival benefit observed with trabectedin treatment was not

statistically significant

• Median OS: 13.4 months vs.12.9 months
• HR: 0.89; 95% CI, 0.65–1.24; p=0.5107
• Lack of cumulative toxicity of trabectedin allowed for prolonged

treatment courses

• 39.3% vs 18.5% received at least 6 cycles
• Trabectedin is an important new treatment option for patients with

advanced uterine LMS after doxorubicin-containing treatment

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Acknowledgment

Patients, Families & Caregivers