1. Sarcoma Medical therapy Paolo G. Casali [email_address]

2. Incidence STS 5 /100,000/year GIST 1.5 Osteosa 0.3 Ewing 0.2 Rhabdomyosa 0.1 benign tumors 300 Sex M > F Median age STS 60 y GIST 60 y Osteosa 15 y Ewing 15 y Rhabdomyosa 5 y

3. STS OS EFT RMS

4. STS OS EFT RMS

5. Soft tissue sarcoma

6. Adipocytic tumours Well deifferentiated / dedifferentiated liposarcoma Myxoid / round cell liposarcoma Pleomorphic liposarcoma … .. Fibroblastic / myofibroblastic tumours Fibromatosis (desmoid) Solitary fibrous tumour / haemangiopericytoma Low grade myofibroblastic tumour Infantile fibrosarcoma Adult fibrosarcoma Mixofibrosarcoma … .. So-called fibrohistiocytic tumours Pleomorphic MFH / Undifferentiated pleomorphic sarcoma … .. Smooth muscle tumours Leiomyosarcoma … .. Skeletal muscle tumours Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma Vascular tumours Epithelioid haemangioendothelioma Angiosarcoma of soft tissue … .. Chondro-osseous tumours Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Tumours of uncertain differentiation Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Extraskeletal Ewing tumour Desmoplastic small round cell tumour Extra-renal rhabdoid tumour Malignant mesenchymoma Neoplasms with perivascular epithelioid cell differentiation (PEComa) Intimal sarcoma

7. …… .

8. Head & neck 5% Superficial trunk 10% Retroperitoneum 15% Viscera 10% Limbs 60%

9. Adjuvant chemotherapy L = limbs – T = trunk – HN = head & neck – R = retrop – U = uterus – V = viscera gruppo aa n. pz setting regime DFS OS EORTC 77-88 468 L T HN ADM CTX DTIC VCR +13% +7% SSG 81-86 181 L T HN ADM +6% +5% DFCI ECOG IGSC 78-83 168 L T HN R V ADM +13% +3% GOG 73-82 156 U ADM +12% +8% UCLA 81-84 119 L ADM +4% +4% IOR 81-86 77 L ADM +28% +21% NCI 77-81 67 L ADM CTX HDMTX +26% +6% Mayo 75-81 61 L T ADM ActD VCR DTIC -3% 0 Bergonié 81-88 59 L T HN R ADM CTX VCR DTIC +41% +34% MDA 73-76 47 L T ADM ActD CTX VCR -7% NCI 77-81 31 T HN ADM CTX HDMTX +28% +10% NCI 77-81 15 R ADM CTX HDMTX -53%

11. Localized disease Woll PJ, ASCO Ann meet 2007; #10008

12. Frustaci S et al, J Clin Oncol 2001;19:1238

14. 0 epiADM+IFX x 3

18. LOCALIZED, HIGH-RISK SOFT TISSUE SARCOMAS (STS) OF THE EXTREMITIES AND TRUNK WALL IN ADULTS: THREE VS FIVE CYCLES OF FULL-DOSE ANTHRACYCLINE AND IFOSFAMIDE ADJUVANT CHEMOTHERAPY: A PHASE III RANDOMIZED TRIAL FROM THE ITALIAN SARCOMA GROUP AND SPANISH SARCOMA GROUP Alessandro Gronchi , Sergio Frustaci, Mario Mercuri, Javier Martin, Antonio Lopez-Pousa, Lidia Mariani, Paolo Verderio, Vittorio Quagliuolo, Paolo G. Casali and Piero Picci

20. Epirubicin 120 mg/m 2 ( ~ DOX 80 mg/m 2 ) + Ifosfamide 9,000 mg/m 2 q 21 days

21. OS by study arm 70% 69% one-sided 95%: 0.941 (95% CI 0.664 - 1.334) 70% 69% N. at risk Arm A 164 154 138 106 77 43 Arm B 164 157 143 114 77 47

22. RFS by study arm 61% 60% N. at risk Arm A 156 123 108 74 55 33 Arm B 158 126 108 77 47 31

23. OS vs previous ISG trial

24. Sarcomas: spread of disease local isolated extra pulmonary pulmonary

25. Isolated pulmonary metastatic disease

27. Advanced disease R ADM 75 mg/sqm + IFX 7.5 g/sqm ADM 75 mg/sqm EORTC Soft Tissue & Bone Sarcoma Group

29. ADM vs ADM+IFX in advanced STS no. pts. Regimen OR OS EORTC , 1991 244 ADM 75 mg/mq 24% = 233 ADM 50 mg/mq 27% = IFX 5000 mg/mq 135 ADM 50 mg/mq 27% = DTIC 750 mg/mq CTX 500 mg/mq VCR 1.5 mg/mq

30. OR OS Duration of response 218 d (PR) 243 d (CR) Time to progression 240 d (SD) 288 d (PR) 317 d (CR)

31. …… .

33. Endometrial stromal sarcoma: progestins, aromatase inhibitors ER PR

34. Dermatofibrosarcoma: Imatinib COL1A1-PDGFB  PDGFB t(17;22)

35. Desmoid tumors (aggressive fibromatosis)

38. L LMS

40. Stacchiotti S et al, Ann Oncol 2010, 21:1130

43. Stacchiotti S et al, Mol Cancer Ther 2010;9:1286

47. Laplante et Sabatini, J Cell Science 2009

48. SUCCEED study standard CT: best response R Ridaforolimus placebo in advanced STS

49. Leiomyosarcoma: Dacarbazine 0 DTIC x 2

50. Dedifferentiated liposa: HD-IFX 0 HD-ci-IFX x 5

51. Sinovyal sa: HD-IFX 0 +3 mos

52. Angiosarcoma: taxanes Fata F et al. Cancer 1999; 86: 2034

54. Angiosarcoma: Gemcitabine 0 +1 mos +4 mos

55. Leiomyosarcoma: Gemcitabine

58. 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 ESMO Congress, 2010

59. Pooled analysis – Progression-free survival

60. Pooled analysis – Progression-free survival

61. Trabectedin (ET-743)

62. L -sarcoma liposarcoma leiomyosarcoma

63. Dedifferentiated liposa 0 ET743 x 16 mos

64. Uterine leiomyosarcoma 0 ET743 x 3

65. Lipo sarcoma well diff  dediff myxoid  round cell pleomorphic

66. well diff  dediff myxoid  round cell pleomorphic

67. t(12;16)(q13;p11) FUS CHOP 12 16 FUS/CHOP q13 p11

70. 0 + 1 c +4 c

72. Mol Cancer Therap 2009;8:449

73. Synovial sa: Trabectedin

74. T -STS simple cariotype with reciprocal translocations complex cariotype

75. Synovial sa t(X;18)(p11;q11) SS18-SSX1 SS18-SSX2 SS18-SSX4 Myxoid liposa t(12;16)(q13;p11) FUS-CHOP t(12;22)(q13;q12) EWS-CHOP Esk. myx. chondrosa t(9;22)(q22;q12) EWS-NR4A3 t(9;17)(q22;q11) RBP56-NR4A3 t(9;15)(q22;q21) TCF12-NR4A3 Fibromyxoid sa t(7;16)(q33;p11) FUS-CREB3L2 t(11;16)(p11;p11) FUS-CREB3L1 Clear cell sa t(12;22)(q13;q12) EWS-ATF1 Dermatofibrosa t(17;22)(q22;q13) COL1A1-PDGFB EFT t(11;22)(q24;q12) EWS-FL1 t(21;22)(q22;q12) EWS-ERG t(7;22)(p22;q12) EWS-ETV1 t(17;22)(q12;q12) EWS-E1AF t(2;22)(q33;q12) EWS-FEV Desmopl. SRCT t(11;22)(p13;q12) EWS-WT1 Alv. rhabdomyosa t(2;13)(q35;q14) PAX3-FOXO1A t(1;13)(p36;q14) PAX7-FOXO1A Alv. soft part sa t(X;17)(p11;q25) TFE3-ASPL Angiomatoid f. histiocytoma t(12;16)(q13;p11) FUS-ATF1 Cong fibrosa t(12;15)(p13;q25) ETV6-NTRK3 Endometrial stromal sa t(7;17)(p15;q21) JAZF1-JJAZ1 Infl. myofibro. t. t(1;2)(q22;p23) TPM3-ALK t(2;19)(p23;p13) TPM4-ALK t(2;17)(p23;q23) CLTC-ALK t(2;2)(p23;q13) RANBP2-ALK

78. Gastrointstinal stromal tumors (GIST)

79. Target therapy in GIST Imatinib SCF

82. Imatinib chemotherapy OS months

84. KIT (CD 117)

85. Lasota J et al, Histopathology 2008 exon 9 (~10%) exon 11 (~70%) exon 13 (~5%) exon 17 (~5 %) PDGFRA (~10%) KIT (~80%) WT (~10%)

86. KIT exon 9

87. KIT exon 9 PDGFRA

89. PDGFRA Corless CL, J Clin Oncol 2005, 23: 5357

90. GIST in syndromes GIST in children 0 – 18+ yrs

94. Tumor response

96. Tumor response: Choi’s criteria 10% 15%

97. 5 HU 57 HU 39 HU 13 HU 61 HU 15 HU 83 HU 36 HU 57 HU 9 HU 52 HU 3 HU - 2 HU - 18 HU -34 HU 9 HU 5 HU -9 HU -13 HU 3 HU 20 HU 10 HU

98. PET scan

99. 0 +3-4 wks +12 mos +18 mos

100. 50 mg/day, 4 weeks on, 2 weeks off SUNITINIB

101. Van den Abbeele AD et al, ECCO Ann meet 2005

102. Sunitinib: interval progression

103. Imatinib: interval progression

104. t

106. from: ASCO 2009 Virtual Meeting Duffaud F et al, ASCO Ann meet 2009; #10508

107. Duffaud F et al, ASCO Ann meet 2009; #10508 from: ASCO 2009 Virtual Meeting

108. Time to secondary resistance…

110. Secondary resistance

111. Sunitinib VEGFR-2 VEGFR-1 VEGFR-3 PDGFR-  KIT FLT-3 PDGFR-  RET N H O N H F H 3 C CH 3 N H O N CH 3 CH 3

113. Negri T al, J Natl Cancer Inst 2009;101:194

114. Secondary resistance: molecular heterogeneity Liegl B, J Pathol, 2008;216:64

115. KIT PDGRA VEGFR …… ..

116. KIT PDGRA VEGFR …… ..

117. KIT PDGRA VEGFR PI3K AKT mTOR …… ..

118. KIT PDGRA VEGFR Hsp90 …… ..

119. GIST: rechallenge with Imatinib 0 +1 mos

120. Surgery of responding residual disease 

121. n = 27 n = 8 Gronchi A, Ann Surg 2007; 245:341

122. Raut CP, J Clin Oncol 2006;24:2325

124. DeMatteo R et al, Lancet 2009

125. OS RFS

126. R OS relapse RFS OS Imatinib Imatinib

127. R R relapse R relapse Imatinib Imatinib Imatinib

128. R R relapse R relapse Imatinib Imatinib Imatinib

129. R R relapse R relapse Imatinib Imatinib Imatinib

130. R R relapse R relapse Imatinib Imatinib Imatinib

131. Paolo G. Casali Study Chair & ISG Coordinator Jean-Yves Blay EORTC Coordinator Axel Le Cesne FSG Coordinator Andres Poveda GEIS Coordinator John Zalcberg AGITG Coordinator Martine van Glabbeke Study Statistician Sandrine Marraud Coordinating Physician Anne Kirkpatrick Study Data Manager Intermediate and high risk localized , completely resected, gastrointestinal stromal tumors ( GIST ) expressing KIT receptor: a controlled randomized trial on adjuvant Imatinib mesylate (Glivec ™ ) versus no further therapy after complete surgery

132. R Imatinib x 2 yrs control

133. German/Scandinavian trial R Imatinib x 3 yrs Imatinib x 1 yr

134. Risk stratification Miettinen M. Semin Diagn Pathol 2006; 23: 70 cm M/50HPF gastric jejunal/ ileal duodenal rectal 1 < 2 < 5 0 none 0 none 0 none 0 none 2 >2 < 5 < 5 1.9% very low 4.3% low 8.3% low 8.5% low 3a >5 < 10 < 5 3.6% low 24% moderate 3b >10 < 5 12% moderate 52% high 34% high 57% high 4 < 2 >5 0 50% 54% high 5 >2 < 5 >5 16% moderate 73% high 50% high 52% high 6a >5 < 10 >5 55% high 85% high 6b >10 >5 86% high 90% high 86% high 71% high

135. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)

136. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)

137. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)

138. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)

139. Osteosarcoma

140. Osteosarcoma

142. N Engl J Med 1986;314:1600

143. Cancer 1979; 43: 2163-2177

144. Cancer 1979; 43: 2163-2177

145. Goorin AM et al. J Clin Oncol 2003; 21: 1574

146. Goorin AM et al. J Clin Oncol 2003; 21: 1574

147. J Clin Oncol 1994;12:2699

149. J Clin Oncol 1988;6:329

150. J Natl Cancer Inst 2007;99:112

153. + IFX + IFX + MTP + MTP + IFX + MTP P<0.05 + IFX + MTP

154. Ewing’s sarcoma

155. Ewing’s sarcoma

157. Cancer 1974;33:384

158. J Clin Oncol 1990;8:1664

159. N Engl J Med 2003;348:694

161. J Clin Oncol 1993;11:1763

162. Ann Oncol 2010; Nov 8 Epub

163. Lancet Oncol 2010;11:129

166. [email_address]