1. Oral Colorectal Presentations: Discussion Abstracts #4009 - #4011 Cathy Eng, M.D. The University of Texas M.D. Anderson Cancer Center May 31, 2008

2. Disclosures: Honararia from Pfizer Oncology Pharmaceutical sponsored grants for clinical trial development: –Bristol Myers Squibb –Genentech –Imclone –Novartis –Sanofi~Aventis

3. Abstracts for Discussion: Role of Ca/Mg in reducing oxaliplatin-induced toxicities: –#4009: Adjuvant colon cancer: NCCTG trial N04C7. (Nikcevich et al) –#4010: Intermittent oxaliplatin administration in metastatic colorectal cancer: CONcePT trial (Grothey et al) Role of combined biologic therapy in metastatic colorectal cancer: –#4011: Capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer: CAIRO2 study (Punt et al)

4. Oxaliplatin-induced neuropathy: Oxaliplatin is currently approved in the adjuvant and metastatic treatment of colorectal cancer (CRC) Dose-limiting toxicity: peripheral neuropathy –Etiology Oxaliplatin metabolite, oxalate, is a chelator of Ca2+ and may alter voltage gated Na+ channels. –Acute vs. chronic neuropathy Acute - cold hypersensitivity and muscle contractions – transient Chronic – cumulative but reversible –Impact on quality of life –Impact on dose intensity –No definitive therapies available for prevention or reduction

5. MOSAIC: Peripheral Neuropathy de Gramont et al: ASCO, #4007. 2007 Evaluable patients n=811 Grade 084.3% Grade 112.0% Grade 22.8% Grade 30.7%

6. Ca ++ /Mg ++ Infusion for Prevention of Oxaliplatin Sensory Neuropathy Gamelin et al. Clin Can Research 10:4055-4061, June 15, 2004 Oxaliplatin WithOxaliplatin WithoutCa/Mg Infusion Withdrew from oxaliplatin4%31% Acute neurotoxicities (%)09% Neuropathy at end of treatment 20 (P=.003)45% Advanced CRC N=161 Ca-gluconate (1 g) Mg-sulfate (1 g) No Ca/Mg infusion n=96 n=65 Oxaliplatin/ 5-FU/LV

7. Prospective Trials: U.S. –N04C7: Ca/Mg in adjuvant colon cancer Endpoint: Gr 2 sensory neuropathy –CONcePT: Ca/Mg in treatment naïve metastatic CRC Endpoint: Time to treatment failure Europe: –Neuroxa: Ca/Mg use in stage III/IV colorectal cancer receiving FOLFOX4 (Gamelin et al, ISGIO, 2007) Endpoint: Rate of acute neuropathy Preliminary results reported at ISGIO, 2007.

8. N04C7 Phase III Trial – Original Study Design 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min immediately before and after oxaliplatin (placebo = 100 mL D5W) Pts to receive adj. FOLFOX N=300 Pts to receive adj. FOLFOX N=300 IV CaMg % of Grade 2+ sNT R IV placebo Nikevich et al. ASCO, #4009, 2008

9. N0C47: Salient Points Phase III placebo-controlled double-blinded trial Primary endpoint: Grade2 peripheral sensory neuropathy (PSN) Secondary endpoints: time to onset and duration of grade2-3 PSN –Discontinuation of therapy –QOL questionnaires –Duration of therapy –Pharmacogenomics Adverse event reporting –NCI CTC v3.0 patient reported outcomes (PRO) –Oxaliplatin specific scale

10. Neurotoxicity Evaluation GradeNCI-CTC 3.0Oxaliplatin-specific scale I loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function sensory symptoms of short duration II objective sensory alteration or paresthesia, including tingling, interfering with function, but not interfering with activities of daily living sensory symptoms persisting between cycles III sensory alteration or paresthesia interfering with activities of daily living sensory symptoms causing functional impairment IV Permanent sensory losses that are disabling -

11. Inclusion of Patient Reported Outcomes (PRO) with NCI-CTC Traditionally adverse events are graded by NCI common toxicity criteria (CTC) –Physician interpretation Novel approach to include patient reported AE’s Advantages: –Allows patient involvement in documentation of adverse events Disadvantages: –May result in additional regulatory paperwork Method of collection should be uniform with ease of collection Continues to be refined and evaluated Trotti et al: JCO; 25: 5121-5127, 2007

12. Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT): Original study design First-line mCRC, 532 patients Primary endpoint: time to treatment failure (TTF) of CO vs. IO Randomization (2x2) mFOLFOX7 + bevacizumab Continued until Treatment Failure (CO) mFOLFOX7 + bevacizumab Intermittent Stop-and-Go oxaliplatin R +/- IV CaMg Grothey et al. ASCO, #4010, 2008 Secondary endpoints: Incidence and severity of pSN RR, PFS, and OS, QOL questionnaires (Quality vs. Quantity)

13. Notification from Sanofi: June 2007 Unplanned interim analysis of CONcePT by an independent data monitoring committee (IDMC) as recommended by the CRO suggesting decreased efficacy in the Ca/Mg arms. Investigator-determined and unconfirmed radiographic response Resulted in the premature closures of N0C47 and CONcePT. Hochster et al. JCO; 25: 4028-4029

14. N04C7 Phase III Trial – Study closure 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min immediately before and after oxaliplatin (placebo = 100 mL D5W) Data cutoff after 127 days (4M and 7 days) Pts to receive adj. FOLFOX N=300 Pts to receive adj. FOLFOX N=300 IV CaMg N=50 % of Grade 2+ sNT R IV placebo N=52 IV placebo N=52 N=102

15. N0C47: Development of Grade 2 Peripheral Neuropathy NCI CTC scale: Neurotoxicity Grade CaMg (N=50) Placebo (N=52) P-value (Chi-Square) Grade 0/178%59%.038 Grade 2+22%41% Oxaliplatin Scale Neurotoxicity Grade CaMg (N=50) Placebo (N=52).018 Grade 0/172%49% Grade 2+28%51%

16. Conclusions of N0C47: Study limitations: –Premature closure of study Significant differences in development of Gr 2 sNT –Difference in time to onset in Gr 2 sNT by CTC vs. oxaliplatin scale (P=.0503 vs. P=.0250) Emphasizes the differences that exist in capturing AE’s based on diagnostic tools utilized. –QOL (PRO): Preliminary, final results pending Acute: Decrease in muscle contractions (P=.012) and trend in swallowing discomfort (P=.065) Chronic: Improvement in numbness (P=.021) and trend in tingling (P=.062) Development and duration of Gr 3 sNT: Unknown

17. Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT): Study Closure First-line mCRC, 532 patients Primary endpoint: time to treatment failure (TTF) Randomization (2x2): mFOLFOX7 + bevacizumab until Treatment Failure (CO) mFOLFOX7 + bevacizumab Stop-and-Go oxaliplatin (IO) +/- IV CaMg R N= 139

18. CONcePT: Interim Analysis of Response Parameter COIO PlaceboCa 2+ Mg 2+ PlaceboCa 2+ Mg 2+ ITT (n=34) Eval (n=28) ITT (n=35) Eval (n=31) ITT (n=36) Eval (n=31) ITT (n=35) Eval (n=28) Best ORR (N) CR PR SD PD Uneval. 0 7 13 9 5 0 6 13 9 - 0 10 15 5 0 11 15 5 - 0 14 15 2 5 0 14 15 2 - 0 12 11 5 7 0 12 11 5 - ORR, % 95% CI 21 8.7-37.9 21 8.3-41.0 29 14.6- 46.3 36 19.2-54.6 39 23.1-56.5 45 27.3-64.0 34 19.1- 52.2 43 24.5- 62.8 Odds ratio95% CIP-value IO relative to CO1.960.86-4.54.089 Ca 2+ Mg 2+ relative to placebo1.290.57-2.98.565 Hochster et al: GI Symposium, #280, 2007 Investigators concluded that Ca/Mg did NOT have a deleterious effect on efficacy

19. CONcePT: Results Intermittent oxaliplatin (IO) vs. continuous oxaliplatin (CO) –Resulted in improved TTF and PFS –Decreased grade ¾ peripheral neuropathy –Less treatment delays and discontinuations The use of Ca/Mg had no impact on: –TTF or PFS –Within IO vs. CO arms: No notable differences: –Grade ¾ peripheral neuropathy –Delays or discontinuations Neurotoxicity by PRO: –Acute neuropathy: Improved with intermittent oxaliplatin vs. continuous oxaliplatin No benefit with Ca/Mg vs. placebo –Chronic neuropathy: Benefit noted with both intermittent oxaliplatin use and the use of Ca/Mg

20. Other Methods to Reduce Neuropathy: TreatmentPhase Reduction in pSN Risk of Toxicities Ca/MgIII InconclusiveNone GabapentinIIEquivocalYes CarbamezapineIIEquivocalYes GlutamineIIPossiblyYes XaliprodenIIIPending- OPTIMOX 1IIIYesLess FLOX regimenIIIYes Saif et al. Ther Clin Risk Manag. 2005 December; 1(4): 249–258 Wang et al. The Oncologist; 12:312-319, 2007 De Gramont et al. JCO. Vol 24, No 3 (January 20), 2006: pp. 394-400 Kuebler et al: JCO Jun 1 2007: 2205-2211.

21. Conclusions of CONcePT: Relevance of neuropathy on QOL Impact on current practice? –Continuous vs. Intermittent oxaliplatin Use of intermittent oxaliplatin fared better Standard of care? –Still not widely adopted –Must be on patient by patient basis –Ca/Mg: Appears to have no impact on efficacy Reduces the incidence of chronic neuropathy but not acute –Palliative setting vs. adjuvant setting? »Physician variability Consideration of use should be physician dependent Future approaches: –Xaliproden (EFC5505): pending –Pharmacogenomics

22. Efficacy of Combined Biologic Therapy? CAIRO2

23. Rationale for CAIRO2: Inhibition of two common but independent pathways (VEGF and EGFR) in CRC may result in increased efficacy. Promising results of BOND2 in heavily pretreated patient mCRC pts. In contrast, data from the Panitumumab Advanced Colorectal Cancer Evaluation Study (PACCE) demonstrated decreased efficacy at risk of increased toxicity. CAIRO2: Early safety data of first 400 patients noted no increased toxicities. Hecht et al: GI Cancers Symposium; Abs#273, 2008 Saltz et al. JCO: 25; 4557-4568, 2007 Tol et al: Annals of Onc; 19: 734–738, 2008

24. PACCE: Panitumumab Advanced Colorectal Cancer Evaluation: Study Schema Panitumumab 6 mg/kg Q2W Ox-CT Bevacizumab Ox-based CT (eg, FOLFOX) N = 800 Inv choice Iri-basedCT (eg, FOLFIRI) N = 200 Inv choice Ox-CT Bevacizumab Panitumumab 6 mg/kg Q2W Iri-CTBevacizumab Iri-CTBevacizumab RANDOMIZERANDOMIZE 1:1 SCREENINGSCREENING 1º endpoint: PFS Hecht et al: 9 th World Congress on GI Cancers, Barcelona 2007

25. PACCE: Overall Inferior Results of Combined Biologic Therapy FOLFOX/Bev/Pmab (N=407) FOLFOX/Bev (N=405) Grade 3/4 Toxicities 53/28 (81%)51/18 (69%) PFS (M)9.0 (HR = 1.29)10.5 OS (M)18.6 (HR = 1.44)NA Hecht et al: 9 th World Congress on GI Cancers, Barcelona 2007

26. Phase III Trial Design of CAIRO2RANDOMIZE Arm A: Capecitabine / Oxaliplatin/Bevacizumab > Cycle > 7: Capecitabine/Bevacizumab Arm B: Capecitabine / Oxaliplatin/Bevacizumab +weekly Cetuximab > Cycle > 7: Capecitabine/Bevacizumab+ weekly Cetuximab Treatment naïve, surgically unresectable patients N= 755 1º Endpoint: PFS 2º Endpoints: RR, OS, toxicities, and QOL Response rate: q3 cycles

27. CAIRO2: Inferior PFS for Combined Biologic Therapy CapeOX/BevCapeOx/Bev + Cetux P-value n= 368 Median PFS (M) (95% CI) 10.7 (9.7-12.5) 9.6 (8.5-10.7).018 HR 1.21 (1.03-1.45) Median OS (M) (95% CI) 20.4 (18.1-26.1) 20.3 (17.9-21.6).21 HR 1.15 (0.93-1.43) Response rate (CR+PR)*44%42%.602 * 660 patients were evaluable for response

28. Phase III Trials of Combined Biologic Therapy with Negative Impact on PFS CAIRO2 Months PACCE HR=1.44 (95% CI: 1.13-1.85) P =.004 HR=1.21 (95% CI: 1.03-1.45) P =.018 Hecht et al; World GI Cancer, Barcelona, 2007 041216208 FOLFOX/Bev FOLFOX/Bev+Pmab 9.6 vs. 10.7 M 9.6 vs. 11.1 M

29. Panitumumab vs. BSC: Impact of KRas on PFS (WT vs. Mutant) Amado et al. JCO; Apr 1;26(10):1626-34, 2008 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0246810121416182022242628303234 Weeks 363840424446485052 115/124 (93)12.319.0 114/119 (96)7.39.3 Pmab + BSC (WT) BSC Alone (WT) Events/N (%) Median In Weeks Mean In Weeks WT: HR = 0.45 (95% CI: 0.34–0.59) Stratified log-rank test, p < 0.0001 Proportion with PFS Pmab + BSC (MT)76/84 (90)7.49.9

30. CAIRO2: Impact of KRas on PFS and OS Wild typeMutantP value Progression-free survival CapeOx/Bev10.712.5.92 CapeOx/Bev+C10.58.6.47 P value.10.043 Overall survival CapeOx/Bev2324.90.90 CapeOx/Bev+C22.219.10.52 P value.49.35

31. Phase II OPUS: Impact of KRas on FOLFOX +/- Cetuximab Bokemeyer et al: ASCO, #4000, 2008 Wild-TypeMutant FOLFOX + CFOLFOXFOLFOX + CFOLFOX RR (%) 61 (n=61) 37 (n=73) 33 (n=52) 49 (n=47) P=.01P=.11 PFS (M) 7.7 (n=61) 7.2 (n=73) 5.5 (n=52) 8.6 (n=47) HR:0.57 P=.02HR:1.83 P=.02

32. Conclusions from CAIRO2: Combined biologic therapy (anti- VEGF/EGFR) is of NO added benefit in RR or OS and negatively impacts PFS. KRas status did not appear to have any impact on outcome in PFS or OS within either arm. However, of those patients with KRas mutant tumors, the use of cetuximab resulted in inferior PFS than the standard chemotherapy regimen alone.

33. CAIRO2: Unanswered Questions of Impact of KRas Wild typeMutantP value Progression-free survival CapeOx??? CapeOx + C??? CapeOx/Bev10.712.5.92 CapeOx/Bev+C10.58.6.47 P value.10.043

34. Future of Combined Biologic Therapy: **Two negative Phase III trials of combined anti-VEGF and EGFR therapy Impact on existing trials: U.S. Cooperative group trials: –CALGB/SWOG 80405: Front-line –SWOG 0600: Second-line Impact on 10 other existing trials?

35. Proposed CALGB/SWOG 80405 Design Untreated advanced or mCRC N = ? Bevacizumab followed by FOLFOX or FOLFIRI q 2 wks Cetuximab followed by FOLFOX or FOLFIRI q 2 wks Cetuximab followed by Bevacizumab followed by FOLFOX or FOLFIRI q 2 wks mCRC = metastatic colorectal cancer Open-label Phase III Study Screen for eligibility Send tumor tissue block to SWOG PCO Randomize Patients w/ Wild type K-ras tumor Register Patient Accrual as of May 22, 2008 = 1386 Courtesy of Alan Venook, M.D.

36. Future of Combined Biologic Therapy: **The use of combined biologic therapy (anti- VEGF/EGFR) should only be conducted as part of a clinical trial Indicates that our understanding of both VEGF and EGFR pathways is not fully understood. Role of KRas? –Evidence to support its role as a predictive marker –*Must be considered when proposing anti-EGFR therapy –To date, the use of anti-EGFR therapy in KRas mutant tumors in combination with chemotherapy negatively impacts PFS and possibly RR.