Hartmann JT 1 , Bauer S 2 , Schädel S 1 , Meisinger I 1 , Kasper B 3 , Kopp HG 1 , Mayer F 1 , Grünwald V 4

1. INTERDISZIPLINÄRE ARBEITSGEMEINSCHAFT WEICHTEILSARKOME Final analysis of a non-comparative phase II study of multi target enzyme inhibitor pemetrexed in patients with refractory soft tissue sarcoma – Medical Oncology Sarcoma Group / AIO 005 - Hartmann JT1, Bauer S2, Schädel S1, Meisinger I1, Kasper B3, Kopp HG1, Mayer F1, Grünwald V4 1University of Tübingen 2University of Essen 3University of Heidelberg 4Medical School Hannover CTOS, Miami 2009 Working group Medical Oncology

2. Background • Refractory sarcoma (sarcomas with complex karyotypes) difficult to treat • Lack of active agents • Only a limited number of agents have shown moderate activity • Gemcitabine (+Docetaxel), Trabectidin, Trofosfamide, Bendamustin, DTIC… • But activity in distinct subgroups • Paclitaxel (AngioS) • Sorafenib (AngioS, LMS) • Trabectidine (myx. LS, LMS, TRS?)

3. Pemetrexed – refractory soft tissue sarcoma Pemetrexed (Alimta) is a antifolate: • Target at least three different enzymes in the folate pathway in vitro: thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT) • Clinical antitumor activity in a variety of tumor types • Approved in the US and the EU for the treatment of advanced mesothelioma and non–small-cell lung cancer • Favorable toxitiy profile with the main toxicity being moderate suppression of bone marrow function • Good subjective tolerability

4. Pemetrexed – refractory soft tissue sarcomaAim of the study • Primary objective: • Overall response rate • complete/partial remissions • Secondary objectives: • Progression free rate (PFR) after 3 and 6 months • Median survival • Progression free survival • Toxicity assessment

5. Pemetrexed – refractory soft tissue sarcomaInclusion criteria (selection) • Histologically proven, unresectable STS • Grading according FNCLCC of 2 or 3, if applicable • Evidence of progression during or relapse after chemotherapy at least one prior line of treatment • Two-dimensional measurable or evaluable disease according to WHO criteria • ECOG performance status  2 • Life expectancy of at least 3 months • Adequate function of bone marrow and kidneys • At least 18 years of age • Written informed consent

6. Pemetrexed – refractory soft tissue sarcomaTreatment schedule

7. Pemetrexed – refractory soft tissue sarcomaFlow of patients through trial N=30 Tuebingen, n=12 Hannover, n=5 Essen,n=4 Heidelberg, je n=1 Halle u. Nuremcberg 53 pts screened/registered N=6 excluded: n=4 never treated n=2 eligibility unable to confirm 47 pts included N=7 received only 1 cycle 40 pts completed protocol as planned 40 pts included in response assessment 47 pts included in safety assessment 47 pts included in survival analysis (intention-to-treat)

8. Pemetrexed – refractory soft tissue sarcomaPatients’ characteristics Male/female ratio: 1.24 Age 53 (range, 20-81) 77% lung and 32% liver mets 98% had received anthracyclines, 66% IFOS, 68% other drugs 40% second-line, 45 % third-line, 15% more than 3 prior tx

9. Pemetrexed – refractory soft tissue sarcomaHistology and grading Histology N pts (%) Leiomyosarcoma 17 (36) Pleom. rhabdomyosarcoma 4 ( 9) Pleom. sarcoma, NOS 3 ( 6) Synovial sarcoma 3 ( 6) Hemangiopericytoma 2 ( 4) Liposarcoma 2 ( 4) MPNST 2 ( 4) DSRCT 2 ( 4) ASPS 2 ( 4) Other 10 (21) Grading acc. to FNCLCC N pts (%) I: 2 (4) II: 15 (32) III: 23 (49) n.a.: 7 (15) NOS, not otherwise specified; MPNST, malignant peripherla nerve sheat tumor; DSRCT, desmoplastic small round cell tumor; ASPS, alveolar soft part sarcoma

10. Pemetrexed – refractory soft tissue sarcomaNon-hematological toxicity 197 cycles applied (median 2, range 1-30) No toxic death was seen grade III grade IV N pts (%) N pts (%) • Elevated ASAT/ALAT 4 (9) 1 (2) • Hyperglycemia 3 (6) 0 (0) • Nausea 1 (2) 0 (0) • Stomatitis 0 (0) 1 (2)* • Infection w/o neutropenia 2 (4) 0 (0) • Fatigue 2 (4) 0 (0) *Pt with pleural effusion not been treated adequately prior to pemetrexed infusion

11. Pemetrexed – refractory soft tissue sarcomaHematological toxicity grade III grade IV N pts (%) N pts (%) • Anemia 6 (13) 1 (2) • Leukocytopenia 3 (6) 5 (11) • Neutropenia 2 (4) 4 (9) • Thrombocytopenia 2 (4) 1 (2) • Febrile Neutropenia 2 (4) 1 (2)

12. Pemetrexed – refractory soft tissue sarcomaResponse assessment (n = 40)

13. Response assessmentExplorative subset analysis according to histology and extent of prior therapy LMS, n=17 (43%) Non-LMS, n=23 (58%) • PR 1 ( 6%) 1 ( 4%) • SD 6 (35%) 10 (43%) • PD 10 (59%) 12 (52%) 2-line, n=15 (38%) > 3 prior therapies, n=25 (63%) • PR 1 ( 7%) 1 ( 4%) • SD 4 (27%) 12 (48%) • PD 10 (67%) 12 (48%) 41 vs. 47% 34 vs. 52%

14. Survival (Kaplan-Meier plot)Intention-to-treat analysis N Number of patients at risk 47 17 8 3 2 2 2 N Number of patients at risk 47 40 23 17 12 10 7 Median Follow-up all pts (n=47): 175 days Median Follow-up surviving pts (n=11): 447 days

15. EORTC baseline reference for 2nd line chemotherapy: active agents Pemetrexed second-third line N OR 3mPFR 6mPFR 124 15% 44% 18% 47 5% 44% 24%

16. Survival (Kaplan-Meier plot)Intention-to-treat analysisLeiomyosarcoma vs. other P=0.36 P=0.64

17. Survival (Kaplan-Meier plot)Intention-to-treat AnalyseSecond-line vs. higher Second line > 3 prior therapies Second line > 3 prior therapies P=0.69 P=0.38

18. Pemetrexed – refractory soft tissue sarcomaSummary • Representative population included • Low remission rate (5%) • Reasonable high rate of disease stabilisation (40%) • Minor responses (shrinkage ≥ 20%): 4 pts (10%) • Different subtypes: LMS, Angio-S., pleom. NOS, pRMS • Efficacy in leiomyosarcoma • Independent of number of prior therapies • Favorable toxicity profile