A pooled analysis of the final results of the two randomized phase II studies comparing Gemcitabine (G) vs Gemcitabine + Docetaxel (G+D) in patients (pts) with metastatic/relapsed leiomyosarcoma (LMS) F.Duffaud, P. Pautier, B. Bui, M.L Hensley, A.Rey, N.Penel, D.Reinke, A. Le Cesne, J.Y Blay, R.G Maki

2 Disclosure Consultant for Novartis Pharma, Pfizer

3 Introduction and Study Rationale Gemcitabine and Docetaxel have been studied in STS with mixed results Gemcitabine (G) – limited single agent activity Phase II studies - 30 min infusion: only low-response rates (RR: 3-18%) Fixed-dose rate (10 mg/m 2 /min): a pharmacologic advantage* Docetaxel (D) – limited single agent activity (RR: 0 -18%) Combination G (fixed-dose-rate infusion) + D Impressive activity in LMS: Response Rate 53% (2/5 extra uterine LMS, 16/25 uterine)** Hypotheses of activity for combination: prolonged G infusion and synergy between combination of these drugs 2 randomized trials compared the activity of G versus G+D in metastatic soft tissue sarcomas Patel S 2001*, Hensley 2002**

4 Introduction and Study Rationale The SARC002 trial compared G vs G+D as 1st to 4th line therapy for metastatic soft tissue sarcomas (mSTS) of many subtypes. Maki RG et al. JCO 2007 “Synergy of G+D accounts for the bulk of the combination’s arm activity, rather than the fixed-dose rate infusion of G” The French TaxoGem study compared the activity of G vs G+D in LMS exclusively, as 2d-line therapy for metastatic disease after a 1st line anthracycline based regimen, with stratification by primary site (uterus vs extra-uterus) G+D failed to demonstrate any advantage (OR, PFS) compared to G in uterine OR extra-uterine LMS Although well tolerated, G+D was more toxic than G alone

5 Methods SARC002 study A Bayesian adaptive randomization procedure was used based on the estimated probabilities of treatment success (RECIST) TaxoGem study Stratification: by primary tumor location (uterine LMS vs. others) Each stratum considered as an independent phase II study The Simon method was used (ASCO 2008 abstr , ASCO 2009 abstr 10527) “Uterus” study, 20 evaluable pts/arm “Uterus” study, 20 evaluable pts/arm for a 74% probability of selecting the best arm with a RR of 50%, Baseline RR= 40% “Extra-uterus” study, 20 evaluable pts/arm “Extra-uterus” study, 20 evaluable pts/arm for a 91.8% probability of selecting the best arm with a RR of 40%, Baseline RR = 20% Pooled analysis Analysis of the primary data from all evaluable LMS patients included in both studies

6 Main eligibility criteria SARC002 study Patients with mSTS recurrent/progressive disease, 0-3 prior chemotherapy regimen(s) Age > 10 TaxoGem study Patients with histologically-proven LMS, metastatic or with unresectable local relapse, Only one prior doxorubicin based regimen, Age ≥18 Both studies Measurable disease (per RECIST), ECOG PS ≤ 2, Adequate organ function

7 Primary end-point : Objective Response Rate (RECIST1.0) –SARC002: Tumor response (CR+PR within 24 weeks) and also defined DISEASE CONTROL AS “response” (SD lasting > 24 weeks), tumor evaluation every 2 cycles –TaxoGem: Best response during treatment, tumor evaluation every 2 cycles, Secondary end-points : PFS, duration of response, toxicity, OS SARC002 and TAXOGEM study objectives SARC002 and TAXOGEM – study objectives

8 Treatment schedule G arm: G delivered as a fixed dose rate of 10 mg/m 2 /min, 1200mg/m 2 IV over 120 min (d1+d8) q21 days in the SARC002 study, and 1000 mg/m 2 IV over 100 min (d1+d8+d15) q21 days in the TaxoGem study. G+D arm, both studies: G 900 mg/m 2 over 90 min (d1+d8) + D 100 mg/m 2 over 60 min d8 + lenograstim (G-CSF) 150 µg/m 2 /d d9-d15 SARC002 and TaxoGem treatment SARC002 and TaxoGem – treatment

9 Pooled analysis- population analysed 121 evaluable LMS patients from both studies SARC002 trial: 38 patients treated between May 2003 – October in the G arm, 29 in the G+D arm TaxoGem trial: 83 patients treated between April 2006 – March in the G arm, 40 in the G+D arm Previous lines of chemotherapy for metastic disease 0 for 15 (12%) patients, 1 for 100 (83%) pts, 2 for 4 pts and 3 for 2 pts → 100 pts received G or G+D as second line of chemotherapy

10 Patient characteristics - Extra uterine LMS

11 Patient characteristics - Uterine LMS

12 Pooled analysis – toxicity * Toxicity known for only 288 cycles out of 330 delivered cycles

13 Pooled analysis – Progression-free survival

14 Pooled analysis – Progression-free survival

15 Responses: Extra - uterine LMS

16 Responses: U terine LMS Responses: U terine LMS

17 Pooled analysis – Overall survival Median follow-up: 25.2 months [ ]

18 Pooled analysis – Overall survival Median follow-up: 28 months [ 2.7 – 37.4 ]

19 Pooled analysis – conclusions High rates of progression-free survival - 3 months PFS of 67% (G) and 59% (G+D) in extra uterine LMS, and of 55% (G) and 63% (G+D) in uterine LMS - 6 months PFS ≥ 46% in both arms and both groups support the hypothesis that both G alone and G+D are active regimens in uterine and extra uterine LMS according to EORTC STBSG EORTC EJC 2002, Active agents 2d line in mSTS: 3mo PFR ≥ 40% and 6mo PFR ≥14% G+D failed to demonstrate any advantage (OR, PFS) compared to G alone in uterine and in extra-uterine LMS Maki et al.2007: median PFS of 3 and 6.2 mo in G and G+D in all mSTS TaxoGem median PFS of 5.5 and 4.6 mo in G and G+D for uterine LMS and 5.5 and 3.4 mo in G and G + D in extra-uterine LMS

20 Pooled analysis – conclusions Even well tolerated, G+D is more toxic than G one toxic death in G+D arm; haematotoxicity, asthenia, neurotoxicity,… It is reasonable to offer G alone as therapy for metastatic LMS PFS curves do not show differences between G and G+D in metastatic LMS (mLMS) and are superimposable Although G and G+D are active to some degree in uterine and extra-uterine LMS new agents of greater efficacy are needed for all metastatic LMS

21 Acknowledgments Patients and families French and US Centers and trial investigators Sponsor : FNCLCC, Paris : M Jimenez, Gosse, V. Bénavent, P. Nezan, C. Delavault, C. Mahier DM and Statistics, Institut Gustave Roussy, Villejuif : G. Danton, A. Laplanche, A. Mauguen With the support of : Institut National du Cancer (INCa), Ligue Nationale Contre le Cancer Chugai Pharma France, Sanofi-Aventis France