1. Intermittent oxaliplatin administration improves time-to-treatment failure in metastatic colorectal cancer: Final results of the phase III CONcePT trial Grothey A 1, Hart L 2, Rowland K 3, Ansari R 4, Alberts SR 1, Chowan N 5, Shpilsky A 6, Hochster HS 7 1 Mayo Clinic, Rochester, MN; 2 Florida Cancer Specialists, Fort Myers, FL; 3 Carle Clinic Association, Urbana, IL; 4 Northern Indiana Cancer Research Consortium, South Bend, IN; 5 Cancer Care Center, Inc., New Albany, NY; 6 sanofi-aventis, Bridgewater, NJ; 7 NYU School of Medicine, New York, NY

2. Disclosures Honorarium: Roche Research support: Genentech, Bayer, Amgen, Sanofi-Aventis, BMS

3. Introduction Oxaliplatin–fluoropyrimidine combinations are widely used in the first-line treatment of metastatic colorectal cancer Addition of bevacizumab to oxaliplatin-based therapy further improves efficacy In all recent phase III trials, most patients discontinued oxaliplatin-based therapy for reasons other than PD – Detailed analysis of N9741 identified neurotoxicity and myelosuppression as most common reasons for treatment discontinuation (Green et al, ASCO GI 2005) Oxaliplatin-induced peripheral sensory neurotoxicity (PSN) – Reversible, acute PSN (e.g. cold-triggered dysethesias, muscle cramps) – Chronic, cumulative PSN = DLT

4. CONcePT: Combined Oxaliplatin Neurotoxicity Prevention Trial Study objective – Optimizing FOLFOX + Bevacizumab by reducing the reasons for premature discontinuation of therapy, i.e. d/c before progression Reducing PSN by – Intermittent oxaliplatin (OPTIMOX1-like strategy) and – Use of IV calcium/ magnesium (CaMg) as neuroprotectant Reducing myelosuppression (mFOLFOX7 = no 5-FU bolus) Primary hypothesis Intermittent oxaliplatin (IO) will allow patients to remain on therapy longer compared with conventional schedule (continuous oxaliplatin; CO)

5. CONcePT: Statistical Design Primary endpoint – Time-to-Treatment Failure (TTF) Time from randomization to withdrawal from study due to: – adverse event, – progressive disease / insufficient therapeutic response, – failure to return, refused treatment / did not cooperate / withdrew consent, – started a new treatment, – or death, whichever comes first – To demonstrate prolonged TTF (7 to 9.2 months, HR 1.306) with IO compared with CO (80% power,  = 0.05) 532 patients needed

6. CONcePT: Statistical Design Secondary endpoints Impact of CaMg infusion on incidence and severity of neurotoxicity in patients receiving either IO or CO RR, PFS, OS, Time of Tumor Control Adverse events Neurotoxicity assessment via QOL questionnaires and physical exam

7. Eligibility criteria Inclusion Histologically or cytologically documented, inoperable mCRC with ≥1 measurable lesion Age ≥18 years ECOG PS 0–1 No prior therapies for metastatic or recurrent CRC Adequate organ function Life expectancy >3 months and no other serious concomitant disease Exclusion Prior treatment with oxaliplatin or bevacizumab Peripheral neuropathy grade >1

8. CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin Study design Primary endpoint: TTF for CO vs IO schedule No randomization to placebo after protocol amendment First-line mCRC, 532 patients Primary endpoint: time to failure (TTF) Randomization (2x2): mFOLFOX7 + bevacizumab CO until Treatment Failure mFOLFOX7 + bevacizumab Intermittent oxaliplatin +/- IV CaMg R 270 pts

9. CONcePT study: IO arm 2400 x 8 Cumulative oxaliplatin 680 mg/m 2 Months 4 2400 x 8 8680 mg/m 2 2400 200 85 5 200 5 85 5 x 8 1360 mg/m 2 12 etc. LV OX BEV 5-FU

10. CONcePT study: IO arm 2400 x 8 Cumulative oxaliplatin 680 mg/m 2 Months 4 2400 x 8 8680 mg/m 2 2400 200 85 5 200 5 85 5 x 8 1360 mg/m 2 12 etc. LV OX BEV 5-FU OPTIMOX1-like design with mFOLFOX7 with 85mg/m 2 oxaliplatin q2w Planned reintroduction of oxaliplatin after 16 weeks Provision for earlier reintroduction of oxaliplatin if tumor progression >50% in maintenance phase

11. Study background - Hochster ASCO GI 2008 Opened February 2005 and terminated June 2007 Per recommendation of IDMC Basis of IDMC recommendation Unplanned interim analysis Confirmed response (CR/PR) on treatment arms A and C (no CaMg) 32.9% versus arms B and D (CaMg) 17.3%. 2-sided Fisher’s exact test (p=0.028) — superiority without CaMg Data provided by CRO Response rates based on tumor measurements from local radiology reports of patients with confirmatory scans No investigator-determined response rates No review of images

12. Sequentially confirmed response rates (RECIST – Independent review) – Hochster ASCO GI 2008 Best response, n COIO Placebo (n=28) CaMg (n=31) Placebo (n=31) CaMg (n=28) PR SD PD 6 13 9 11 15 5 14 15 2 12 11 5 RR, % 95% CI 21 8.3– 41.0 36 19.2– 54.6 45 27.3– 64.0 43 24.5– 62.8 Odds ratio95% CIp-value IO / CO1.960.86–4.540.089 CaMg / Placebo1.290.57–2.980.565 Exact logistic regression with effect of treatment schedule and CaMg on RR

13. Sequentially confirmed response rates (RECIST – Independent review) – Hochster ASCO GI 2008 Best response, n COIO Placebo (n=28) CaMg (n=31) Placebo (n=31) CaMg (n=28) PR SD PD 6 13 9 11 15 5 14 15 2 12 11 5 RR, % 95% CI 21 8.3– 41.0 36 19.2– 54.6 45 27.3– 64.0 43 24.5– 62.8 Odds ratio95% CIp-value IO / CO1.960.86–4.540.089 CaMg / Placebo1.290.57–2.980.565 Exact logistic regression with effect of treatment schedule and CaMg on RR CaMg did NOT interfere with activity of FOLFOX + BEV per independent radiologic review

14. Study cohorts Randomized: n=180 Original 2x2 design: n=140 (Cohort 1) After amendment (all pts to receive CaMg) 40 pts randomized (Cohort 2) Due to early study closure, collection of data was stopped on July 12, 2007 (date of Last Patient Last Visit) Data are presented for original 2x2 design = Cohort 1 (139/140 pts treated)

15. Patient and disease characteristics at baseline N Patients CO (n=68)IO (n=71) Total (n=139) Placebo (n=33) CaMg (n=35) Placebo (n=36) CaMg (n=35) Mean age (years)6163626763 Age ≥65 yrs1415 2468 Male162418 76 ECOG PS 0/119/1317/1722/1416/1974/63 Stage IV at dx1922252187 Primary tumor Colon Rectum CRC, NOS 25 5 3 27 6 1 31 2 3 28 6 1 111 19 8 Prior treatment Radiation Chemotherapy 4949 5656 3838 4747 16 30

16. Time to Treatment Failure (TTF) Primary Endpoint CO (n=68)IO (n=71) Placebo (n=33) CaMg (n=35) Placebo (n=36) CaMg (n=35) Pts with event97%100%86%97% Median TTF (mos) 95% CI 4.0 3.3–5.5 4.6 3.6–6.0 6.9 5.6–8.9 4.6 3.6–6.9 4.25.6 Cox regression model Hazard ratio 95% CIp-value IO / CO0.58 0.41–0.83 0.0025 CaMg / placebo1.320.93–1.860.12

17. Kaplan-Meier estimate of TTF for IO vs CO a log rank test Unstratified (IO relative to CO), p=0.002 a Stratified by CaMg (IO relative to CO), p=0.003 a TTF (mos) 95% CI CO4.23.7 - 5.5 IO5.64.7 - 7.0

18. Progression-Free Survival (PFS) CO (n=68)IO (n=71) Placebo (n=33) CaMg (n=35) Placebo (n=36) CaMg (n=35) Pts with event46%26%25%34% Median (mos) 95% CI 3.9 2.3–NE 10.9 7.3–10.9 NE 8.2–NE 9.6 5.6–13.9 7.312.0 Cox regression model Hazard ratio 95% CIp-value IO / CO0.530.29–0.990.048 CaMg / Placebo0.990.55–1.790.976 NE, not estimable

19. Kaplan-Meier estimate of PFS for IO vs CO PFS (mos) 95% CI CO7.36.9 - NE IO12.08.2 - NE

20. Grade 3/4 Adverse Events a n (%) COIO Total (n=139) Placebo (n=33) CaMg (n=35) Placebo (n=36) CaMg (n=35) Neurotoxicity Neutropenia Leukopenia Thrombocytopenia Nausea Vomiting Fatigue Diarrhea Dehydration Hypertension Small intestinal obstr. Hyperglycemia Hand–Foot syndrome 8 (24) 4 (12) 1 (3) 2 (6) 1 (3) 2 (6) 1 (3) 0 2 (6) 0 8 (23) 1 (3) 2 (6) 1 (3) 2 (6) 1 (3) 0 3 (8) 5 (14) 0 2 (6) 3 (9) 1 (3) 3 (9) 0 1 (3) 3 (8) 2 (6) 0 4 (11) 3 (9) 1 (3) 4 (11) 2 (6) 4 (11) 2 (6) 3 (9) 2 (6) 1 (3) 0 3 (9) 23 (17) 20 (14) 3 (2) 4 (3) 10 (7) 8 (6) 9 (7) 8 (6) 7 (5) 6 (4) 5 (4) 3 (2) a Occurring in >2% patients for hematologic events and >3% patients for non-hematologic events 16 (24)7 (10)

21. Neurotoxicity Events (NTE) leading to dose reduction, discontinuation, or delay N pts (%) with >1 NTE leading to CO (n=68) IO (n=71) Placebo (n=33) CaMg (n=35) Placebo (n=36) CaMg (n=35) Discontinuation 8 (24)7 (20)3 (8)4 (11) 15 (22)7 (10) Delay1 (3)0 0 Dose reduction7 (21)6 (17)2 (6) Delay and dose reduction 01 (3) Delay or dose reduction 8 (24)7 (20)3 (8)3 (9) 15 (22)6 (8)

22. Neurotoxicity assessment — Patient Neurotoxicity Questionnaire (PNQ) Qualitative assessment of PSN (none, mild, moderate, moderate to severe, or severe PSN) Quantitative comparison of neurotoxicity effects in CO vs IO and placebo vs CaMg Answers to 2 items assessed: Item 1 — sense of touch in hands/fingers, or feet/toes or mouth area (chronic PSN) Item 2 — difficulty in swallowing, breathing, drinking or chewing food, or muscle spasms (acute PSN)

23. Mean PNQ by cycle Item 1 – chronic PSN

24. Mean PNQ by cycle Item 2 – acute PSN

25. Effect of treatment schedule and CaMg on change in PNQ (Cycle ≥ 8) PNQComparison Point estimate of difference Difference95% CIp-value Item 1CO / IO-0.28-0.55, -0.010.04 Placebo / CaMg-0.31-0.58, -0.040.02 Item 2CO / IO-0.39-0.64, -0.140.002 Placebo/CaMg-0.11-0.36, +0.150.42

26. Conclusions Several limitations of this analysis Trial not primarily intended to evaluate effects of CaMg on RR Small sample size Early discontinuation of trial Activity of FOLFOX + BEV unaffected by CaMg Suggestion of neuroprotection by CaMg IO is associated with significant improvement of TTF compared with CO – without compromising PFS CO leads to higher number of discontinuations from the study due to PSN compared with IO IO = OPTIMOX1-like strategy should be considered standard of care for first-line oxaliplatin-based therapy

27. BACKUP

28. Assessments Tumor assessments q 8 weeks Neurotoxicity evaluation q 2 weeks PE including patient neurotoxicity questionnaire (PNQ) Follow-up: q 3 months from end of treatment  3 years from randomization After study closure, an Independent Radiology Review Committee (IRRC) conducted a retrospective analysis of CT/MRI scans

29. Disposition and discontinuation data Number of pts CO n=69 IO n=71Total PlaceboCaMgPlaceboCaMg Randomized34353635140 Received treatment34 3635139 Discontinued treatment Adverse event Disease progression Investigator/pt decision/non- compliance Other 16 9 8 1 12 5 15 2 8 12 8 12 8 11 4 48 30 46 15

30. Exposure to Oxaliplatin COIO Placebo (n=33) CaMg (n=35) Placebo (n=36) CaMg (n=35) Duration of study treatment (months) Median (Range) 3.5 (0–15.1) 3.9 (0.5–12.5) 6.4 (0–15.8) 4.2 (0–13.9) Cumulative dose per patient (mg/m 2 ) Median (Range) 680 (88–2624) 745 (169–2262) 706 (85–1412) 682 (79–1752)

31. CaMg effect on categorized measures of neurotoxicity in PNQ Item 1 (as-treated population) Neurotoxicity N pts (%) Placebo (n=69) CaMg (n=70) A - None7 (11)13 (20) B - Mild19 (29)26 (39) (A or B)26 (40)30 (59) C - Moderate26 (40)17 (26) D - Moderate to severe13 (20)5 (8) E - Severe05 (8) (C or D or E)39 (60)27 (41) p-value0.036