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New Agents in the Treatment of Esophageal and Gastric Cancers

New Agents in the Treatment of Esophageal and Gastric Cancers. Heinz-Josef Lenz, MD Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine Los Angeles, CA. Can Gastric Cancer be the next GIST? Intestinal versus Diffuse?.

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New Agents in the Treatment of Esophageal and Gastric Cancers

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  1. New Agents in the Treatment of Esophageal and Gastric Cancers Heinz-Josef Lenz, MD Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine Los Angeles, CA

  2. Can Gastric Cancer be the next GIST?Intestinal versus Diffuse?

  3. Critical Pathways • Her2 • VEGF/VEGFR • EGFR • IGFR1 • C-met • PI3K/AKT • E-Cadherin

  4. Frequent Genetic and Molecular Abnormalities In Sporadic Gastric Cancer E-cadherin In 92%, down regulation or mutation Fibroblast growth factor 70% expression, esp. undifferentiated tumors Telomerase expression 85% of advanced tumors, poor prognosis VEGF/VEGFR about 50% overexpression poor prognosis MET, c-met Over-expression in approximately 50%, a marker for poor prognosis Epidermal Growth Factor (EGF) Over-expression in over 50% of advanced cancers PI3K Mutations 35% have PI3K mutations HER2 over expression: 10-25% overexpression (FISH) intestinal type Hundahl, Macdonald, & Smalley Chapter 45: Stomach in Chang F et al (eds) Oncology: An Evidence Based Approach, New York: Springer Verlag, 2008, Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006

  5. Overall Survival among Different Ethnicities (Differences in Genetic Make up?)

  6. Targeted Therapies • Conventional, cytotoxic chemotherapy has limited benefit • Targeted agents: attempt to block specific tumor growth pathways • Monoclonal antibodies • Tyrosine kinase inhibitors • Soluble receptors/Ligands to growth factors • Inhibition of pathways involved in protein synthesis and degradation

  7. Targeted Agents in Phase II

  8. Advanced Gastric Cancer:Targeted Agents 1. Shah et al. J Clin Oncol. 2006;24:5201; 2. Di Fabio et al. ESMO, 2006. Abstract 1077PD;3. Pinto et al. Ann Oncol 2007; 4. Lordick et al. Ann Oncol 2008.

  9. Targeted Agents in Phase III(EGFR/VEGF/Her2) REAL 3: ECX + / - Panitumumab (U.K.) EXPAND: Cape-Cis + / Cetuximab AVAGAST: Cape-Cisplatin + / - Bevacizumab LOGIC: Cape-Ox + / - Lapatinib (HER2+) TOGA: HER+Cape-Cisplatin + / - Trastuzumab

  10. Angiogenesis in GC & EC • VEGF-A expressed in 51% GC specimens w/o stage correlation (Feng, 2002) but w/ OS correlation (Maeda,1996) • Serum VEGF-A correlated with OS in resected GC (Yoshikawa, 2000; Karayiannakis, 2002) • Serum VEGF-A increased in SCC EC and correlated with stage and response to CT/RT (Shimada, 2001) • VEGF-D & VEGFR-3 expression in GC correlated with poor OS (all pts & pN+) (Jüttner, 2006) • Tight correlation between VEGF and EGFR pathways in GC (Akagi, 2003)

  11. VEGFD & VEGFR-3 in GC Total (n=91) pN+ (n=63) • VEGF-D & VEGFR-3 expression was correlated with decreased survival in the total population • Combined analysis of VEGF-D & VEGFR-3 can be useful to identify patients with favourable vs unfavourable outcome (even pN+) Jüttner S, et al. JCO 2006

  12. Hypoxia EGF EGFR Thrombin Thrombin PAR-1 HIf1 ARNT PAR-4 Tumor cell HIF1 NFkb DNA 2-granules 1-granules Platelet VEGF IL-8 IL-1 β VEGFR Endostatin IL-1R CXCR NRP1 Endothelial cell Tumor associated angiogenesis

  13. Overall Survival among different IL-8 Polymorphisms Lurje et al Annals of Oncology 2009

  14. Overall Survival among different PAR-1 Polymorphisms Lurje et al Annals of Oncology 2009

  15. Overall Survival among different Endostatin Polymorphisms Lurje et al Annals of Oncology 2009

  16. EGF and PAR1 associated with Time to Tumor Recurrence in Esophageal Cancers (n=237)

  17. Anti VEGF (Bevacizumab) • Shah, et al. JCO 2007 • Phase II met gastric or GEJ adenoca • First line therapy – cisplatin/irinotecan/bev • N = 47, 34 with measurable disease • RR 65%, OS 12.3 mo • Enzinger, et al. ASCO 2008, Abstr 4552 • Phase II met esophagogastric cancer • First line therapy – docetaxel/cisplatin/irinotecan • N = 32 • RR 63% • Jhawer, et al. GI ASCO 2009, Abstr 10 • mDCF plus bevacizumab • N = 45 • RR 67%, PFS 12 mo, OS 16.2 mo • AVAGAST study accrual completed • XP +/- bevacizumab • Following toxicities carefully – thrombosis, perforation

  18. Anti-VEGFR (Sorafenib) • ASCO 2008, Abstr 4535, Sun, et al. • ECOG 5203 • Phase II study of sorafenib, docetaxel, cisplatin • 44 pts with advanced gastric or GE junctional cancers • RR 38.6%, PFS 5.8 mo, OS 14.9 mo

  19. EGF Receptor: A Rational Target for CRC Therapy Ligand: AREG, EREG EGFR-TK Target for EGFT-TK inhibitor pY GRB2 pY SOS P13K RAS RAF pY STAT MEK AKT PTEN MAPK Gene transcription Cell-cycle progression P P Cyclin D1 MYC JUN FOS Cyclin D1 MYC Proliferation/maturation Survival (anti-apoptosis) Chemotherapy/radiotherapy resistance Invasion and metastasis Angiogenesis Meyerhardt JA, Mayer RJ. N Engl J Med. 2005;352:476-487; Venook A. Oncologist. 2005;10:250-261.

  20. EGFR/HER-2 Expression in GE cancer EGFR expression correlates with OS in EC (Kitagawa, 1996) EGFR and TGF- expression correlate with OS in EC (Lihara, 1993) and GC (Yonemura, 1992) HER2 gene amplification correlates with OS in EC (adeno) (Brien, 2000)

  21. EGFr Tyrosine Kinase Inhibitors: Phase II, Adenocarcinoma Doi 1036 Proc ASCO 22, 2003; Ferry Clin Can Res 132:5869; 2007 Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005; Dragovich JCO 24: 4922; 2006

  22. EGFr Tyrosine Kinase Inhibitors: Phase II, Squamous Carcinoma Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005;

  23. EGFR/HER-2 inhibitors in GE cancerShould KRAS gene status be revisited? • No major impact of KRAS gene status in patients with • esophageal and gastric cancer

  24. Phase II CALGB 80403/ECOG 1206Completed, ASCO 2010 Metastatic Esophagogastric Cancer FOLFOX +Cetuximab ECF +Cetuximab Irinotecan +Cisplatin +Cetuximab • Primary end point: Response rate

  25. Rationale for targeting other receptors & downstream signaling proteins • Insulin-like growth factor receptor • ILGF1R expression in GC: 77%. Correlation with EGFR/HER2 expression, intestinal type and poor survival (Matsubara, 2007) • 9 EC cell lines sensitive to picropodophyllin (PPI), an IGF1R TKI (Bergqvist, 2007)

  26. CpG Island Methylator Phenotype (CIMP) Tumor A: Tumor B: Tumor C: Tumor D: Tumor E: Tumor F:

  27. HER2 Inhibitors:Trastuzumab and Lapatinib • ASCO 2008, Abstr 4526, Bang, et al. • Analysis of 2484 gastric cancer samples from the Ph III ToGA trial • 21.9% HER2 positivity • ASCO 2009, Abstr LBA 4509, ToGA Trial • Rand Ph III, HER2+ gastric cancer • 5-FU/capecitabine + cisplatin +/- trastuzumab • RR 47.3 vs. 34.5%, OS 13.5 vs. 11.1 mo (p = 0.0048) • HR 0.74 (0.60-0.91) • Practice changing!!! • LOGIC Trial • Rand Ph III, HER 2+ gastric cancer • Capecitabine + oxaliplatin +/- lapatinib

  28. Her2 gene expression associated with OS in patients with metastatic gastric cancer treated with lapatinib

  29. Il-8 associated with PFS in patients with metastatic gastric cancer treated with lapatinib

  30. ToGA trial design Phase III, randomized, open-label, international, multicenter study 5-FU or capecitabinea+ cisplatin (n=290) 3807 patients screened1 810 HER2-positive (22.1%) HER2-positiveadvanced GC (n=584) R 5-FU or capecitabinea+ cisplatin + trastuzumab (n=294) • Stratification factors • advanced vs metastatic • GC vs GEJ • measurable vs non-measurable • ECOG PS 0-1 vs 2 • capecitabine vs 5-FU aChosen at investigator’s discretion GEJ, gastroesophageal junction 1Bang et al; Abstract 4556, ASCO 2009

  31. Primary end point: OS MedianOS 13.811.1 1.0 Event Events 167182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 0.9 FC + T 0.8 FC 0.7 0.6 0.5 0.4 0.3 0.2 11.1 13.8 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 0 1 0 0 0 T, trastuzumab

  32. Secondary end point: tumor response rate Intent to treat p=0.0017 Patients (%) F+C + trastuzumab p=0.0145 F+C 47.3% 41.8% 34.5% 32.1% p=0.0599 5.4% 2.4% CR PR ORR ORR= CR + PRCR, complete response; PR, partial response

  33. Nucleotide excision repair

  34. Pre-clinical studies showing ERCC1 to be a determinant of platinum efficacy • Youn et al Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based Anticancer Agents Cancer Res 2004:64, 4849-4857.

  35. ERCC1 mRNA Levels vs Response in Gastric Cancer Patients Receiving FP 20 16 12 8 4 0 ERCC1 Expression Response No Response ERCC1: p=.004 by Kruskal-Wallis test. Metzger R, et al. J Clin Oncol. 1998;16(1):309-316.

  36. ERCC1 Thresholds and Increased Benefit from Platin Therapy (Low ERCC1)

  37. ERCC-1 gene expression associated with overall survival in 76 patients with gastric cancer treated with 5-FU/oxaliplatin Wei Jia et al Br j Cancer 2008

  38. SWOG Prospective Trial Proposed ERCC1 of FOLFOX versus CPT11/Taxotere PI: Iqbal ASSIGNMENT High ERCC1 CPT11/Taxotere RANDOM Genotypic Arm ERCC1 Selection Low ERCC1 FOLFOX n=99 Endpoints feasibility and increase of PFS Her2+ receive trastuzumab in both arms

  39. Future Directions: Tailoring of Therapy Molecular Signatures for Targeted and Cytotoxic Therapies Her2 ERCC-1 Identification of critical pathways in Gastric Cancer (IGFR, cmet, HSP90) to introduce novel therapies Identification of Predictive and Prognostic Markers Tumor, Host, Environment

  40. Sharon Carpenter Laboratory

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