Medical Therapy of Colorectal Cancer in the Biomarker Era

Medical Therapy of Colorectal Cancer in the Biomarker Era Axel Grothey Professor of Oncology Mayo Clinic College of Medicine Rochester, Minnesota Disclosures Consulting activities (honoraria went to the Mayo Foundation) Amgen Bayer Pfizer Roche/Genentech BMS Imclone/Eli Lilly Eisai/Morphotek I WILL include discussion of investigational or off-label use of a product in my presentation. Learning Objectives Describe the key practice changes for management of stage III and IV colorectal cancer (CRC) and critical targeted therapy additions to the treatment armamentarium for metastatic CRC Become familiar with the unique side effect profiles of the targeted agents used to treat metastatic colorectal cancer and best management strategies advanced practitioners can implement to support patients on therapy Identify means to improve collaboration among oncologists and advanced practitioners in oncology 1

Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 Best supportive care (BSC) 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Panitumumab median overall survival Treatment Paradigms for mcrc Some patients with stage IV disease can be cured by an interdisciplinary approach In the palliative setting: FOLFOX = XELOX = FOLFIRI (XELIRI has problems with toxicity) The addition of biologics to chemotherapy has improved outcomes, but not as much as we had hoped We are on the verge of individualized therapy based on molecular predictive factors A high number of agents is currently available for the treatment of mcrc 5-FU Capecitabine Irinotecan Oxaliplatin Cetuximab Regorafenib Aflibercept Panitumumab 2

ESMO Guidelines 2012 Schmoll. Ann Oncol 2012 Until 2012, Biologic Agents in Colorectal Cancer = Monoclonal Antibodies Fab Fc Murine Ab momab (17-1A) Chimeric Mouse-Human Ab ximab Cetuximab Humanized Ab zumab EGFR VEGF Human Ab mumab Panitumumab Nomenclature of Monoclonal Antibodies -mab monoclonal antibody -mo-mab mouse mab -xi-mab chimeric mab -zu-mab humanized mab -mu-mab human mab -tu-xx-mab tumor-directed xx mab -li-xx-mab immune-directed xx mab -ci-xx-mab cardiovascular-directed xx mab -vi-xx-mab virus-directed xx mab Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab 3

PlGF VEGF-B VEGF-A Y Ramucirumab Y VEGF-C, VEGF-D Aflibercept (VEGF Trap) Functions VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangiogenesis Conclusion Anti-VEGF Therapy Duration of VEGF-inhibition matters Treatment to progression Maintenance strategies Treatment beyond progression Clinical synergism between FP + bevacizumab Positive distinguishing factors for aflibercept vs BEV in 2 nd line Tx not clear Head-to-head comparison? BEV combinable with FOLFOXIRI (TRIBE) No predictive biomarker identified! Ligand mabs Target Tumor Cell-Bound EGFR EGF-R Extracellular PTEN PI3K Akt Ras Raf MEK Intracellular MAPK Cell survival Proliferation DNA Angiogenesis Cell Motility Metastasis 4

Ligand mabs Target Tumor Cell-Bound EGFR EGF-R Extracellular PTEN PI3K Akt Ras Raf MEK Intracellular MAPK Cell survival Proliferation DNA Angiogenesis Cell Motility Metastasis NCIC CTG CO.17: Randomized Phase III Trial in mcrc Cetuximab vs. BSC (no crossover) KRAS mut KRAS wild-type All patients BSC n=83 Cetux n=81 BSC n=113 Cetux n=117 BSC n=285 Cetux n=287 RR 0% 1.2% 0% 12.8% 0% 6.6% PFS (mo) OS (mo) Karapetis et al. NEJM 2008 1.8 1.8 1.9 3.8 1.8 1.9 <0.0001 <0.0001 4.6 4.5 4.8 9.5 4.6 6.1 <0.0001 0.0046 CRYSTAL Study (1st Line) FOLFIRI + Cetuximab N = 599 EGFR-expressing metastatic CRC R PFS Stratified by: Regions ECOG PS FOLFIRI N = 599 Primary Endpoint: PFS (independent review) Secondary Endpoints: RR, DCR, OS, Safety, QoL Sample Size: 1217 patients randomized, ITT: 1198 pts Van Cutsem et al. NEJM 2009 5

PFS estimate 5-FU/LV/IRI (FOLFIRI) ± Cetuximab: PFS Non-KRAS Adjusted 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Van Cutsem et al, 2009 FOLFIRI + Cetuximab FOLFIRI Subgroup effect No benefit HR = 0.851 P = 0.0479 8.0 vs 8.9 mo 0 2 4 6 8 10 12 14 16 18 20 PFS (mo) Number of patients FOLFIRI +/- Cetuximab PFS in Patients With KRAS wt Tumors Probability of PFS FOLFIRI 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 FOLFIRI FOLFIRI + cetuximab FOLFIRI (n=350) FOLFIRI + cetuximab (n=316) No of events 189 146 Median PFS 8.4 months 9.9 months [95% CI] [7.4 9.2] [9.0 11.3] HR [95% Cl] p-value 0.696 [0.558 0.867] 0.0012 0 4 8 12 16 20 Time (months) 350 237 111 22 4 0 FOLFIRI + cetuximab 316 227 128 40 8 1 van Cutsem et al., JCO 2011 Proportion Event-Free 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status Final Analysis WT KRAS MT KRAS 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Months Proportion Event-Free 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Months Panitumumab + FOLFOX4 Median (mo) (95% CI) 10.0 (9.3 11.4) FOLFOX4 8.6 (7.5 9.5) HR = 0.80 (95% CI: 0.67 0.95) Log-rank p-value = 0.01 Panitumumab + FOLFOX4 Median (mo) (95% CI) 7.4 (6.9 8.1) FOLFOX4 9.2 (8.1 9.9) HR = 1.27 (95% CI: 1.04 1.55) Log-rank p-value = 0.02 Douillard et al., JCO 2011 6

Mutations Beyond KRAS Codon 12/13 KRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 40% 61 117 146 4% 6% NRAS EXON 1 EXON 2 EXON 3 EXON 4 BRAF NT = not tested EXON 11 12 13 3% EXON 15 600 NT 8% 59 61 117 146 4% NT 17% additional mutations in KRAS and NRAS! Douillard et al., NEJM 2013 Hazard Ratios for RAS Subgroups Potential detriment Douillard et al., NEJM 2013 FIRE-3 Phase III Study Design mcrc 1st-line therapy KRAS wild-type N= 592 Randomize 1:1 FOLFIRI + Cetuximab Cetuximab: 400 mg/m2 i.v. 120 min initial dose i m 00 a b : 4 m g / m i. v. 120 m i n i n i t i a l d o s e 2250 m mg/m g / m 2 2 i.v. i. v. 60 60 min m in q 1w 1 w q FOLFIRI + : 5 mg/kg i.v. 30-90min q 2w FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400 mg/ m 2 irinotecan: 180 mg/m 2 5-FU: 2,400 mg/m2 (i.v. 46h) Primary objective: Overall response rate (ORR) (inv assessed) Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%) 284 evaluable patients per arm needed to achieve 80% power for a one-sided Fisher's exact test at an alpha level of 2.5% Heinemann et al., ASCO 2013 7

FIRE-3 ORR Primary Endpoint FOLFIRI + Cetuximab FOLFIRI + ORR % 95% CI % 95% CI ITT population 62.0 56.2 67.5 58.0 52.1 53.7 (N = 592) Odds ratio 1.18 0.85-1.64 p 0.183 Assessable for response (N = 526) 72.2 66.2 77.6 63.1 57.1 68.9 1.52 1.05-2.19 0.017 p = Fisher's exact test (one-sided) Heinemann et al., ASCO 2013 Probability of survival 1.0 0.75 0.50 0.25 FIRE-3 PFS Events n/n (%) FOLFIRI + Cetuximab 250/297 (84.2%) FOLFIRI + 242/295 (82.0%) Median (months) 10.0 95% CI 8.8 10.8 10.3 9.8 11.3 HR 1.06 (95% CI 0.88 1.26) Log-rank p= 0.547 0.0 12 24 36 48 60 72 Months since start of treatment Number 297 100 19 10 5 3 s at risk 295 99 15 6 4 Heinemann et al., ASCO 2013 FIRE-3 Overall Survival Probability of survival 1.0 0.75 0.50 PFS FOLFIRI + Cetuximab FOLFIRI + Events n/n (%) 158/297 (53.2%) 185/295 (62.7%) Median (months) 28.7 95% CI 24.0 36.6 25.0 22.7 27.6 HR 0.77 (95% CI: 0.62 0.96) Log-rank p = 0.017 0.25 0.0 Number 297 218 s at risk 295 214 Split of curves 12 24 36 48 60 72 Months since start of treatment 111 111 60 47 29 18 9 2 Heinemann et al., ASCO 2013 8

FIRE-3 Overall Survival Probability of survival 1.0 0.75 0.50 FOLFIRI + Cetuximab FOLFIRI + Who are these pts? Analysis of RAS, PIK3CA, BRAF, PTEN, EGFR ligands 0.25 0.0 12 24 36 48 60 72 Months since start of treatment Number 297 218 111 60 29 9 s at risk 295 214 111 47 18 2 Heinemann et al., ASCO 2013 FIRE-3 Update: Tested Mutations KRAS wt exon 2 subset KRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 wt 61 146 4.3% 4.9% NRAS EXON 2 EXON 3 EXON 4 BRAF EXON 11 12 13 3.8% 2% EXON 15 600 0% 10% 59 61 117 146 0% 15% additional RAS mutations! % 70 60 50 40 30 20 Summary of Results 14 RR months 12 10 8 6 4 PFS * 10 2 0 KRAS ex2 wt RAS wt RAS mut BRAF mut 0 KRAS ex2 wt RAS wt RAS mut BRAF mut OS months 35 30 25 20 15 10 * * FOLFIRI + Cetuximab FOLFIRI + BEV * significant 5 0 KRAS ex2 wt RAS wt RAS mut BRAF mut Heinemann et al., ECC 2013 9

Probability of survival FIRE-3 ESMO/ECCO Update Overall Survival All-RAS* wild type 1.0 0.75 0.50 0.25 Events n/n (%) FOLFIRI + Cetuximab 91/171 (53.2%) FOLFIRI + 110/171 (64.3%) Median (months) 95% CI 33.1 24.5 39.4 25.6 22.7 28.6 HR 0.70 (95% CI: 0.53 0.92) p (log-rank)= 0.011 Median Δ = 7.5 months 0.0 No. at 171 risk 171 12 24 36 48 60 72 months since start of treatment 128 71 39 20 6 127 68 26 9 1 Heinemann et al., ECC 2013 RAS* wild-type: KRAS 61/146; NRAS Exon2, NRAS Exon3 Conclusions EGFR mabs Cetuximab and panitumumab are interchangeable (see ASPECT trial results ECC 2013) Further molecular refinement of patient population beyond KRAS codon 12/13 essential To avoid detrimental effect of therapy To enrich patient population with better benefit/sideeffect margin More data on H2H cetuximab vs BEV will come from 80405 (RAS wt analysis!) At this point chemo + bevacizumab still viable option as first-line therapy in KRAS wt mcrc Don t use EGFR mabs in micrometastatic setting as long as we do not understand what is going on Optimized Treatment Strategy 67-year-old female Unresectable Lung and Liver Metastases Molecular testing Any RAS mut (60%) All RAS wt (40%) + CT doublet + CT doublet Regorafenib PD1 PD2 PD3 + CT doublet + CT doublet EGFR inhibitor +/- irinotecan EGFR inhibitor + CT doublet + CT doublet Regorafenib BSC PD4 Regorafenib BSC BSC 10

Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 2010 2015 OS (months) BSC 35 30 25 20 15 10 5 5-FU median overall survival Irinotecan Capecitabine Oxaliplatin Cetuximab Panitumumab Aflibercept Regorafenib BBP 0 1980 1985 1990 1995 2000 2005 2010 2015 Mayo Clinic NP/PA and Consultants Old model NP/PAs have own calendars Supervised by consultants Patient has primary MD provider, but NP/PAs order chemotherapy, write scripts, and bill 1 st chemotherapy or change in therapy has to be cosigned by MD All study patient orders and forms have to be co-signed by MD New model NP/PAs share calendars with MDs Focus on team, not individual providers 11

A Collaborative Practice Approach to Managing Patients With Metastatic Colorectal Cancer: Update on Molecular Biomarkers to Guide Treatment Decisions Jackie Weatherly PA-C MD Anderson Cancer Center Colorectal Cancer Third most common newly diagnosed cancer Third most common cause of cancer death among US men and women Decreased incidence and death rates attributed to prevention and early detection through screening 96% are adenocarcinomas, majority arise from an adenomatous polyp Courtesy of the American Cancer Society Screening Flexible sigmoidoscopy every 5 years Colonoscopy every 10 years Fecal occult blood test annually 1

Risk Factors Heredity History of inflammatory bowel disease Obesity Smoking Diet Alcohol consumption Signs and Symptoms Rectal bleeding Change in stool/bowel habits Weight loss Abdominal pain Anemia Staging T1: Tumor invades submucosa T2: Tumor invades muscularis propria T3: Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or pericolorectal tissues T4a: Tumor penetrates to the surface of the visceral peritoneum T4b: Tumor directly invades or is adherent to the other organs or structures N1a: Metastasis in 1 regional LN N1b: Metastasis in 2-3 regional LNs N1c: Tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional node mets N2a: Metastasis in 4-6 regional LNs N2b: Metastasis in 7 or more regional LNs M0: No distant mets M1a: Metastasis confined to one organ or site M1b: Metastasis in more than one organ/site or the peritoneum T1 T2 T3 T4a T4b N0 I I IIA IIB IIC N1 IIIA IIIA IIIB IIIB IIIC N2a IIIA IIIB IIIB IIIC IIIC N2b IIIB IIIB IIIC IIIC IIIC M1a IVA IVA IVA IVA IVA M1b IVB IVB IVB IVB IVB 2

FDA-Approved Systemic Agents, US 2013 1990 1995 2000 2005 2010 2015 2020 2025 5-Fluorouracil Irinotecan Capecitabine Oxaliplatin Adapted from Kelly, H. (2005). J Clin Oncol, 23, 4553-4560. Cetuximab Panitumumab Regorafenib Aflibercept NCCN Guidelines: Advanced/MCRC 2014 Cetuximab and panitumumab are only recommended for patients with tumors that express the wild-type KRAS gene First Line Second Line Third Line FOLFOX + BEV or CapeOx + BEV FOLFIRI + FOLFOX ± panitumumab FOLFIRI + Cetuximab or Panitumumab 5-FU/LV + BEV FOLFIRI or Irinotecan + or Aflibercept FOLFIRI + Cetuximab or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept Irinotecan or FOLFIRI + or Aflibercept Irinotecan + or Aflibercept + Irinotecan clinical trial or BSC + Irinotecan FOLFOX or CapeOx or Cetuximab + Irinotecan Fourth Line Poor tolerance to intensive therapy Capecitabine ± BEV or 5-FU + LV ± BEV Cetuximab or Panitumumab Improvement in functional status No improvement in functional status Therapy after first progression as above Best supportive care NCCN = National Comprehensive Cancer Network; BSC = best supportive care. Adapted from NCCN. (2014). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ). Colon cancer. Version 2.2014. Case Study 48 y/o woman presented with hematochezia and change in bowel habits Colonoscopy revealed cecal mass Right hemicolectomy 2008 3

Pathology: Moderately differentiated adenocarcinoma of sigmoid polyp invading through the muscularis mucosa into the subserosal soft tissue, measuring 1.5 1 0.6 cm. Tumor cells were immunopositive for MLH1, MSH2, PMS2, and MSH6. T3N0M0, MSI-high, Kras wild type No adjuvant therapy Staging T1: Tumor invades submucosa T2: Tumor invades muscularis propria T3: Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or pericolorectal tissues T4a: Tumor penetrates to the surface of the visceral peritoneum T4b: Tumor directly invades or is adherent to the other organs or structures N1a: Metastasis in 1 regional LN N1b: Metastasis in 2-3 regional LNs N1c: Tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional node mets N2a: Metastasis in 4-6 regional LN N2b: Metastasis in 7 or more regional LN M0: No distant mets M1a: Metastasis confined to one organ or site M1b: Metastasis in more than one organ/site or the peritoneum T1 T2 T3 T4a T4b N0 I I IIA IIB IIC N1 IIIA IIIA IIIB IIIB IIIC N2a IIIA IIIB IIIB IIIC IIIC N2b IIIB IIIB IIIC IIIC IIIC M1a IVA IVA IVA IVA IVA M1b IVB IVB IVB IVB IVB Adjuvant Therapy Stage I: No adjuvant treatment Stage II q Microsatellite stable (MSS): Adjuvant therapy given based on other risk factors q MSI-H: No adjuvant therapy, associated with lower survival vs. surgery alone Stage III: 6 months adjuvant therapy 4

Overall Survival by MSI Ribic CM, et al.,(2003). New Engl J Med, 349, 247-257. Case Study Continued 2011, admission for bowel obstruction CT showed peritoneal and liver metastases What would you do now? A. FOLFOX/bevacizumab B. FOLFOX C. FOLFIRI D. FOLFIRI/bevacizumab E. Irinotecan + cetuximab or panitumumab 5

NCCN Guidelines: Advanced/MCRC 2014 Cetuximab and panitumumab are only recommended for patients with tumors that express the wild-type KRAS gene First Line Second Line Third Line FOLFOX + BEV or CapeOx + BEV FOLFIRI + FOLFOX ± panitumumab FOLFIRI + Cetuximab or Panitumumab 5-FU/LV + BEV FOLFIRI or Irinotecan + or Aflibercept FOLFIRI + Cetuximab or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept Irinotecan or FOLFIRI + or Aflibercept Irinotecan + or Aflibercept + Irinotecan clinical trial or BSC + Irinotecan FOLFOX or CapeOx or Cetuximab + Irinotecan Fourth Line Poor tolerance to intensive therapy Capecitabine ± BEV or 5-FU + LV ± BEV Cetuximab or Panitumumab Improvement in functional status No improvement in functional status Therapy after first progression as above Best supportive care NCCN = National Comprehensive Cancer Network; BSC = best supportive care. Adapted from NCCN. (2014). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ). Colon cancer. Version 2.2014. What would you do now? A. FOLFOX/bevacizumab B. FOLFOX C. FOLFIRI D. FOLFIRI/bevacizumab E. Irinotecan + cetuximab or panitumumab FOLFOX/ 17 mo 6

LV5FU2 + 6 mo Maintenance Therapy Proportion progression-free PFS 1.00 FOLFOX4 (median 9.0 mo) FOLFOX7 (median 8.7 mo) 0.75 0.50 0.25 HR = 1.06 (95% CI, 0.89-1.20) P =.47 0 0 25 50 75 100 Proportion alive OS 1.00 FOLFOX4 (median 19.3 mo) FOLFOX7 (median 21.2 mo) 0.75 0.50 0.25 HR = 0.93 (95% CI, 0.72-1.11) P =.49 0 0 25 50 75 100 125 150 175 Weeks Weeks Efficacy is similar between stop-and-go (FOLFOX7) and continuous (FOLFOX4) oxaliplatin CT regimens Tournigand, C., et al. (2006). J Clin Oncol, 24, 394-400. Side effects Nausea/vomiting Pancytopenia Oxaliplatin Infusion-related reactions Neuropathy Sensitivity to cold Extravasation/pain and skin damage at site of injection Diarrhea 7

Side effects High blood pressure Proteinuria/nephrotic syndrome Infusion reaction Thromboembolism Wound dehiscence Gastrointestinal perforation Hemorrhage Case Study Continued CT showed progression of disease Resumed FOLFOX/bevacizumab Case Study Continued FOLFOX/bevacizumab 3 mo CT showed progression of disease 8

What would you do now? A. FOLFOX/bevacizumab B. FOLFOX C. FOLFIRI D. FOLFIRI/bevacizumab E. Irinotecan/cetuximab or panitumumab NCCN Guidelines: Advanced/MCRC 2014 Cetuximab and panitumumab are only recommended for patients with tumors that express the wild-type KRAS gene First Line Second Line Third Line FOLFOX + BEV or CapeOx + BEV FOLFIRI + FOLFOX ± panitumumab FOLFIRI + Cetuximab or Panitumumab 5-FU/LV + BEV FOLFIRI or Irinotecan + or Aflibercept FOLFIRI + Cetuximab or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept Irinotecan or FOLFIRI + or Aflibercept Irinotecan + or Aflibercept + Irinotecan clinical trial or BSC + Irinotecan FOLFOX or CapeOx or Cetuximab + Irinotecan Fourth Line Poor tolerance to intensive therapy Capecitabine ± BEV or 5-FU + LV ± BEV Cetuximab or Panitumumab Improvement in functional status No improvement in functional status Therapy after first progression as above Best supportive care NCCN = National Comprehensive Cancer Network; BSC = best supportive care. Adapted from NCCN. (2014). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ). Colon cancer. Version 2.2014. What would you do now? A. FOLFOX/bevacizumab B. FOLFOX C. FOLFIRI D. FOLFIRI/bevacizumab E. Irinotecan/cetuximab or panitumumab 9

1.0 Chemotherapy (n=410) Bev + Chemotherapy (n=409) OS estimate 0.8 0.6 0.4 Unstratified a HR: 0.81 (95% CI: 0.69 0.94) p =.0062 (log-rank test) Stratified b HR: 0.83 (95% CI: 0.71 0.97) p =.0211 (log-rank test) 0.2 9.8 mo 11.2 mo 0 0 6 12 18 24 30 38 42 48 Time (months) Bennouna, J., et al. (2013). Lancet Oncol, 14, 29-37. FOLFIRI/ 4 mo Progression of disease Irinotecan Side effects Diarrhea Nausea/vomiting Pancytopenia Hair loss or thinning Fatigue 10

What would you do now? A. FOLFOX/bevacizumab B. Continue FOLFIRI/bevacizumab C. Irinotecan/cetuximab or panitumumab D. Regorafenib NCCN Guidelines: Advanced/MCRC 2014 Cetuximab and panitumumab are only recommended for patients with tumors that express the wild-type KRAS gene First Line Second Line Third Line FOLFOX + BEV or CapeOx + BEV FOLFIRI + FOLFOX ± panitumumab FOLFIRI + Cetuximab or Panitumumab 5-FU/LV + BEV FOLFIRI or Irinotecan + or Aflibercept FOLFIRI + Cetuximab or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept or Cetuximab + Irinotecan FOLFOX or CapeOx + or Aflibercept Irinotecan or FOLFIRI + or Aflibercept Irinotecan + or Aflibercept + Irinotecan clinical trial or BSC + Irinotecan FOLFOX or CapeOx or Cetuximab + Irinotecan Fourth Line Poor tolerance to intensive therapy Capecitabine ± BEV or 5-FU + LV ± BEV Cetuximab or Panitumumab Improvement in functional status No improvement in functional status Therapy after first progression as above Best supportive care NCCN = National Comprehensive Cancer Network; BSC = best supportive care. Adapted from NCCN. (2014). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ). Colon cancer. Version 2.2014. What would you do now? A. FOLFOX/bevacizumab B. Continue FOLFIRI/bevacizumab C. Irinotecan/cetuximab or panitumumab D. Regorafenib 11

Case Study Continued Therapy changed to irinotecan/panitumumab 9 months Proportion with PFS 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 Wild-type KRAS Subgroup: PFS by Treatment Events/N (%) Median (wk) Mean (wk) Pmab + BSC 115/124 (93) 12.3 19.0 BSC Alone 114/119 (96) 7.3 9.3 HR = 0.45 (95% CI: 0.34 0.59) Stratified log-rank test, p <.0001 0. 1 0. 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks Amado, R. G., et al. (2008). J Clin Oncol, 26, 1626-1634. CRYSTAL, by KRAS Van Cutsem, E., et al. (2008). Proc ASCO, Abstract 2. 12

Cetuximab and Panitumumab Side effects Infusion reaction Acneiform rash Diarrhea/constipation Low magnesium levels Sensitivity to sunlight Associated with risk for thromboembolic events Case Study Progressive disease Therapy changed to regorafenib Regorafenib Side effects Hand foot skin reaction (17%) Fatigue (10%) Hypertension (7%) Diarrhea (7%) Severe liver toxicity (0.3%) 13

Regorafenib Case Study 71 y/o woman initially diagnosed in 2003 with metastatic colon cancer to the liver s/p resection and adjuvant 5-FU Kras mutant Recurrence to the lung FOLFOX 8 cycles with PD FOLFIRI with PD Proportion with PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Mutant KRAS Subgroup: PFS by Treatment Pmab + BSC BSC Alone Events/N (%) Median (wk) Mean (wk) 76/84 (90) 7.4 9.9 95/100 (95) 7.3 10.2 HR = 0.99 (95% CI: 0.73 1.36) 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 Amado, R. G. (2008). J Clin Oncol, 26, 1626-1634. Weeks Regorafenib Phase III CORRECT trial q 760 patients randomized to regorafenib vs placebo q Limited to good performance status (ECOG 0, 1) q OS 6.4 mo with regorafenib vs. 5 mo with placebo q PFS 1.9 mo vs. 1.7 mo Used on patients who have progressed on all other standard therapy/heavily pretreated 14

Progression-Free Survival Grothey, A. (2013). Lancet, 381, 303-312. Overall Survival (Primary Endpoint) Grothey, A. (2013). Lancet, 381, 303-312. Regorafenib Jan 2013 March 2013 CEA 29 CEA 12.8 15

May 2013 Regorafenib CEA 25.1 Thank you! 16