Trabectedin in ASTS. Le Cesne A, et al. J Clin Oncol. 2018;36(suppl): Abstract

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1 Results of a Prospective Randomized Phase III T-SAR Trial Comparing Trabectedin vs Best Supportive Care (BSC) in Patients With Pretreated Advanced Soft Tissue Sarcoma (ASTS) Abstract Le Cesne A, Blay JY, Cupissol D, Italiano A, Delcambre C, Penel N, Isambert N, Chevreau C, Bompas E, Bertucci F, Chaigneau L, Piperno-Neumann S, Salas S, Rios M, Guillemet C, Bay JO, Ray-Coquard I, Haddag L, Mir O, and Foulon S, for the French Sarcoma Group

2 Trabectedin in ASTS Trabectedin has demonstrated single-agent activity in patients with pretreated ASTS and was approved in 2007 in Europe in this indication Trabectedin has proved effective in liposarcoma and in leiomyosarcoma (L-sarcomas or L-STS) (approval in US in 2015) 1 Clinical benefit with trabectedin was also observed in other histologic types of STS 2,3 With the exception of a study in translocation-related sarcomas, 4 trabectedin was never compared to BSC in a randomized study in patients with all STS histotypes STS, soft tissue sarcoma 1. Demetri GD, et al. J Clin Oncol. 2016;34(8): ESMO/European Sarcoma Network Working Group. Ann Oncol. 2014;25(Suppl 3):v Le Cesne A, et al. Eur J Cancer. 2015;51(6): Kawai A, et al. Lancet Oncol. 2015;16(4):

3 TSAR: Randomized Phase III Trial Overview Advanced STS Unresponsive or intolerant to standard CT regimens 2 nd to 4 th CT line Randomization 1:1 Trabectedin 1.5 mg/m 2 in 24h IV infusion q 3 w BSC* *Cross-over allowed at progression Primary endpoint: PFS Number of patients required: 100 patients (90% power to detect a hazard ratio [HR] of 0.50) Centralized review to confirm progression before switch Stratification L-STS vs non L-STS Secondary endpoints: RR, safety, QoL, cost effectiveness, and OS Trial required by French Health Authorities in 2014 CT, chemotherapy; OS, overall survival; PFS, progression-free survival; QoL, quality of life; RR, response rate; TSAR, Trabectedin to the Best Supportive Care in Patients With Sarcoma

4 TSAR: Main Eligibility Criteria Inclusion Inoperable or metastatic STS after at least one anthracycline-containing regimen in advanced setting Measurable lesions in accordance with RECIST 1.1 Progressive disease before inclusion Performance status 1 Age 18 years -PNN 1500/mL Hb level 9 g/dl Platelets /mL -Bilirubin ULN SGPT and SGOT 2.5 x ULN -Albumin 25 g/l -Creatinine clearance >30mL/min CPK 2.5 x ULN -Normal LVEF function Exclusion More than 3 regimens of CT in advanced setting Prior trabectedin treatment GIST, RMS, PNET, chondrosarcoma, DFSP, DSRCT Symptomatic brain metastasis Patients unable to receive corticotherapy CPK, creatine phosphokinase; DFSP, dermatofibrosarcoma protuberans; DSRCT, desmoplastic small round cell tumor; GIST, gastrointestinal stromal tumor; LVEF, left ventricular ejection fraction; PNET, primitive neuroectodemal tumor; PNN, polynuclear neutrophil; RECIST, Response Evaluation Criteria in Solid Tumors; SGOT, Serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; ULN, upper limit of normal

5 TSAR: Inclusion Status 100 ' 80 Trial opened in January 2015, closed in November 2015 N 60 A total of 103 patients were enrolled by 16 FSG centers Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2015 Date Included Expected (100 patients/1 year) Expected (according to number of activated centers) FSG, French Sarcoma Group

6 TSAR: Description of Included Patients Trabectedin (N = 52) BSC (N = 51) *Two patients discontinued the study just after their randomization in the BSC arm Total (N = 103) Randomized ITT population 52 (100%) 51 (100%) 103 (100%) Treated* 52 (100%) 49 (96.1%) 101 (98.1%) Assessable for safety 52 (100%) 49 (96.1%) 101 (98.1%) Assessable for efficacy 52 (100%) 51 (100%) 103 (100%) In both arms: Tumor assessments performed every 3 weeks during the 2 first cycles and every 2 cycles thereafter

7 TSAR: Patients Characteristics (1) Trabectedin (N = 52) BSC (N = 51) Total (N = 103) Median age, years Performance status (PS) PS % 34% 39.2% PS % 66% 58.8% PS 2 3.8% 0 2% Gender Male 24 (46.2%) 31 (60.8%) 55 (53.4%) Female 28 (53.8%) 20 (39.2%) 48 (46.6%) Tumor histology Liposarcoma 14 (26.9%) 16 (31.4%) 30 (29.1%) Leiomyosarcoma 18 (34.6%) 14 (27.5%) 32 (31.1%) Undifferentiated sarcoma 5 (9.6%) 6 (11.8%) 11 (10.7%) Myxofibrosarcoma 5 (9.6%) 3 (5.9%) 8 (7.8%) Synovial sarcoma 2 (3.8%) 3 (5.9%) 5 (4.9%) Other histologies 8 (15.4%) L-Sarcomas: 9 (17.6%) 60.2% 17 (16.5%) Non L-Sarcomas: 39.8%

8 TSAR: Patients Characteristics (2) Trabectedin (N = 52) BSC (N = 51) Total (N = 103) Location of the primary Retroperitoneal 14 (26.9%) 13 (25.5%) 27 (26.2%) Lower limb and/or hip 11 (21.2%) 15 (29.4%) 26 (25.2%) Uterus 12 (23.1%) 4 (7.8%) 16 (15.5%) Trunk 4 (7.7%) 5 (9.8%) 9 (8.7%) Abdominal 5 (9.6%) 9 (17.6%) 14 (13.6%) Other 6 (11.5%) 5 (9.8%) 11 (10.7%) Histopronostic grade Grade 1 3 (8.3%) 3 (7.5%) 6 (7.9%) Grade 2 14 (38.9%) 13 (32.5%) 27 (35.5%) Grade 3 19 (52.8%) 24 (60%) 43 (56.6%) Tumor status Locally advanced 4 (7.7%) 6 (11.8%) 10 (9.7%) Metastases 48 (92.3%) 45 (88.2%) 93 (90.3%) Lung metastases 35 (67.3%) 33 (64.7%) 68 (66%)

9 TSAR: Patients Characteristics (3) Trabectedin (N = 52) BSC (N = 51) Total (N = 103) Chemotherapy 52 (100%) 51 (100%) 103 (100%) Neoadj/adj CT 17 (32.7%) 18 (35.3%) 35 (34%) N of CT lines (advanced setting) Median 2 (range 0-3) 1 (range 0-3) 1 (range 0-3) 0* 6 (11.5%) 6 (11.8%) 12 (11.7%) 1 18 (34.6%) 26 (51%) 44 (42.7%) 2 19 (36.5%) 14 (27.5%) 33 (32%) 3 9 (17.3%) 5 (9.8%) 14 (13.6%) Prior drugs Anthracyclines 50 (96.2%) 50 (98%) 100 (97.1%) Ifosfamide 25 (49%) 31 (60.8%) 56 (54.9%) Gemcitabine (+/- docetaxel) 13 (25.5%) 14 (27.5%) 27 (26.5%) Dacarbazine 11 (21.6%) 13 (25.5%) 24 (23.5%) Pazopanib 11 (21.6%) 6 (11.8%) 17 (16.7%) Oral cyclophosphamide 7 (13.5) 3 (5.9%) 10 (9.7%) a Patients who received 0 line of chemotherapy in advanced setting but had received chemotherapy in the neoadjuvant/adjuvant setting

10 TSAR: Treatment Administration (N = 101) Trabectedin (N = 52) BSC (N = 49) Number of cycles Total = 274 Total = 139 Median 3 2 Mean Range Relative dose intensity, % Median 86 - Range 52 to 102 -

11 TSAR: Treatment Administration (N = 101) Number of Cycles, n (%) Trabectedin (N = 52) BSC (N = 49) 1 13 (25) 19 (38.8) 2 8 (15.4) 10 (20.4) 3 7 (13.5) 5 (10.2) 4 4 (7.7) 6 (12.2) 5 3 (5.8) 4 (8.2) 6 2 (3.8) 0 >6 15 (28.8) 5 (10.2) >9 12 (23.1) 1 (2%) >12 5 (9.6) 0

12 TSAR: Dose Modification/Cycles Delayed % of Cycles Trabectedin BSC No dose modification or delay* 59 0 Cycle delay and dose modification Cycle delay only Dose modification only Main reasons for delay Hematologic toxicity Hepatic toxicity Main reasons for dose reduction Hematologic toxicity Hepatic toxicity *A cycle was defined as delayed if it started more than 6 days after the planned date (as calculated from the previous cycle)

13 TSAR: Severe AE (Grade 3) By Patients* *Patient with at least 1 toxicity grade 3 or more during the randomized part ** Including one fatal event during a febrile neutropenic event Trabectedin (N = 52) BSC (N = 49) Number of Cycles, n (%) Hematology Anemia 8 (15.4) 3 (6.1) Leukopenia 18 (34.6) 0 Neutropenia 23 (44.2) 1 (2) Thrombocytopenia 13 (25) 0 Febrile neutropenia** 5 (9.6) 0 Liver Transaminases increased 17 (32.7) 1 (2.1) Alkaline phosphatase increased 3 (5.8) 0 Bilirubin elevation 1 (1.9) 1 (2.1) Other Nausea/vomiting 1 (2) 0 Diarrhea 1 (2) 0 Creatinine increased 1 (1.9) 1 (2.1) CPK elevation 1 (2) 0

14 TSAR: PFS Overall Population (Central Review) Median PFS (95% CI) P Value * HR [95% IC] BSC (n = 51) 1.51 months ( ) 1 TRAB (n = 52) 3.12 months ( ) < ( ) Response, n (%) TRAB BSC PR 7 (13.7) 0 SD 34 (66.7) 30 (61.2) PD 10 (19.6) 19 (38.8) Probability of Survival Median follow-up 26 months Months From Randomization PD, progressive disease; PR, partial response; SD, stable disease *Log-rank test stratified on the histologic type

15 TSAR: PFS L-Sarcomas (Central Review) Median PFS (95% CI) P Value * HR [95% IC] BSC (n = 30) 1.41 months ( ) 1 TRAB (n = 32) 5.13 months ( ) < ( ) Response, n (%) TRAB BSC PR 7 (21.9) 0 SD 21 (65.6) 18 (64.3) PD 4 (12.5) 10 (35.7) Probability of Survival Months From Randomization

16 TSAR: PFS Non L-Sarcomas (Central Review) Median PFS (95% CI) P Value * HR [95% IC] BSC (n = 21) 1.51 months ( ) 1 TRAB (n = 20) 1.81 months ( ) ( ) Response, n (%) TRAB BSC PR 0 0 SD 13(68.4) 12 (57.1) PD 6 (31.6) 9 (42.9) Probability of Survival Months From Randomization

17 TSAR: Crossover to Trabectedin for Patients Randomized in the BSC Arm Frequency (n = 49) Crossover to trabectedin Yes 45 (91.8%) No 4 (8.2%) Frequency (n = 4) Reason for not having crossed-over to trabectedin Deceased before the crossover 2 OMS = 3 1 Radiotherapy for brain metastases 1 97/103 patients included in the protocol have received trabectedin

18 TSA: Treatment During the Crossover Period (276 Cycles) Trabectedin (n = 52) Tr Post-BSC (n = 45) Number of cycles N total = 274 N total = 276 Median 3 4 Mean Range Median relative dose intensity (%) 86% 81% Trabectedin (n = 52) Tr Post-BSC (n = 45) Number of cycles N total = 274 N total = (25%) 7 (15.6%) 2 8 (15.4%) 10 (22.2%) 3 7 (13.5%) 4 (8.9%) 4 4 (7.7%) 6 (13.3%) 5 3 (5.8%) (3.8%) 4 (8.9%) More than 6 cycles 15 (28.8%) 14 (31.1%) More than 9 cycles 12 (23.1%) 8 (17.8%) More than 12 cycles 5 (9.6%) 5 (11.1%)

19 TSAR: Severe AE (Grade 3) By Patients During Crossover *including one fatal event during febrile neutropenic event in both arms Trabectedin (n = 52) Tr Post-BSC (n = 45) Hematology Anemia 8 (15.4%) 9 (20%) Leukopenia 18 (34.6%) 16 (35.6%) Neutropenia 23 (44.2%) 23 (51%) Thrombocytopenia 13 (25%) 6 (13.3%) Febrile neutropenia 5* (9.6%) 2* (4.4%) Liver Transaminases increased 17 (32.7%) 24 (53.3%) Alkaline phosphatase 3 (5.8%) 3 (6.7%) increased Bilirubin elevation 1 (1.9%) 1 (2.2%) Other Nausea/vomiting 1 (2%) 3 (6.7%) Diarrhea 1 (2%) 0 Creatinine increased 1 (1.9%) 3 (6.7%) CPK elevation 1 (2%) 3 (6.7%)

20 TSAR: Post-Protocol Treatments Trabectedin (N = 52) BSC (N = 51) Total (N = 103) Number of lines of chemotherapy post-study (median) (35.3%) 22 (44%) 40 (39.6%) 1 13 (25.5%) 11 (22%) 24 (23.8%) 2 13 (25.5%) 10 (20%) 23 (22.8%) 3 5 (9.8%) 4 (8%) 9 (8.9%) 4 2 (3.9%) 2 (4%) 4 (4%) Post-protocol regimen Pazopanib 10 (19.6%) 15 (30%) 25 (24.8%) Gemcitabine (+/- docetaxel/dacarbazine) 13 (25.5%) 11 (22%) 24 (23.8%) Oral cyclophosphamide 14 (27.5) 4 (8%) 18 (17.8%) Dacarbazine 2 (3.9%) 7 (14%) 9 (8.9%) Eribulin 3 (5.9%) 3 (6%) 6 (5.9%) Ifosfamide 1 (2%) 3 (6%) 4 (4%) Anthracyclines 0 2 (4%) 2 (2%) Others 13 (25.5%) 7 (14%) 20 (19.8%)

21 TSAR: Overall Survival Deaths, no Median OS (95% CI) P Value HR (95% CI) Therapeutic arm.86 SDS (n = 51) months ( ) 1 Trab (n = 52) months ( ) 1.04 ( ) Probability of Survival Months From Randomization

22 TSAR: Overall Survival According to Stratification OS: L-STS OS: Non L-STS Median OS (95% CI) P Value HR (95% CI) Therapeutic arm.39 SDS (n = 30) 15.0 months ( ) 1 Trab (n = 32) 16.7 months (8.1-NE) 0.77 ( ) Median OS (95% CI) P Value HR (95% CI) Therapeutic arm.22 SDS (n = 21) 8.3 months ( ) 1 Trab (n = 20) 6.9 months ( ) 1.50 ( )

23 TSAR: Discussion (1) This study met its first endpoint as a preplanned PFS analysis showed a significant improvement in median PFS with trabectedin (T) over BSC in patients with pretreated ASTS including multiple histologies (HR 0.39) A major impact of T was observed in the L-STS cohort (median PFS in the BSC and T arm were 1.4 m and 5.13 months (HR 0.29, P<.0001), respectively), whereas in the non L-STS group the median PFS were 1.51 months and 1.8 months (P =.16) The benefit observed with T in the L-STS cohort of patients is similar to those observed in the US trial in the same population (4.2 months vs 1.5 months for DTIC) 1 and in the Japanese trial including patients with only TRS (5.8 months vs 0.9 months for BSC) 2 DTIC, dacarbazine 1. Demetri GD, et al. J Clin Oncol. 2016;34(8): Kawai A, et al. Lancet Oncol. 2015;16(4):

24 TSAR: Discussion (2) Tumor control rate after 6 cycles of T is similar (30%) to previous study in French referral centers (T-DIS trial) 1 evaluating T in all subtypes of STS As already reported, trabectedin is well tolerated (flexible dose/schedule in 40% of patients) After the crossing over, safety and efficacy profiles of trabectedin remains similar We did not observe a difference in terms of OS between the two arms, probably due to the crossover planned by the protocol. Patients with L-STS live longer than those with a non L-STS Trabectedin allows increasing PFS without impairing HRQoL in patients with ASTS (final results of the QoL analysis will be presented at ESMO 2018) HRQoL, health-related quality of life 1. Le Cesne A, et al. Lancet Oncol. 2015;16(3):

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