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Addressing Tumor Molecular Heterogeneity using A Novel Clinical Trial Design - PANGEA Daniel Catenacci, MD Assistant Professor of Medicine Associate Director GI Oncology Program May 12, 2017 Addressing Molecular Heterogeneity Gastroesophageal

  1. Addressing Tumor Molecular Heterogeneity using A Novel Clinical Trial Design - PANGEA Daniel Catenacci, MD Assistant Professor of Medicine Associate Director GI Oncology Program May 12, 2017

  2. Addressing Molecular Heterogeneity Gastroesophageal Cancer “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  3. Addressing Molecular Heterogeneity Gastroesophageal Cancer “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  4. The Gastroesophageal Nomenclature Esophageal (SCC) Esophagus EGJ AC Diaphragm Type I, II, III Seiwert TYPE I Fundus TYPE II Esophagogastric Junction (EGJ) TYPE III Cardia Lesser curvature Angular notch Gastric or (incisura angularis) Body Gastric Pylorus Stomach (non-Cardia) Cancer AC Pyloric Duodenum Antrum Greater curvature Esophageal vs. Gastric Adenocarcinoma 7 th edition 2010 AJCC/UICC Staging Sehdev A, Catenacci D. Discov Med 2013

  5. Gastroesophageal Adenocarcinoma Epidemiology US 2010 Gastric Cancer Esophageal Cancer • 26,370 new cases/year (70% EGJ Adenocarcinoma) • 10,730 deaths/year • 16,940 new cases/year • EGJ 400% increase in the last decades • 15,690 deaths/year Kris et al . J Clin Oncol. Dec, 2010; www.cancer.org. • Worldwide Gastroesophageal Cancer 2012: – >1,000,000 deaths/year – 3 rd cancer incidence – 2 nd cancer death Ferlay et al . Int J Can. 2014; www.cancer.org

  6. First Line Management of Advanced Gastroesophageal Cancer BSC 1 FAMTX 2 SP 3 FP 4 IF 5 EOF 6 DCF 4 ECF 6 ECX 6 EOX 6 XP 7 FOLFIRI 8 FOLFOX 9 mOS Months 0 2 4 6 8 10 12 1. Murad, et al. Cancer 1993 6. Cunningham, et al. NEJM 2008 2. Vanhoefer, et al. JCO 2000 7. Kang, et al. Ann Oncol 2009 BSC = best support ive care; MTX = met hot rexat e; S = S -1; A = doxorubicin 3. Aj ani, et al. AS CO 2009 8. Guimbaud, et al. JCO 2014 4. Van Cut sem, et al. JCO 2006 9. S hah, et al. JAMA ONC 2016 F = 5-FU; C/P = cisplat in; I = irinot ecan; 5. Dank, et al. Ann Oncol 2008 E = epirubicin; O = oxaliplat in; D = docet axel FOLFOX  FOLFIRI  FOLTAX

  7. BSC 1 FAMTX 2 SP 3 FP 4 IF 5 EOF 6 DCF 4 ECF 6 ECX 6 EOX 6 XP 7 FOLFIRI 8 FOLFOX 9 +T HER2 (+) X/FP+/-T 10 +T X/FP+/-T 10 HER2 IHC3+ or IHC2+/FISH+ +T X/FP+/-T 10 HER2 IHC3+/FISH+ mOS Months 0 2 4 6 8 10 12 16 14 18 1. Murad, et al. Cancer 1993 2. Vanhoefer, et al. JCO 2000 3. Ajani, et al. ASCO 2009 4. Van Cutsem, et al. JCO 2006 5. Dank, et al. Ann Oncol 2008 6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 2009 8. Guimbaud, et al. JCO 2014 9. Shah et al. JCO Abstr 4012 ASCO 2015. 10. Bang et al. Lancet 2010.

  8. Molecular Phenotyping- Solid Tumors “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  9. Addressing Molecular Heterogeneity “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  10. How Gene Alterations Can Cause Cancer DNA  Transcription  RNA  Translation  protein ALTERED ALTERED ALTERED GENES PATHWAYS PROTEINS RAS CDKN2a PTEN Code Resulting RAS RAF for in RAF MAPK mTOR AKT MAPK CANCER 11

  11. Addressing Molecular Heterogeneity “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  12. Inter-Patient Tumor Heterogeneity Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  13. Mutation Profile: Targeted Multiplex Inter-patient Heterogeneity 1. TP53 mt, ARID1A mt 2. TP53 mt, APC mt 3. MET amp+, TP53 mt, NOTCH1 mt 4. FGFR2 amp+, TP53 mt, E-cadherin mt 5. KRAS amp+, TP53 mt, CDKN2A/B mt 6. PI3KCA mt, PTCH1 mt, MLH1 mt, MSH1 mt 7. HER2 amp+, SRC amp+, TOP1 amp+ 8. HER2 amp+, KRAS amp+, AKT amp+, CCNE1 amp+, CCND1 amp+, MCL1 amp+ 9. TP53 mt, PIK3CA mt, CTNNB1 mt, SMAD4 mt 10. IGF1R amp+ 11. CEBPA mt 12. MET amp+ 13. HER2 amp+, PIK3CAmt, PTEN mt, CDK6 amp, TP53 mt 14. MDM2 amp+ 15. CDH1 mt 16. Src amp+, AURKA amp+, CCND1 amp+, CDK4 amp+, RICTOR amp+, CDKN2A/B loss, ATM mt

  14. Mutation Profile: Targeted Multiplex Inter-patient Heterogeneity 1. TP53 mt, ARID1A mt 2. TP53 mt, APC mt 3. MET amp+, TP53 mt, NOTCH1 mt 4. FGFR2 amp+, TP53 mt, E-cadherin mt 5. KRAS amp+, TP53 mt, CDKN2A/B mt 6. PI3KCA mt, PTCH1 mt, MLH1 mt, MSH1 mt 7. HER2 amp+, SRC amp+, TOP1 amp+ 8. HER2 amp+, KRAS amp+, AKT amp+, CCNE1 amp+, CCND1 amp+, MCL1 amp+ 9. TP53 mt, PIK3CA mt, CTNNB1 mt, SMAD4 mt 10. IGF1R amp+ 11. EGFR amp+, CEBPA mt 12. MET amp+ 13. HER2 amp+, PIK3CAmt, PTEN mt, CDK6 amp, TP53 mt 14. MDM2 amp+ 15. CDH1 mt 16. Src amp+, AURKA amp+, CCND1 amp+, CDK4 amp+, RICTOR amp+, CDKN2A/B loss, ATM mt

  15. Addressing Molecular Heterogeneity “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  16. Baseline Spatial Heterogeneity Revealed by Multi-site NGS Sequencing Pectasides…Catenacci. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. 2017 in review

  17. Temporal Heterogeneity: Tumors Evolve Over Time to Develop Treatment Resistance Response Progression Sensitive Resistant Clone Clones Misale et al. Cancer Discovery (2014)

  18. Addressing Molecular Heterogeneity “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  19. Tumor Heterogeneity: Inter-patient!! How to characterize economically? Stricker, Catenacci, Seiwert. Semin Oncol 2011

  20. Addressing Molecular Heterogeneity “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  21. Classic Biomarker-Driven Clinical Trial Designs “Retrospective - prospective” “Biomarker-stratified” “Biomarker population enriched” Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  22. Predictive Prognostic Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  23. “Biomarker-stratified” Predictive Prognostic Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  24. “Biomarker population enriched” Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  25. “Biomarker population enriched” eg. ‘TOGA’ trial HER2 amp+ Screened 4000 patients To get 584 (~20% positive rate) (and this had ~130 HER2- pts) Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  26. “Biomarker population enriched” eg. ‘Phase I expansions’  PIK3CA mt Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  27. Addressing Molecular Heterogeneity “Molecular Drivers” “Oncogene Addiction” Next-Generation Inter-patient Heterogeneity Companion Diagnostics & Intra-patient Heterogeneity Next-Generation Trials ‘Classic’ Companion Diagnostics ‘Classic’ Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

  28. How do we molecularly profile? Now…NGS (DNA/RNA), MS Stricker, Catenacci, Seiwert. Semin Oncol 2011

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