Efficacy and Safety of Trabectedin or Dacarbazine for Treatment of Patients with Uterine Leiomyosarcoma after Prior Chemotherapy: A Subgroup Analysis Martee L. Hensley 1* , Shreyaskumar R. Patel 2 , Margaret von Mehren 3 , Kristen Ganjoo 4 , Robin L Jones 5 , Arthur Staddon 6 , Daniel Rushing 7 , Mohammed Milhem 8 , Bradley Monk 9 , George Wang 10 , Sharon McCarthy 10 , Roland E. Knoblauch 10 , Trilok V. Parekh 10 , Robert G. Maki 11 , George D. Demetri 12 * Presenting author 1 MSK Cancer Center, New York, NY; 2 The University of Texas M.D. Anderson Cancer Center, Houston, TX; 3 Fox Chase Cancer Center, Philadelphia, PA; 4 Stanford Hospital and Clinics, Stanford, CA; 5 Seattle Cancer Care Alliance, Seattle, WA; 6 Arthur James Cancer Center, Columbus, OH; 7 Indiana University, Simon Cancer Center, Indianapolis, IN; 8 University of Iowa Hospitals and Clinics, Iowa City, IA; 9 St. Joseph's Hospital & Medical Center, Phoenix, AZ; 10 Janssen Research & Development LLC Raritan, NJ; 11 Mount Sinai School of Medicine New York, NY; 12 Dana-Farber Cancer Institute and Ludwig Center at Harvard, Boston, MA
Disclosures for Presenter: Dr. Martee L. Hensley Consulting or Advisory Role: Janssen Pharmaceuticals Research Funding: Janssen Research & Development, LLC Other: Spouse employed by Sanofi
Background Trabectedin mechanisms of action 1 Impacts DNA Binding and Repair: • Distorts DNA structure resulting in the initiation of DNA repair mechanisms • Binds and inhibits repair mechanisms thereby activating apoptosis Trabectedin (ET743) Inhibits Transcriptional Activation: • Inhibits activated transcription process C • Induces degradation of RNA polymerase II • Detachment of fusion chimeras from their target promoters A Modifies Tumor Microenvironment: B • Decreases IL-6 and CCL2 production • Decreases macrophage and monocyte recruitment • Decreases angiogenesis 1 D’Incalci and Galmarini, Mol Cancer Therapeutics. 2010, 9(8): 2157-63
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<0.001 1 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
ET743-SAR-3007 Study Design and Methods Key Eligibility Criteria: Randomization Trabectedin 1.5 mg/m² Histologically proven LPS or LMS 24h infusion q3wks N=577 Previously treated with an anthracycline and ifosfamide (N=384) containing regimen, or an anthracycline containing regimen and pretreated with Dexamethasone 1 additional cytotoxic chemotherapy regimen 20 mg IV Adequate bone marrow, renal and hepatic function 2:1 Stratified By: Prior lines chemotherapy (1 vs 2+) ECOG PS (0 vs 1) Dacarbazine 1 g/m 2 Sarcoma subtype (LPS vs LMS) 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 Overall Survival (OS) Progression-free survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), Safety, Secondary Endpoints Patient-Reported Outcomes (PRO)
Patient Disposition at Final Analysis Total Patients Randomized (N=577) Dacarbazine (N=193) Trabectedin (N=384) Subgroup Analysis of Patients with Uterine LMS Randomized (N=88) Randomized (N=144) Treated (n=81) Treated (n=140) Untreated (n=4) Discontinued (n=138) Untreated (n=7) Discontinued (n=80) Withdrew consent (n=3) Disease progression (n=108) Withdrew consent (n=7) Disease progression (n=69) Adverse event (n=1) Adverse event (n=20) Adverse event (n=6) Physician decision (n=1) Physician decision (n=1) Withdrew consent (n=5) Withdrew consent (n=4) Other (n=1) Death (n=2) Subsequent therapy (n=1) Ongoing (n=2) Ongoing (n=1)
Patient Demographics and Disease Characteristics: Uterine LMS Subset Dacarbazine Trabectedin N=88 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 (%) 0 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)
Prior Treatment Information: Uterine LMS Subset Dacarbazine Trabectedin N=88 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)
Safety Profile: Uterine LMS Population Dacarbazine Trabectedin (N=81) (N=140) n (%) 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 0 2 (1.4) Death within 60 days of initiation of study drug 6 (7.4) 10 (7.1)
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 0 74.3 8.6 0 Fatigue 50.6 0 1.2 65.7 8.6 0 ALT increased 7.4 1.2 0 49.3 32.9 0.7 Vomiting 22.2 1.2 0 48.6 7.1 0 Anemia 32.1 13.6 0 47.1 19.3 0.7 Neutropenia # 29.6 16.0 6.2 46.4 20.7 15.7 Constipation 39.5 0 0 35.0 0 0 Decreased appetite 19.8 0 1.2 33.6 1.4 0 Diarrhea 29.6 0 0 32.9 1.4 0 Leukopenia 16 9.9 3.7 32.1 20.7 5 AST increased 7.4 0 0 31.4 14.3 0.7 Thrombocytopenia 27.2 9.9 6.2 26.4 5 10 Headache 18.5 0 0 26.4 0.7 0 Edema peripheral 9.9 1.2 0 25.7 0.7 0 Abdominal pain 22.2 7.4 0 24.3 8.6 0 Dyspnea 17.3 1.2 0 24.3 4.3 0 Cough 21.0 0 0 22.9 0 0 Pyrexia 14.8 0 0 20.7 0.7 0 # Febrile neutropenia: Trabectedin (4.8%) and Dacarbazine (1.7%)
Study Treatment Exposure Dacarbazine Trabectedin N=81 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)
Dose Modifications Dacarbazine Trabectedin N=81 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 0 17 (12.1)
Progression-Free Survival : ET743-SAR-3007 Total Population 1 Uterine Leiomyosarcoma Population HR (95% CI)=0.57 (0.41, 0.81) HR (95% CI)=0.55 (0.44, 0.70) p=0.0012 p<0.0001 PFS events 329 PFS events 141 Median PFS Trabectedin 4.2 months Median PFS Trabectedin 4.0 months Median PFS Dacarbazine 1.5 months Median PFS Dacarbazine 1.5 months ET743-SAR-3007 PFS results confirmed through independent radiological audit of 60% of study patients 1 1 Demetri et al, JCO, September 2015, doi: 10.1200/JCO.2015.62.4734
Additional Secondary Endpoints 1 Dacarbazine Trabectedin Odds ratio (95%CI) p-value (N=78) (N=134) 7 (9.0%) 15 (11.2%) Overall Response Rate (all PR) 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) Dacarbazine Trabectedin Hazard Ratio (95% CI) p-value (N=7) (N=15) Median Time to Response, 2.79 (1.3; 8.3) 3.22 (1.2; 10.4) Months (range) Median Duration of Response, 4.07 (2.14, 4.17) 6.47 (1.12, 7.62) 0.463 (0.099, 2.156) 0.316 Months (95% CI) 1 Analysis of secondary efficacy endpoints performed at the time of the interim analysis of OS
Overall Survival: ET743-SAR-3007 Total Population 1 Uterine Leiomyosarcoma Population HR (95%CI)=0.92 (0.75, 1.15) HR (95% CI)=0.89 (0.65, 1.24) p=0.4920 p=0.5107 OS events 381 OS events 161 Median OS Trabectedin 13.7 months Median OS Trabectedin 13.4 months Median OS Dacarbazine 13.1 months Median OS Dacarbazine 12.9 months 1 Patel et al, Presented at ESMO 2015
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