Conflicts of Interest GI Malignancies: An Update on Current Treatment Options

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1 Conflicts of Interest GI Malignancies: An Update on Current Treatment Options Nothing to disclose Trevor McKibbin, PharmD, MS, BCOP Clinical Specialist, Hematology/Oncology Winship Cancer Institute of Emory University Learning Objectives Outline traditional and novel therapies in the treatment of colon and gastric cancers including the benefits and limitations of each regimen. Develop a treatment plan for a patient with either colon cancer or gastric cancer, using a given set of biomarkers Discuss emerging therapies for the treatment of gastric and colorectal cancers Outline Colorectal Cancer Initial chemotherapy Addition of targeted therapies Biomarkers aiding in selection of targeted therapies Treatments on the Horizon Gastric Cancer Addition of targeted therapies Biomarkers aiding in selection of targeted therapies Treatments on the Horizon Chemotherapy Backbones Initial Therapy Oxaliplatin FOLFOX CapeOX FOLFOXIRI Irinotecan FOLFIRI FOLFOXIRI Fluoropyrimidine 5 FU/LV Capecitabine KRAS/NRAS Wild Type FOLFOX + cetuximab or panitumumab FOLFIRI+ cetuximab or panitumumab KRAS/NRAS Mutation or Wild Type FOLFOX CapeOx FOLFOX+ CapeOx + FOLFIRI FOLFIRI + FOLFOXIRI +/ Colon Cancer. NCCN Guidelines Version Colon Cancer. NCCN Guidelines Version

2 Angiogenesis As a Target Bevacizumab VEGF A Ziv Aflibercept VEGF A and VEGF B VEGFR2 Regorafenib RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR alpha, PDGFR beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF 1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl Bevacizumab Key Trials Study Name n Treatment Endpoint Result AFV2017 n=813 IFL +/ NO16966 n=1401 XELOX or FOLFOX +/ AVEX n=280* Capecitabine +/ *all patients were over 70 years of age OS PFS PFS Abbreviations: OS, overall survival; PFS, progression free survival 20.3 months (IFL+ ) v 15.6 months IFL p< months (+) v 8 months (control) p= months (+) v 5.1 months (control) p<0.001 Hurwitz, et al. N Engl J Med Saltz, et al. J Clin Oncol Cunningham, et al. Lancet Oncol Bevacizumab Beyond Progression mcrc progression on 1 st line chemotherapy* and *chemotherapy included irinotecan or oxaliplatin Bennouna, et al. Lancet Oncol 2013 TML (ML18147) Trial Primary End Point = Overall Survival Bevacizumab 5 mg/kg q2week + second line chemotherapy n=409 Second line chemotherapy n=411 Overall Survival Bevacizumab Beyond Progression Bevacizumab + Chemotherapy p value chemotherapy Overall survival 11.2 months 9.8 months p=0.006 Progression free survival 5.7 months 4.1 months P=<0.001 Bennouna, et al. Lancet Oncol 2013 ziv Aflibercept VELOUR Trial Soluble fusion protein Consists of portions of the extracellular domains of human VEGFR1 and VEGFR2 fused to a human IgG1 Fc portion Binds all VEGF-A isoforms, VEGF-B, and PlGF High affinity: binds VEGF-A and PlGF more tightly Half-life ~ 17 days Prefix ziv added to avoid confusion with ocular product mcrc after failure of an oxaliplatinbased regimen N = 1200 Overall Survival (OS) Aflibercept 4 mg/kg IV + FOLFIRI (n = 611) Placebo + FOLFIRI (n = 605) Note: 30% had prior Van Cutsem E, et al. Ann Oncol; 2011;22(suppl 5). V18. Van Cutsem E, et al, J Clin Oncol 2012:30;

3 Van Cutsem E, et al, J Clin Oncol 2012 Aflibercept: Overall Survival Van Cutsem E, et al. al, Ann J ClinOncol; 2011;22(suppl 2012:30; ). V18. Aflibercept Safety Aflibercept + FOLFIRI n=611 Placebo + FOLFIRI n=605 All Grades Grades 3+ All Grades Grades 3+ Diarrhea Neutropenia Asthenia Stomatitis Thrombocytopenia Infection Weight loss PPE Hyperpigmentation Dehydration Abbreviation: PPE, palmar plantar erythrodysesthesia Fully Human IgG 1 monoclonal antibody to VEGFR2 Fully human monoclonal antibody targeting vascular endothelial growth factor (VEGF) 2 Indications Single agent or with paclitaxel for gastric and gastroesophageal adenocarcinoma after platinum and fluoropyrimidine 8 mg/kg q2weeks Non small cell lung cancer in combination with docetaxel after progression on platinum containing regimen 10 mg/kg q3weeks Colorectal cancer with FOLFIRI after progression on 5 FU, oxaliplatin and Beyond Progression with Bevacizumab RAISE Trial RAISE Results mcrc progression on 1 st line chemotherapy* and *chemotherapy included 5FU and oxaliplatin 8 mg/kg +FOLFIRI n=536 FOLFIRI n=536 Primary End Point = Overall Survival Tabernero, et al. Lancet Oncol 2015 Tabernero, et al. Lancet Oncol

4 Safety + FOLFIRI n=529 Placebo + FOLFIRI n=528 Grades 1 2 Grades 3+ Grades 1 2 Grades 3+ Diarrhea Fatigue Nausea Stomatitis Neutropenia Thrombocytopenia Epistaxis Hypertension PPE <1 GI Hemorrhage Tabernero, et al. Lancet Oncol 2015 Regorafenib CORRECT Trial Pretreated advanced mcrc N = 760 Overall Survival (OS) Grothey A, et al. Lancet 2013 Regorafenib 160 mg PO daily (3 weeks on, 1 week off) & Best Supportive Care (n = 505) Note: No Crossover Placebo & Best Supportive Care (n = 255) Overall Survival Regorafenib Responses Response, % Regorafenib n=505 Placebo n=255 Complete 0 0 Partial Stable Disease Progressive Disease Overall survival (months) Regorafenib Placebo p value Grothey A, et al. Lancet 2013 Grothey A, et al. Lancet 2013 Regorafenib Safety ( 10% Patients) Adverse event, % Regorafenib n=500 Placebo n=253 FOLFOXIRI + Bevacizumab All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 PPE <1 8 <1 0 Diarrhea 34 7 < Anorexia Voice changes 29 < Hypertension Mucositis Rash Thrombocytopenia 13 3 < Grothey, Proteinuria GI Symposium , J 1Clin Oncol 030, 2012 (suppl 2 4; abstr <1LBA385) 0 Untreated advanced/ mcrc N = 508 Progression free survival FOLFOXIRI + 12 cycles max (n=250) FOLFIRI + 12 cycles max (n=254) Note: all patients received 5FU/leucovorin+ Maintenance if stable disease or better after 12 cycles Grothey A, et al. Lancet 2013;381: Loupakis, et al. N Engl J Med

5 Treatments FOLFOXIRI+ Bevacizumab FOLFIRI + Bevacizumab Bevacizumab 5 mg/kg Irinotecan 180 mg/m 2 Leucovorin 200 mg/m 2 5FU bolus 400mg/m 2 5FU infusion 2400 mg/m 2 over 46 hours FOLFOXIRI + Bevacizumab Bevacizumab 5 mg/kg Irinotecan 165 mg/m 2 Oxaliplatin 85 mg/m 2 Leucovorin 200 mg/m 2 5FU infusion 3000 mg/m 2 over 48 hours Loupakis, et al. N Engl J Med Loupakis, et al. N Engl J Med Progression Free Survival Overall Survival Response Rate FOFLOXIRI+ B months* 31 months 63%* FOLFIRI + B 9.7 months 25.8 months 53% Abbreviation: B=, *=p<0.05 FOLFOXIRI + Bevacizumab Safety Grade 3 and 4 events, % FOLFIRI+ FOLFOXIRI + P value Neutropenia <0.001 Febrile Neutropenia Diarrhea Stomatitis Vomiting Peripheral 0 5 <0.001 neuropathy Hypertension Asthenia Epidermal Growth Factor Receptor Cetuximab & Panitumumab Loupakis, et al. N Engl J Med Dasari, et al. Clin Cancer Res Stintzing S et al. Hematol Oncol Clin N Am 2015 RAS Mutation KRAS Mutation and Progression Free Survival KRAS wild type KRAS mutant Intervention Control EGFR MoAb Control EGFR MoAb NCIC CO 17 BSC vs cetuximab EPIC Irinotecan vs irinotecan + cetuximab CRYSTAL FOLFIRI vs FOLFIRI + cetuximab OPUS FOLFOX vs FOFLOX + cetuximab PRIME FOLFOX vs FOLFOX panitumumab 181 study FOLFIRI vs FOLFIRI + panitumumab Karapetis CS, et al. N Engl J Med

6 Cetuximab + FOLFIRI in KRAS Exon 2 Wild Type (FIRE 3) FIRE 3 Results Untreated advanced/ mcrc N = 508 Objective response FOLFIRI + Cetuximab (n=297) FOLFIRI + (n=295) Intention to treat, n Objective Response, % RAS wild type, n Objective Response, % RAS mutant*, n Objective Response,% FOLFIRI + cetuximab FOLFIRI + P value nr nr nr=not reported *KRAS exon 2 wild type; other RAS mutation in KRAS exon 3 or 4 or NRAS exon 2, 3, or 4. Heinemann et al. Lancet Oncol Clin 2014 Heinemann et al. Lancet Oncol 2014 FIRE 3 Safety FOLFIRI+ Cetuximab FOLFIRI+Bevacizumab Events, % Grades 1 2 Grades 3+ Grades 1 2 Grades 3+ Diarrhea Skin reaction Stomatitis PPE <1 Thromboembolic event Infusion reaction 4 4 <1 0 Hematologic toxicity Gastric and Gastroesophageal Adenocarcinomas Second leading cause of cancer related deaths worldwide Poor prognosis Metastatic overall survival < 12 months Targeted Therapy VEGF HER2 Heinemann et al. Lancet Oncol 2014 Jemal, et al. CA Cancer J Clin 2014 ToGA TRIAL ToGA Trastuzmab Efficacy Untreated metastatic gastric or gastroesophageal adenocarcinoma Overall Survival Capecitabine or 5FU + cisplatin + trastuzumab (n=294) Capecitabine or 5FU + cisplatin (n=290) Bang, et al. Lancet 2010 Bang, et al. Lancet

7 ToGA Trastuzumab Safety Chemotherapy + Chemotherapy Trastuzumab Events, % Grades 1 2 Grades 3+ Grades 1 2 Grades 3+ Diarrhea Stomatitis Neutropenia Chills 8 <1 0 0 Pyrexia PPE LVEF decrease >10% 5 1 Multiple indications for gastric cancer Single agent (REGARD) With paclitaxel (RAINBOW) Bang, et al. Lancet 2010 REGARD Trial REGARD Efficacy Previously treated metastatic gastric or gastroesophageal adenocarcinoma Overall Survival 8 mg/kg q2wks (n=238) Placebo (n=117) Overall survival, months Progression free survival, months (n=238) Placebo (n=217) P value <0.001 Response, % 3 3 nr Stable disease,% nr Disease control rate, % <0.001 nr=not reported Fuchs, et al. Lancet 2014 Fuchs, et al. Lancet 2014 REGARD Safety Placebo Events, % All grades Grades 3+ All grades Grades 3+ Hypertension Bleed/hemorrhage Proteinuria 3 <1 3 0 Venous thromboembolism Infusion related reaction <1 0 <1 0 + Paclitaxel Overall Survival (months) Progressionfree survival (months) Paclitaxel + (n=335) Paclitaxel (n=335) P value <0.001 Response, % Fuchs, et al. Lancet 2014 Wilke, et al. Lancet Oncol

8 + Paclitaxel Safety Conclusion Biomarker Assessment Colorectal cancer Extended RAS mutation assessment Gastric HER2 Antiangiogenesis Colorectal Cancer Bevacizumab, aflibercept, ramucirumab, regorafenib Gastric Cancer ramucirumab Fuchs, et al. Lancet In a patient with metastatic colorectal cancer (RAS) wild type, which of the following is the preferred first line regimen? 1. FOLFOXIRI + Bevacizumab 2. FOLFIRI + Bevacizumab 3. FOLFIRI + Cetuximab 4. FOLFOX + Bevacizumab 5. All the above are correct 6. Not sure 2. Which of the following anti angiogenesis therapies can be used after progression on? 1. Bevacizumab 2. Aflibercept Regorafenib 5. All of the above 6. Not sure 3. Which of the following biomarkers is used to select targeted therapy for metastatic gastric adenocarcinoma? 1. EGFR 2. KRAS 3. BRAF 4. HER2 5. Not sure QUESTIONS? 8