1. Monoclonal Antibodies EGFR Inhibitors for Metastatic Colorectal Cancer: Where are we and What’s next Discussion of Abstracts 4032-4035 Jeffrey Meyerhardt, MD MPH Dana-Farber Cancer Institute Boston, MA

2. Monoclonal EGFR Inhibitor History for CRC at ASCO 2001 – Abstract 7 (Saltz) Irinotecan + Cetuximab  ~20% response rate in irinotecan-refractory patients 2002 – Abstract 504 (Saltz) Single agent Cetuximab  ~11% response rate in irinotecan-refractory patients 2003 – Abstract 1012 (Cunningham) BOND trial

3. Monoclonal EGFR Inhibitor History for CRC at ASCO 2004 – Abstract 3512 (Tabernero) – Cetuximab + FOLFOX  50 patients -> 70% RR 2004 – Abstract 3513 (Rougier) – Cetuximab + FOLFIRI  23 patients -> 44% RR but TTP 10.9 months 2005 – Abstract 3508 (Saltz) – Cetuximab + Bevacizumab with or without Irinotecan 2005 – Abstract 3520 (Malik) – Single agent panitumumab

4. Monoclonal EGFR Inhibitor History for CRC at ASCO 2006 – Abstract 3509 (Venook) – CALGB 80203  2 x 2 trial – FOLFIRI v FOLFOX +/- Cetuximab  Efficacy FOLFOXFOLFOX + Cetuximab FOLFIRIFOLFIRI + Cetuximab N58535855 Response rate40%60%36%44% Venook et al Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3509 PFS9.8 m8.2 m8.4 m10.6 m

5. Monoclonal EGFR Inhibitor History for CRC at ASCO 2007 – Abstract 4000 (Van Cutsem) – CRYSTAL FOLFIRIFOLFIRI + Cetuximab N599 Response rate39%47% Median PFS8.08.9 p = 0.047 Van Cutsem et al JCO, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4000

6. Monoclonal EGFR Inhibitor History for CRC at ASCO 2008 – Abstract 237 @ GI ASCO (Hecht) - PACCE Bevacizumab + Ox-CT (n = 410) Pmab+ Bevacizumab + Ox-CT (n = 413) Bevacizumab + Iri-CT (n = 115) Pmab+ Bevacizumab + Iri-CT (n = 115) Best ORR46 %45 %37 %40 % Median PFS11 m9.5 m10.7 m10.6 m Hecht GI ASCO, abstract 273

7. Conclusions regarding efficacy til ASCO 2008 Single agent cetuximab or panitumumab – about 10% response rate, 30% stable disease rate – benefit often short lived, some long Cetuximab + irinotecan active in 2 nd and 3 rd line Cetuximab + combination cytotoxics active in first line therapy  Maybe not as initially reported (not 70% RR)  Interaction with oxali regimens in PFS?  Activity comparable to bevacizumab + combination cytotoxics in first line

8. Where do 4 anti-EGFR abstracts from today’s colorectal cancer poster discussion session fit? 3 trials regarding safety and efficacy of first-line cetuximab/panitumumab  German AIO CRC Study Group led by Heinemann: XELOX + Cetuximab v XELIRI + Cetuximab (4033)  CECOG led by Ciuleanu: FOLFOX + Cetuximab v FOLFIRI + Cetuximab (4032)  PRIME led by Siena: FOLFOX +/- Panitumumab (4034) Meta-analysis of small K-ras studies  Di Fiore and colleagues combined data from 7 studies (4035)

9. Heinemann et al Cetuximab plus XELIRI or XELOX Randomized multi-center trial – 35 centers 185 previously untreated met CRC Primary objective: Response Rate Secondary objectives: TTP, Disease control, Tolerability

10. Heinemann et al Cetuximab plus XELIRI or XELOX (*): 20% dose reduction for patients > 65 years, arm A (**):Cetuximab initial dose: 400mg/m², 120min

11. Heinemann et al Cetuximab plus XELIRI or XELOX XELIRI + CetuximabXELOX + Cetuximab Response rate47%48% Median TTP6.7 m7.9 m Median TTF4.75.1 m Higher rates of grade III+ toxicity Neutropenia/AnemiaNeuropathy Dose reductions34 %44 % Dose delay17 %

12. Heinemann et al Cetuximab plus XELIRI or XELOX What did we learn?  XELIRI + Cetuximab and XELOX + Cetuximab can be given in first line with good responses but lower TTP than usually seen with combination cytotoxics + biologic in this trial  Though not statistically different, skin changes meaningful XELIRI + CetuximabXELOX + Cetuximab Grade 3 + Exanthema / desquamation 14 %6 % Grade 3+ Skin (other)5 %21 %

13. Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX Randomized multi-center trial 151 previously untreated met CRC Primary objective: 9 months PFS rate Secondary objectives: PFS at 3,6,12 months, OS, RR, safety

14. Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX RANDOMIZERANDOMIZE Arm A: Cetuximab + FOLFOX 6 Arm A: Cetuximab + FOLFOX 6 Cetuximab 400 mg/m2 day 1 then 250mg/m2 weekly Oxaliplatin 100 mg/m2 day 1 5-FU bolus 400 mg/m2 day 1 Leucovorin day 1 every 2 wks 5-FU CI 2400 mg/m2 over 46 hours Arm A: Cetuximab + FOLFOX 6 Arm A: Cetuximab + FOLFOX 6 Cetuximab 400 mg/m2 day 1 then 250mg/m2 weekly Oxaliplatin 100 mg/m2 day 1 5-FU bolus 400 mg/m2 day 1 Leucovorin day 1 every 2 wks 5-FU CI 2400 mg/m2 over 46 hours Arm B: Cetuximab + FOLFIRI Arm B: Cetuximab + FOLFIRI Cetuximab 400 mg/m2 day 1 then 250mg/m2 weekly Irinotecan 180 mg/m2 day 1 5-FU bolus 400 mg/m2 day 1 Leucovorin day 1 every 2 wks 5-FU CI 2400 mg/m2 over 46 hours Arm B: Cetuximab + FOLFIRI Arm B: Cetuximab + FOLFIRI Cetuximab 400 mg/m2 day 1 then 250mg/m2 weekly Irinotecan 180 mg/m2 day 1 5-FU bolus 400 mg/m2 day 1 Leucovorin day 1 every 2 wks 5-FU CI 2400 mg/m2 over 46 hours

15. Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX FOLFIRI + CetuximabFOLFOX + Cetuximab PFS @ 9 months34 %45 % Median PFS8.3 m8.6 m Response rate45 %43 % Higher rates of grade III+ toxicity --ANC / Platelets Dose reductions30 %45 % Dose delay > 14 days20 %32 %

16. Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX What did we learn?  1 st line FOLFIRI + Cetuximab and FOLFOX + Cetuximab similar efficacy and tolerability  Results similar-ish to first line bevacizumab trials  9.4 m PFS N016966 (FOLFOX + Bevacizumab)  11.2 m PFS BICC-C (FOLFIRI + Bevacizumab)  Differential interaction with cytotoxic backbone not answered

17. Siena et al FOLFOX +/- Panitumumab Randomized multi-center trial 1183 previously untreated met CRC Primary objective: PFS Secondary objectives: OS, RR, duration of response, TTP, safety, tolerability

18. Siena et al FOLFOX +/- Panitumumab RANDOMIZERANDOMIZE Arm A: Panitumumab + FOLFOX 4 Arm A: Panitumumab + FOLFOX 4 Panitumumab 6 mg/kg FOLFOX – 4 Every 2 weeks Arm A: Panitumumab + FOLFOX 4 Arm A: Panitumumab + FOLFOX 4 Panitumumab 6 mg/kg FOLFOX – 4 Every 2 weeks Arm B: FOLFOX 4 Arm B: FOLFOX 4 FOLFOX – 4 Every 2 weeks Arm B: FOLFOX 4 Arm B: FOLFOX 4 FOLFOX – 4 Every 2 weeks

19. Siena et al FOLFOX +/- Panitumumab Safety analysis  The safety interim analyses were prospectively planned for enrollment milestones :  25, 100, 300, 600, and 900 patients  The analysis set presented here is for the 900 patient cutoff

20. Siena et al FOLFOX +/- Panitumumab No red flags in safety Safety data not broken down by treatment arm Investigators promise in the future…  Further safety – presumably by treatment arm  Efficacy for all patients and for K-ras wildtype  Blocks required for enrollment but not prospectively tested

21. K-ras story Khambata-Ford et al Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3230-3237

22. K-ras story Lievre, A. et al. Cancer Res 2006;66:3992-3995 30 pts MCRC Most with prior irinotecan exposure 97% irinotecan + cetuximab regimen

23. K-ras story Khambata-Ford et al Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3230-3237 Single agent cetuximab therapy

24. K-ras story K-ras Mutation Wild-Type K-ras Amado RG, et al. J Clin Oncol. 2008;26:1626-1634. Panitumumab registration trial

25. Di Fiore et al K-ras meta-analysis 281 irinotecan-refractory patients treated with cetuximab plus irinotecan based-chemotherapy from 7 studies ranging in size 27-113 patients Patients received a mean of 2.4 ± 1.0 chemotherapy lines before cetuximab 35% had KRAS mutation

26. Di Fiore et al K-ras meta-analysis K-ras Wildtype 2 % 41 % 36 % 21 % 5.4 m 13.2 m Response to cetuximab-Irinotecan (n,%) Complete response31.1% Partial response7426.3% Stable disease10738.1% Progressive disease9734.5% Survival Times in months (median, IC95) Progression-free Survival (PFS) 4.53.8-5.1 Overall Survival (OS)108.7-11.2 K-ras mutation 0 % 41 % 58 % 2.7 m 8 m

27. Di Fiore et al K-ras meta-analysis 6

29. What did we learn?  Another confirmation that in 2 nd line and beyond use of cetuximab (and p-mab), K-ras is predictive of response rate, progression-free survival and likely overall survival  Should we start testing?  Should we stopping using cetuximab and panitumumab in patients with K-ras mutations?  Do THESE data move monoclonal EGFR inhibitors to first- line? YES PROBABLY YES NO

30. K-ras story At ASCO 2008 Clinical Science Symposium Saturday 1:15 pm  OPUS Trial RANDOMIZERANDOMIZE FOLFOX FOLFOX + Cetuximab n = 110 n = 113 Response RatePFSResponse Rate PFS Wild-type K-ras (n = 134)37%7.2 m61%7.7 m Mutant K-ras (n = 99)49%8.6 m33%5.5 m Bokemeyer ASCO 2008; JCO 28: May 20 suppl; abstr 4000. FOLFOX FOLFOX + Cetuximab

31. K-ras story At ASCO 2008 Oral Colorectal Session Saturday 3 pm  CAIRO-2 Trial RANDOMIZERANDOMIZE CAPEOX + Bevacizumab CAPEOX + Bevacizumab + Cetuximab All patients CAPEOX + Bevacizumab 10.7 m CAPEOX + Bevacizumab + Cetuximab 9.6 m P value 0.02 Punt ASCO 2008; JCO 28: May 20 suppl; abstr 4011 K-ras wildtypeK-ras mutant 10.7 m12.5 m 10.5 m8.6 m 0.10.04

32. K-ras story At ASCO 2008 Plenary Session TODAY 1 pm  CRYSTAL Trial RANDOMIZERANDOMIZE FOLFIRI FOLFIRI + Cetuximab n = 599 Van Cutsem ASCO 2008; JCO 28: May 20 suppl; abstr 2. K-ras subset analysis to be presented

33. Conclusions Monoclonal antibodies against EGFR continue to prove to be active in metastatic colorectal cancer Role in first-line setting has more questions than answers  Equivalence to bevacizumab – unknown  Differential interaction with oxaliplatin and irinotecan? K-ras story  our first step to tailoring therapy to the patient  We avoid toxicity to 30-40% of patients  We lost an option for 30-40% of patients Current and future trials will need to incorporate K-ras data