1. 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. 2 Disclosure Consultant for Novartis Pharma, Pfizer

3. 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. 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. 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. 10511, 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. 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. 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. 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. 9 Pooled analysis- population analysed 121 evaluable LMS patients from both studies SARC002 trial: 38 patients treated between May 2003 – October 2005 9 in the G arm, 29 in the G+D arm TaxoGem trial: 83 patients treated between April 2006 – March 2009 43 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. 10 Patient characteristics - Extra uterine LMS

11. 11 Patient characteristics - Uterine LMS

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

13. 13 Pooled analysis – Progression-free survival

14. 14 Pooled analysis – Progression-free survival

15. 15 Responses: Extra - uterine LMS

16. 16 Responses: U terine LMS Responses: U terine LMS

17. 17 Pooled analysis – Overall survival Median follow-up: 25.2 months [ 0.7 - 37.8 ]

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

19. 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. 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. 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