SAMO Master Class Colorectal Cancer

SAMO Master Class Colorectal Cancer Roger von Moos Kantonsspital Graubünden 12.9.2014

Potential conflict of interest and other statements Thanks to Bernhard Pestalozzi to share some slides Advisory board: Amgen, Merck, Roche, Sanofi, Pfizer Unrestricted research grant: Amgen, Merck, Roche Speaker: Amgen, Roche, Bayer

Incidence 2012 447 000 new cases Second most frequent cancer Responsible for 215 000 deaths 25% of patients presents with metastases 50% will develop metastasis 5 year survival rate 60% Van Cutsem, Annals of Oncol, 2014

Epidemiologie - Männer Journal of Clinical Oncology 2007

Epidemiologie - Frauen Journal of Clinical Oncology 2007

Risk of Colorectal Cancer (CRC) General population 5% Personal history of colorectal neoplasia Inflammatory bowel disease HNPCC mutation FAP 15% 20% 15% 40% 70% 80% >95% 0 20 40 60 80 100 Lifetime risk (%)

Familial Risk for Colorectal Cancer Approximate lifetime CRC risk (%) 100 80 60 40 20 0 2% 6% 8% 10% None One 1 One 1 and two Aarnio M et al. Int J Cancer 64:430, 1995 Houlston RS et al. Br Med J 301:366, 1990 St John DJ et al. Ann Intern Med 118:785, 1993 2 17% One 1 age <45 Two 1 HNPCC Affected family members 70% HNPCC mutation

Adjuvant Therapy of Colon Cancer 1990 5-FU/lev better than surgery alone 1994 5-FU/LV better than surgery alone 1998 5-FU/LV better than 5-FU/lev 1998 6 months = 12 months 1998 Levamisole unnecessary 1998 HDLV = LDLV 1998 Weekly = monthly 2002 LV5FU2 = monthly bolus

MOSAIC: Treatment arms FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² R LV5FU2 Endpoints Primary: 3-yr Disease Free Survival (DFS) Secondary: Safety (including long-term) Overall Survival (OS)

DFS by treatment arm (ITT) Probability 1 0,9 FOLFOX4 (n=1123) 77.8% LV5FU2 (n=1123) 72.9% 3-year 0,8 0,7 0,6 Hazard ratio: 0.77 [0.65 0.92] p < 0.01 0,5 0 10 20 30 40 50 DFS (months) 23% risk reduction in the FOLFOX4 arm

Disease-Free Survival Stage III patients Probability 1 0,9 3-year FOLFOX4 (n=672) 71.8% LV5FU2 (n=675) 65.5% 0,8 0,7 0,6 0,5 Hazard ratio: 0.76 [0.62-0.92] 0.92] 0 10 20 30 40 50 DFS (months) 24% risk reduction for stage III patients in the FOLFOX4 arm

Conclusion Initial data showed DFS improvment (77.8 vs 72.9%) Follow up after 6 years no OS benefit for all patients Stage III subset 72.9 vs 68.7% stat significant (HR 0.80; 0.65-0.97) 0.97) More neutropenia and more neurotoxicity

X-ACT trial in adjuvant treatment of Dukes C colon cancer Recruitment 1998 2001 Capecitabine 1250mg/m 2 twice daily, d1 14, q21d n = 1004 Chemo-naïve Dukes C, resection 8 weeks 24 weeks Bolus 5-FU/LV 5-FU 425mg/m 2 plus LV 20mg/m 2, d1 5, q28d n = 983 1 endpoint: disease-free survival (DFS) 2 endpoints relapse-free survival (RFS) overall survival tolerability (NCIC CTG) pharmacoeconomics QoL

X-ACT powered to establish at least equivalence of capecitabine to bolus 5-FU/LV Primary endpoint DFS 80% power for at least equivalence if upper limit of 95% CI for HR <1.25, then primary endpoint met DFS = RFS + all deaths from other causes RFS: relapses/new colon cancer + all deaths due to colon cancer or treatment All analyses shown were prospectively planned

Primary endpoint met and trend to superior DFS (ITT) 1.0 3-year Capecitabine (n=1004) 64.2% 5-FU/LV (n=983) 60.6% Estimated probability 0.8 0.6 HR = 0.87 (95% CI: 0.75 1.00) p=0.0528 0.4 0 1 2 3 4 5 6 Years Confirmed by per protocol analysis, HR 0.89 (95% CI 0.76-1.04)

Trend to improved overall survival (ITT) 1.0 3-year Capecitabine (n=1004) 81.3% 5-FU/LV (n=983) 77.6% Estimated probability 0.8 0.6 HR = 0.84 (95% CI: 0.69 1.01) p=0.0706 0.4 0 1 2 3 4 5 6 Years

X-ACT study conclusions DFS at 3 years equivalent to 5FU/LV HFS and hyperbilirubinemia more often, diarhoea, nausea and vomiting, stomatitis and neutropenia significantly less In 57% of patients required dose modification Capecitabine is the standard today

Metastatic colorectal cancer

Management of MCRC: Placement comes first: Interdisciplinary tumorboard Diagnosis of MCRC Resectable (20%) Unresectable Neoadjuvant/ Preoperative Therapy Borderline/ Potentially Resectable (20%) First-Line Second-Line Surgery Palliation +/- Adjuvant Therapy NCCN, 2010.

Liver metastases from colorectal cancer Liver is the most common site of metastases from CRC - 50 to 75% of patients with advanced CRC will develop liver metastases (1) - 15 to 25% of patients have liver metastases at presentation (1, 2) - 20 to 35% of patients will have metastatic disease confined to the liver (3) Improving the outlook of advanced colorectal cancer necessitates better management of liver metastases 1 - N. Kemeny, F. Fata, J. Hepatobiliary Pancreas Surg., 1999; 6: 39-49 2 - JK. Seifert, J. R. Coll. Surg. Edinb., 1998; 43: 141-54 3 - MM. Borner, Ann. Oncol., 1999; 10, 6: 623-26

Original EPOC Trial: Phase III EORTC 40983 FOLFOX4 6 cycles (3 months) Surgery FOLFOX4 6 cycles (3 months) Surgery Primary endpoint: PFS N=364 patients Nordlinger et al: Lancet 2008; Lanc Onc 2013

EORTC 40983: Peri-Op FOLFOX for Liver Mets Overall Survival HR=0.88 (p=0.34) mos, 61m vs 54m Absolute difference: 3.4% No survival advantage to peri-operative chemo! Nordlinger, Lancet Oncology 2013;14:1208-15 Progression-Free Survival HR=0.81 (p=0.068) (p=0.035 for eligible pts) mpfs, 20m vs 12.5m Absolute difference: 8.2%

Chemotherapy Liver Toxicity: Selected Reports Karoui, Ann Surg 2006 More is not better! But some is OK! Influence of Number of Cycles of Pre-Op Chemo on Morbidity

2 History of different agents 2000 2005 2008 2009 2010 2012 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab Aflibercept Regorafenib KRAS 5-FU, fluorouracil. National Cancer Institute. Colon cancer treatment (PDQ). 2012. National Cancer Institute. Cancer drug information. 2011. Full RAS

2 Würde Zeitachse um 2012 ergänzen und Targeted therapies wegennehmen, erstens englisch zweitens müsste sonst die Klammer Aflibercept und Regorafenib auch umfassen Roger von Moos; 13.10.2013

RAS Wild type, what is the standard treatment? Selection for EGFR wild typ PRIME data (phase III disadvantage for panitumumab in KRAS mutant) Data to use EGFR antibodies or Bevacizumab in first line in wild type patients? FIRE-3 PEAK (not shown) CALGB 80405

Prevalence KRAS, NRAS,BRAF in the Prime trial RAS Analysis Subset EXON 1 EXON 2 EXON 3 EXON 4 KRAS 12 13 59 61 117 146 40% 3.8% 5.8% 90%* EXON 1 EXON 2 EXON 3 EXON 4 NRAS 12 13 59 61 117 146 3.5% 4.1% 0% 90%* EXON 1. EXON 15 EXON 16 BRAF RAS/RAF Analysis Subset 600 8.6% *Tumor sample ascertainment Rate

CRC: Clonal evolution Discordance in primary vs metastatic CRC Kopetz S et al #3509; N = 115 samples from MDACC Pestalozzi PostASCO June 12, 2014 #3509 ASCO 2014

Pestalozzi PostASCO June 12, 2014 Courtesy E. van Cutsem

Phase III study design mcrc 1st-line therapy KRAS wild-type N= 592 Randomize 1:1 FOLFIRI + Cetuximab Cetuximab: 400 mg/m 2 i.v. 120min initial dose 250 mg/m 2 i.v. 60min q 1w FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v. 30-90min q 2w Key inclusion criteria FOLFIRI: 5-FU: 400 mg/m 2 (i.v. bolus); folinic acid: 400mg/m 2 irinotecan: 180 mg/m 2 5-FU: 2,400 mg/m 2 (i.v. 46h) Patients 18 years with histologically confirmed diagnosis of mcrc ECOG PS 0-2 prior adjuvant chemotherapy allowed if completed >6 month before inclusion Amendment in October 2008 to include only KRAS wildtype patients 150 active centers in Germany and Austria

Endpoints Primary endpoint ORR (mrecist 1.0, investigators read) Secondary endpoints Progression-free survival (PFS) Overall survival (OS) Time to failure of strategy (time to failure of 1st-line therapy) (TFS) Deepness of response (percent of tumor shrinkage compared to baseline) Secondary resections of liver metastases with potentially curative intention Safety and tolerability according to NCI-CTCAE criteria analyses were performed in the ITT and assessable for response population

Progression-free survival 1.0 Events n/n (%) Median (months) 95% CI FOLFIRI + Cetuximab 250/297 (84.2%) 10.0 8.8 10.8 Probability of survival 0.75 0.50 FOLFIRI + Bevacizumab 242/295 (82.0%) 10.3 9.8 11.3 HR 1.06 (95% CI 0.88 1.26) Log-rank p= 0.547 0.25 numbers at risk 0.0 297 295 12 24 36 48 60 72 months since start of treatment 100 99 19 15 10 6 5 4 3

Overall survival 1.0 Events n/n (%) Median (months) 95% CI FOLFIRI + Cetuximab 158/297 (53.2%) 28.7 24.0 36.6 Probability of survival 0.75 0.50 FOLFIRI + Bevacizumab 185/295 (62.7%) 25.0 22.7 27.6 HR 0.77 (95% CI: 0.62 0.96) Log-rank p= 0.017 0.25 numbers at risk 0.0 297 295 12 24 36 48 60 72 months since start of treatment 218 214 111 111 60 47 29 18 9 2

CALGB/SWOG 80405: Conclusion Venook A et al LBA3, Plenary Session LBA #3 LBA #3 Pestalozzi PostASCO June 12, 2014 36

LBA #3 CALGB/SWOG 80405: Conclusion Venook A et al LBA3, Plenary Session 37

Second Line Data

ML18147 study design (Phase III) BEV + standard first-line CT (Oxaliplatin oder Irinotecan-basiert) (n=820) Standard second-line CT (oxaliplatin oder irinotecan-based) bis PD (n=411) PD Randomisierung 1:1 CT switch: Oxaliplatin Irinotecan Irinotecan Oxaliplatin Primärer Endpunkt Gesamtüberleben (OS) ab Randomisierung Sekundäre Endpunkte Progressionsfreie Überleben (PFS) Ansprechrate (ORR) Verträglichkeit Explorative Endpunkte Tumor, Plasma und DNA Biomarker BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin oder irinotecan-based) bis PD (n=409)

Gesamtüberleben und Progressionsfreies Überleben in der ITT ITT--Population PFS 1.0 1.0 0.8 0.8 0.6 HR: 0.81 (95% CI: 0.69 0.94) p=0.0062 (log-rank test) 0.4 0.2 CT (n=410) BEV + CT (n=409) 0.6 HR: 0.68 (95% CI: 0.59 0.78) p<0.0001 (log-rank test) 0.4 0.2 9.8 0 0 No. at risk CT BEV + CT PFSestimate OS estimate OS 410 409 6 293 328 11.2 12 162 188 18 51 64 4.1 0 24 30 36 Time (months) 24 29 7 13 3 4 42 2 1 48 0 0 0 410 409 5.7 6 119 189 12 20 45 18 24 30 Time (months) 6 12 4 5 0 2 36 42 0 2 0 0

3 VELOUR: Aflibercept Phase III Studie bei vortherapierten mcrc Patienten 600 pts Aflibercept 4 mg/kg IV + FOLFIRI q 2 Wochen Patienten mit mcrc nach Versagen von Oxaliplatinbasierten Regime R 1:1 PROGRESSION TOD 600 pts STRATIFIKATIONSFAKTOREN: Vorghergehende Bevacizumab Therapie(J/N) ECOG PS (0 vs 1 vs 2) FIRST PATIENT IN: November 2007 ENROLLMENT BEENDET: 1226 randomisiert, 1216 behandelt Finale Analyse be 863 OS events Placebo + FOLFIRI q 2 Wochen Primärer Endpunkt: OS Sekundäre Endpunkte: ORR, PFS, safety, PK E. Van Cutsem et al, J Clin Oncol 2012;30:3499-506

3 Uebersetzung Roger von Moos; 13.10.2013

4 VELOUR: Gesamtüberleben: ITT Population Zensiert Placebo/FOLFIRI: Median = 12.06 Monate Aflibercept/FOLFIRI: Median = 13.50 Monate 1.0 0.9 0.8 Stratifizierte HR = 0.817 [95.34% CI, 0.713 0.937] Log-rank P = 0.0032 KAPLAN KAPLAN-MEIER ESTIMATE 0.7 0.6 0.5 0.4 0.3 ZEIT (MONATEN) 0.2 NUMBER AT RISK Cut-off Datum: Februar 7, 2011 Mediane Follow-up: 22.28 Monate 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 614 612 573 566 485 498 401 416 286 311 193 216 131 148 87 104 51 75 31 49 14 33 ÜBERLEBENSWAHRSCHEINLICHKEIT 79.1% 81.9% 50.3% 56.1% 30.9% 38.5% 18.7% 28.0% 33 36 39 12.0% 22.3% E. Van Cutsem et al, J Clin Oncol 2012;30:3499-506

4 Hier müssten Farben angepasst werden und Uebersetzung Roger von Moos; 13.10.2013

CORRECT: Multicenter, Randomisiert, Doppelt Doppelt--Blind, Placebo Placebo-Kontrollierte, Phase III Studie von Regorafenib im mcrc Regorafenib + BSC Patienten mit mcrc therapiert mit allen vorhandenen Standardtherapien und progredient von 3 Monaten RA ND O MI S I E R UN G (n = 505) 160 mg 1 x tgl. 3 Wochen on, 1 Woche off 2:1 Behandlung bis zur Progression / nicht tolerierbarer Toxizität/ Arztoder Patientenentscheidung Placebo + BSC (n = 255) 3 Wochen on, 1 Woche off Stratification: Vorhergehende Anti-VEGF Therapie Zeitpunkt Diagnose metasasierten Erkrankung Geographische Region Radiologische Evaluierung alle 8 Wochen Grothey A, Van Cutsem E, et al. Lancet. 2013;381:303-312..

Gesamtüberleben Regorafenib versus Placebo OS Raten waren konstant höher mit Regorafenib vs. Placebo nach 6 Monaten und 9 Monaten Regorafenib Placebo 100 Mediane OS, Monate(IQRa) Gesamtüberleben % 5 n = 505 n = 255 6.4 (3.6-11.8) 5.0 (2.8-10.4) HR (95% CI) 75 0.77 (0.64-0.94) P value.0052 50 25 0 Regorafenib + BSC (n = 505) Placebo + BSC (n = 255) 0 2 Patients at Risk, N Regorafenib 452 Placebo 221 4 352 150 aiqr, 6 8 Zeit ab Randomisierung, Monate 187 75 93 32 10 33 9 interquartile range 12 14 7 3 BSC, best supportive care; IQR, interquartile range; OS, overall survival. Grothey A, Van Cutsem E, et al. Lancet. 2013;381:303-312..

5 Bitte alles auf deusch übersetzen Roger von Moos; 13.10.2013

CORRECT: Therapie assoziierte Nebenwirkungen in 10% der Patienten Nebenwirkungen, % Hand-Fuß Hautreaktionen Fatigue Hypertension Diarrhö Rash / desquamation Anorexie Mucositis, oral Thrombozytopenie Fieber Nausea Nasenbluten Stimmveränderungen Gewichtsverlust Regorafenib + BSC arm n = 500 Alle Grade Grad 3/4 47 17 47 9 28 7 34 7 26 6 30 3 27 3 13 3 10 1 14 <1 7 0 29 <1 14 0 Placebo + BSC arm n = 253 Alle Grade Grad 3/4 8 <1 28 5 6 1 8 1 4 0 15 3 4 0 2 <1 3 0 11 0 2 0 6 0 2 0 Therapie-assoziierte Nebenwirkungen welche in Therapieabbruch resultierten: 8.2% im Regorafenib-Arm vs. 1.2% unter Placebo Grothey A, Van Cutsem E, et al. Lancet. 2013;381:303-312. Stivarga PI.

Treatment algorithm by ESMO OxaliplatinBased First-line First line FOLFOX + pan or ceta 5-FU/OX Second line 5-FU/IRI + bev FOLFIRI + aflib 5-FU/IRI Third line Regorafenib Pan/ceta ± IRI 5-FU + bev Fourth line IrinotecanBased First-Line 5-FU/OX + bev Regorafenib FU/IRI + ceta (FOLF)IRI + pan/ceta ChemoTriplet 5-FU/IRI 5-FU/IRI + bev 5-FU/ OX/IRI 5-FU/OX + bev 5-FU/OX FOLFOX + cet/(pan)a Pan/ceta ± IRI or FU/bev Regorafenib Pan/ceta ± IRI 5-FU + bev Regorafenib Regorafenib akras wildtype only. 5-FU, 5-fluorouracil; aflib, aflibercept; bev, bevacizumab; cet, cetuximab; FOLFIRI, 5-FU + leucovorin + irinotecan; FOLFOX, 5-FU + leucovorin + oxaliplatin; IRI, irinotecan; OX, oxaliplatin; pan, panitumumab; ESMO, European Soceity for Medical Oncology. Schmoll HJ, et al. Ann Oncol. 2012;23:2479-2516.

ESMO Guidelines 2014 Resectable Potentially resectable Disseminated

Conclusion Full RAS and BRAF analysis is necessary in all patients who are candidate for systemic treatment Irinotecan and Oxaliplatin regimens are both effective in first and second line Capecitabine as monotherapy is an alternative for patients not tolerating a combination chemotherapy In RAS wild type patients, EGFR antibodies seems to be more effective than bevacizumab (lets wait for new data at ESMO in 2 weeks) Good data for Bevacizumab are available for RAS mutant, and second line treatment The TML showed a survival benefit for patients treated with Bevacizumab in first and second line Aflibercept has shown acitivity in second line therapy Patients in good condition are candidates for further line treatment with Regorafenib