1. Anti-EGFR Antibodies in Metastatic Colorectal Cancer: Which Patients, When, and How? J. Randolph Hecht, MD David Geffen School of Medicine at UCLA

2. Disclosures Research Funding Amgen Novartis GSK Pfizer ImClone Genvec Roche

3. Anti-EGFR Ab: Clinical Development Single Agent Phase II, Salvage –Saltz, JCO, 2004 –Hecht, Cancer, 2007 Single Agent Randomized Trials, Salvage –408 Van Cutsem, JCO 2007 –CO.17 Jonker, NEJM, 2008 Modest RR ~10% Modest improvement in PFS, OS

4. CO.17 Jonker, NEJM, 2007

5. Combination Trials Cetuximab –Saltz (Salvage) Cetuximab+ Irinotecan –Cunningham (2nd line, Salvage) Cetuximab+Irinotecan –EPIC (2nd line) Sobrero PhIII Irinotecan +/- cetuximab –80203 (1st line) Venook rPhII FOLFOX/FOLFIRI +/- cetuximab –OPUS (1st line) Bokemeyer rPhII FOLFOX +/- cetuximab –CRYSTAL (1st line) Van Cutsem PhIII FOLFIRI +/- cetuximab –COIN (1st line) Maughan PhIII FOLFOX/XELOX +/- cetuximab –CAIRO2 (1st line) Tol CapeOx/bev +/- cetuximab Panitumumab –Berlin (1st line) PhII 5-FU/Irinotecan + panitumumab –PRECEPT (2nd line) PhII Cohn FOLFIRI + panitumumab –STEPP (2nd line) PhII Mitchell FOLFIRI + panitumumab –PACCE (1st line with bev) Hecht PhIII FOLFOX/IRI + bev +/- panitumumab

6. Progression-free survival time (months) PFS estimate 1.0 0.8 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 02468101214161820 HR = 0.851; 95% CI = [0.726-0.998] Stratified log-rank p-value = 0.0479 8.9 mo 8.0 mo FOLFIRI, n=599 Cetuximab + FOLFIRI, n=599 1-year PFS rate 23% vs 34% Subjects at risk FOLFIRI alone 599492402293178833516741 Cetuximab + FOLFIRI 59949939229819610358291251 CRYSTAL Trial: PFS Van Cutsem ASCO 2007

7. Bokemeyer, JCO, 2009 OPUS

8. Standard Therapy of Metastatic CRC: US 2007 1st Line: FP/oxaliplatin (usually) + bevacizumab 2nd Line: –FOLFIRI + bevacizumab –Irinotecan + cetuximab 3rd Line: –Irinotecan + cetuximab –Single agent cetuximab or panitumumab

9. Questions Regarding EGFR Abs: Clearly only a subset of patients benefit from EGFR antibody therapy, yet almost all patients get some toxicity How do we determine which patients will benefit from such therapy? Should anti-EGFR Mabs be used earlier in treatment?

10. EGFR Signaling Pathway Extracellular Intracellular Ligand EGFR PI3K Akt Ras Raf MEK MAPK Cell motility Metastasis Angiogenesis Proliferation Cell survival DNA PTEN

13. KRAS GTPase downstream from numerous receptors Mutations (codons 12, 13, 61) activating and found in ~40% of CRC regardless of stage Smaller retrospective trials indicated lack of response with EGFR antibodies (Lievre, De Roock, Khambata-Ford, etc.)

14. KRAS as a Biomarker for Panitumumab Response in Metastatic CRC Patients With Mutant KRAS Mean in Wks Stratified log rank test: P <.0001 115/124 (93) Patients With Wild-Type KRAS 1.0 0.9 Proportion With PFS 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 024 6810 Events/N (%) Median in Wks Pmab + BSC BSC alone 114/119 (96) 12.3 7.3 19.0 9.3 HR: 0.45 (95% CI: 0.34–0.59) 12141618 20 2224262830 32 343638 40 42 44 46485052 Weeks Proportion With PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 24 681012141618 20 2224262830 32 343638 40 42 44 464850 Weeks Pmab + BSC BSC alone Mean in Wks 76/84 (90) Events/N (%) Median in Wks 95/100 (95) 7.4 7.3 9.9 10.2 HR: 0.99 (95% CI: 0.73–1.36) 52 Amado et al., JCO 2008.

15. What About EGFR Ab/Chemotherapy Combinations 1st Line in KRAS WT Pts?

16. 1st Line Chemotherapy/Ab Trials KRAS WT Maughan ESMO 2009 CRYSTAL PFS 9.9 vs 8.7m HR 0.68 p=0.017 OPUS PFS 7.7 vs 7.2 HR 0.57 p=0.016 COIN PFS 8.6 vs 8.6 m HR 0.96 (0.84-1.09) p=0.60

17. What About Panitumumab/ Chemotherapy (without Bevacizumab) Combinations First Line?

18. Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as first-line treatment in patients with metastatic colorectal cancer: the PRIME trial S. Siena, 1 J. Cassidy, 2 J. Tabernero, 3 R. Burkes, 4 M.E. Barugel, 5 Y. Humblet, 6 D. Cunningham, 7 F. Xu, 8 J. Gansert, 8 J.Y. Douillard 9 1 Ospedale Niguarda Ca’ Granda, Milan, Italy; 2 The Beatson West Of Scotland Cancer Centre, Glasgow, United Kingdom; 3 Vall d'Hebron University Hospital, Barcelona, Spain; 4 Mount Sinai Hospital, Toronto, Canada; 5 Hospital de Gastroenterología, Buenos Aires, Argentina; 6 Centre du Cancer de l'Université Catholique de Louvain, Brussels, Belgium; 7 The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8 Amgen Inc., Thousand Oaks, California, 9 Centre René Gauducheau, Nantes, France;

19. Study Schema and Stratification Treatment Arm 1: Panitumumab 6.0 mg/kg Q2W + FOLFOX4 Q2W ENROLLMENTENROLLMENTENROLLMENTENROLLMENT END OFEND OFTREATMENTTREATMENTEND OFEND OFTREATMENTTREATMENT L O N G T E R M F O LL O W U P Disease assessment every 8 weeks Treatment Arm 2: FOLFOX4 Q2W Enrollment Target: 1150 patients Randomization stratification: ECOG score: 0-1 vs. 2 ECOG score: 0-1 vs. 2 Geographic Region: Western Europe, Canada, and Australia vs. Rest of the World Geographic Region: Western Europe, Canada, and Australia vs. Rest of the World SCREENINGSCREENINGSCREENINGSCREENING PRIME Study Countries Canada United Kingdom BelgiumFranceSpainSwitzerlandItalyPoland Czech Republic HungaryLatvia SouthAfrica MexicoCostaRica BrazilChileArgentina Australia

20. Siena Results Primary Endpoint (KRAS WT) –PFS: 9.5 vs 8.0m; HR 0.80 (0.66-0.97) p=.02 Secondary Endpoints (KRAS WT) –OS: 23.9 vs 19.7m; HR 0.83 (0.67-1.02) p=.07 –RR: 55 vs 48% Increased toxicity: skin, diarrhea, mucositis ECOG 2 HR 1.99 (0.96-4.15)

21. Conclusions Large, well done randomized trial KRAS WT data analyzed prospectively Reached PFS endpoint Improved OS, but p=0.07 Worse outcome has been seen in ECOG 2 pts in similar trials How does this compare to other EGFR Ab 1st line trials? –Overlapping CI with CRYSTAL and OPUS –Where does COIN fit in? Does the chemotherapy backbone matter? Should panitumumab be approved 1st line?

22. Conclusions (cont.) The question is not cetuximab vs panitumumab but EGFR Ab vs bevacizumab in KRAS WT Increased RR with EGFR Ab Increased GI, skin toxicity vs rare ATE, perforation PEAK (rPhII) –mFOLFOX6 + panitumumab –mFOLFOX6 + bevacizumab CALGB 80405 (PhIII) –FOLFOX/FOLFIRI + cetuximab –FOLFOX/FOLFIRI + bevacizumab –FOLFOX/FOLFIRI + cetuximab + bevacizumab

23. What About EGFR Ab/Chemotherapy Combinations Second Line? EPIC (Sobrero) PFS 4.0 vs 2.6m HR 0.78 p=<.0001 RR 16.4 vs 4.2% No OS difference (? crossover) KRAS ODAC HR 0.70 but <25%of pts What about panitumumab/chemotherapy combinations second line in KRAS WT patients?

24. Randomized phase 3 study of panitumumab with FOLFIRI vs FOLFIRI alone as 2nd-line treatment in patients with metastatic colorectal cancer: Patient reported outcomes (PRO) M. Peeters, 1 T. Price, 2 Y. Hotko, 3 A. Cervantes, 4 M. Ducreux, 5 T. André, 6 A. H. Strickland, 7 G. Wilson, 8 Y. Tian, 9 J. Gansert 9 1 University Hospital Ghent, Ghent, Belgium; 2 Queen Elizabeth Hospital, Woodville, Australia; 3 Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod, Ukraine; 4 Hospital Clínico Universitario de Valencia, Valencia, Spain; 5 Institut Gustave Roussy, Villejuif, France; 6 Pitié-Salpétrière Hospital, Paris, France; 7 Monash Medical Center, East Bentleigh, Australia; 8 Christie Hospital, Manchester, United Kingdom; 9 Amgen Inc., Thousand Oaks, California 1 University Hospital Ghent, Ghent, Belgium; 2 Queen Elizabeth Hospital, Woodville, Australia; 3 Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod, Ukraine; 4 Hospital Clínico Universitario de Valencia, Valencia, Spain; 5 Institut Gustave Roussy, Villejuif, France; 6 Pitié-Salpétrière Hospital, Paris, France; 7 Monash Medical Center, East Bentleigh, Australia; 8 Christie Hospital, Manchester, United Kingdom ; 9 Amgen Inc., Thousand Oaks, California

25. Peeters Results Primary Endpoints (KRAS WT) –PFS: 5.9 vs 3.9m; HR 0.73 (0.59-0.90) p=.004 –OS: 14.5 vs 12.5m; HR 0.85 (0.70-1.04) p=.12 Secondary Endpoint –RR: 35 vs 10% Increased toxicity: skin, diarrhea, mucositis EQ-5D OHR (VAS) but not HSI (5 dimensions) in KRAS wt –Improved EQ-5D OHR (VAS) but not HSI (5 dimensions) in KRAS wt

26. Conclusions Large well done study First prospective second line in KRAS WT Expected toxicity, ? significance of PRO Excellent PFS, OS in both arms Statistical improvement in PFS, but not OS in a “good” KRAS wt group but wide Cis Should panitumumab be approved in 2nd line combined with irinotecan based therapy? Is this the new standard in second line KRAS WT metastatic CRC?

27. Conclusions (cont) How does this compare with bevacizumab containing regimens? –ECOG 3200 (Giantonio, JCO 2007) –BRITE “study” (Grothey, JCO, 2008) Randomized Trials (KRAS WT) –ML18147/AIO0504 (PhIII) FP/Ox vs FP/Ox + bevacizumab FP/Iri vs FP/Iri + bevacizumab –SPIRITT (rPhII) FOLFIRI + panitumumab FOLFIRI + bevacizumab –S0600 (PhIII) FOLFIRI/Iri + cetuximab FOLFIRI/Iri + bevacizumab

28. Does BRAF Mutation Identify Nonresponders? Extracellular Intracellular Ligand EGFR PI3K Akt Ras Raf MEK MAPK Cell motility Metastasis Angiogenesis Proliferation Cell survival DNA PTEN

29. BRAF Background BRAF is a serine/threonine kinase downstream of KRAS V600E mutation is found in 5-10% of CRCs Mutation mutually exclusive with KRAS mut Correlatated with poor prognosis –Ogino, Gut, 2009 –Tol, NEJM, 2009 (letter) Retrospective studies correlated with lack of response –Di Nicolantonio, JCO, 2008

30. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer: the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial Eric Van Cutsem*, I Lang, G. Folprecht, M.P. Nowacki, S. Cascinu, I. Shchepotin, J. Maurel, D. Cunningham, Ph Rougier, I. Celik, C.H. Köhne *University Hospital Gasthuisberg, Leuven, Belgium

31. Updated CRYSTAL Results KRAS WT (From Paper and ASCO) More pts analyzed, longer follow-up, retrospective analysis PFS – 9.9 vs 8.4m HR 0.70 p=.0012 OS –23.5 vs 20.0m HR 0.80 p=.0093 PS 2 ? less benefit (small numbers) Yes, OS is now statistically significant, but does this change anything?

32. Clinical efficacy in KRAS wild-type tumors by BRAF mutation status KRAS wt/BRAF wt (n=566) KRAS wt/BRAF mt (n=59) FOLFIRI (n= 289) Cetuximab +FOLFIRI (n= 277) FOLFIRI (n=33) Cetuximab +FOLFIRI (n=26) Median OS mo [95% CI] 21.6 [20.0–24.9] 25.1 [22.5–28.7] 10.3 [8.4–14.9] 14.1 [8.5–18.5] HR [95% CI] p-value a 0.830 [0.687–1.004] 0.0549 0.908 [0.507–1.624] 0.7440 Median PFS mo [95% CI] 8.8 [7.6–9.4] 10.9 [9.4–11.8] 5.6 [3.5–8.1] 8.0 [3.6–9.1] HR [95% CI] p-value a 0.679 [0.533–0.864] 0.0016 0.934 [0.425–2.056] 0.8656 OR rate (%) [95% CI] 42.6 [36.8–48.5] 61.0 [55.0–66.8] 15.2 [5.1–31.9] 19.2 [6.6–39.4] p-value b <0.00010.9136 CI, confidence interval; OR, best overall response; OS, overall survival; PFS, progression-free survival; mo, months; mt, mutant; wt, wild-type a Stratified log-rank test; b Cochran-Mantel-Haenszel test

33. Conclusions BRAF confirmed as marker of poor prognosis Not so fast on excluding people from EGFR treatment (NCCN guidelines), but small numbers Need to look at randomized studies to validate predictive markers Possible target for therapy (PLX4032 in melanoma)

34. Standard Therapy of Metastatic CRC: US 2010 KRAS WT 1st Line: FP/oxaliplatin or Iri + bevacizumab FP/Ox or Iri + cetuximab* FP/Ox + panitumumab* 2nd Line: FP/oxaliplatin or Iri + bevacizumab Irinotecan + cetuximab (if EGFR Ab not used 1st line) FOLFIRI + panitumumab* (if EGFR Ab not used 1st line) 3rd Line: Irinotecan + cetuximab (if EGFR Ab not used earlier) Single agent cetuximab or panitumumab (if not used earlier)

35. Standard Therapy of Metastatic CRC: US 2010 KRAS Mut 1st Line: FP/oxaliplatin or Iri + bevacizumab 2nd Line: FOLFIRI or FP/ox + bevacizumab 3rd Line: Clinical trial BSC