1. Safety and efficacy of oxaliplatin – fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE study HS Hochster H. S. Hochster, L. L. Hart, R. K. Ramanathan, J. D. Hainsworth, S. Griffing, R. D. Mass, Y. Nagarwala, G. Jirau-Lucca, A. Shpilsky, B. H. Childs

2. Background Oxaliplatin – fluoropyrimidine regimens: standard combination chemotherapy for stage III and IV CRC TREE-1 trial: comparison of three different oxaliplatin – fluoropyrimidine regimens (mFOLFOX, bFOL, CapeOx) for toxicity Bevacizumab: promising results in mCRC when added to first-line chemotherapy (bIFL or 5-FU – LV) 1,2 TREE-2 trial: TREE-1 trial modified to include bevacizumab 1. Hurwitz H, et al. N Engl J Med 2004; 2. Kabbinavar F, et al. J Clin Oncol 2003

3. Study design mFOLFOX CapeOx R bFOL (n=50) Nov 2002 – Oct 2003 mFOLFOX + bevacizumab bFOL + bevacizumab CapeOx (reduced dose) + bevacizumab (n=75) (n=74) Nov 2003 – Apr 2004 R TREE-1 TREE-2 n=150 n=223

4. mFOLFOX6: 14-day cycle bFOL: 28-day cycle LV (350 mg IV, 2 h) OX (85 mg/m 2 IV, 2 h) 5-FU (400 mg/m 2, IV bolus) 5-FU (2400 mg/m 2 IV, 46 h) Day 1 CapeOx: 21-day cycle OX (130 mg/m 2 IV, 2 h) Day 1Days 1 – 15 CAPE (1000 mg/m 2 orally bid a ) a 28 doses in total Day 1 Day 8 OX (85 mg/m 2 IV, 2 h) 5-FU (500 mg/m 2, IV bolus) LV (20 mg/m 2, IV bolus) Day 15 Day 2 OX (85 mg/m 2 IV, 2 h) Treatment regimens: TREE-1

5. mFOLFOX6 + bev: 14-day cycle bFOL + bev: 28-day cycle LV (350 mg IV, 2 h) OX (85 mg/m 2 IV, 2 h) 5-FU (400 mg/m 2, IV bolus) 5-FU (2400 mg/m 2 IV, 46 h) Day 1 CapeOx + bev: 21-day cycle OX (130 mg/m 2 IV, 2 h) Day 1Days 1 – 15 CAPE (850 mg/m 2 orally bid a ) a 28 doses in total; 650 mg/m 2 bid for patients with creatinine clearance 30–50 mL/min Day 1 Day 8 OX (85 mg/m 2 IV, 2 h) 5-FU (500 mg/m 2, IV bolus) LV (20 mg/m 2, IV bolus) Day 15 Day 2 OX (85 mg/m 2 IV, 2 h) Treatment regimens: TREE-2 BEV (5 mg/kg IV, 30–90 min) BEV (7.5 mg/kg IV, 30–90 min)

6. Inclusion criteria Histologically documented adenocarcinoma of the colon or rectum Inoperable metastatic disease No prior chemotherapy for metastatic/recurrent disease Age ≥18 years; ECOG performance status 0 – 1 At least 1 unidimensional measurable lesion

7. Exclusion criteria Prior treatment with oxaliplatin or bevacizumab Myocardial infarction within 6 months, current clinical evidence of congestive heart failure, or non-stable coronary artery disease Blood pressure >160/110 mmHg on medication; symptomatic peripheral vascular disease a Peripheral neuropathy a TREE-2 cohort only

8. Objectives Primary:  Incidence of grade 3/4 toxicity during initial 12 weeks of therapy Secondary:  Response rate (RECIST)  TTP (censored for second-line treatment)  TTF (treatment discontinuation, progression, or death)  Survival

9. Demographic and baseline characteristics a TREE-1TREE-2 mFOLFOX (n=49) bFOL (n=50) CapeOx (n=48) mFOLFOX + bev (n=71) bFOL + bev (n=70) CapeOx + bev (n=72) Median age (years) [range] 62 [35 – 79] 62 [31 – 84] 62 [32 – 84] 64 [31 – 83] 57 [30 – 85] 62 [32 – 82] Male (%)576265614958 ECOG PS 0 (%)615852615465 Prior adjuvant chemotherapy (%) 4516272431 a With the exception of tumor response, all data are presented for the as-treated population, defined as all patients who received at least one dose of treatment

10. Grade 3 /4 adverse events during first 12 weeks Patients (%) TREE-1TREE-2 (primary endpoint) mFOLFOX (n=49) bFOL (n=50) CapeOx (n=48) mFOLFOX + bev (n=71) bFOL + bev (n=70) CapeOX + bev (n=72) Related event a [95% CI] 59 [44 – 73] 36 [ 23 – 51] 67 [52 – 80] 59 [47 – 71] 51 [39 – 64] 56 [43 – 67] All events [95% CI] 76 [61 – 87] 44 [30 – 59] 73 [58 – 85] 65 [53 – 76] 60 [48 – 72] 58 [46 – 70] a Determined by the investigator to be related (possibly or probably) to study drug

11. Grade 3 /4 adverse events occurring in ≥5% of patients Patients (%) TREE-1TREE-2 mFOLFOX (n=49) bFOL (n=50) CapeOx (n=48) mFOLFOX + bev (n=71) bFOL + bev (n=70) CapeOX + bev (n=72) Neutropenia531815491910 Dehydration a 812276148 Diarrhea a 332631132619 Hypertension00271315 TE, arterial TE, other 2 10 0404 0202 0 10 0 10 3434 Nausea161419611 Vomiting14101911310 Neurotoxicity181023141115 Hand – foot82190010 Any grade 3/4967685 7476 a The high incidence of dehydration and diarrhea in the CapeOx arm in TREE-1 was effectively reduced by capecitabine dose reduction in TREE-2. TE, Thromboembolic events

12. Adverse events of special interest Adverse event (all grades), n (%) of patients TREE-1TREE-2 mFOLFOX (n=49) bFOL (n=50) CapeOx (n=48) mFOLFOX + bev (n=71) bFOL + bev (n=70) CapeOX + bev (n=72) Sepsis0 (0) 2 (4.2)3 (4.2)3 (4.3)1 (1.4) Bowel perforation 0 (0) 03 (4.2)2 (2.9)2 (2.8) Impaired wound healing 0 (0) 1 (2.1)4 (5.6)1 (1.4)4 (5.6) Treatment- related death 0 (0)1 (2.0)3 (6.3)0 (0)3 (4.3)3 (4.2)

13. Best confirmed tumor response (per-protocol population) a Tumor response (RECIST) (% patients) TREE-1TREE-2 mFOLFOX (n=46) bFOL (n=45) CapeOx (n=37) mFOLFOX + bev (n=70) bFOL + bev (n=63) CapeOX + bev (n=69) CR003653 PR432232473745 SD264751394132 PD2829146139 NE2203512 ORR (CR+PR) [95% CI] 43 [29 – 59] 22 [11 – 37] 35 [20 –53 ] 53 [41 – 65] 41 [29 – 54] 48 [36 – 60] a All patients who received at least 1 treatment with oxaliplatin  fluoropyrimidine ± bevacizumab and who have sufficient data to allow assessment of response

14. Time to treatment failure 1.0 0.8 0.6 0.4 0.2 0 Probability 0510 Time to treatment failure (months) 152025 1.0 0.8 0.6 0.4 0.2 0 Probability 0510 Time to treatment failure (months) 15 2025 TREE-1TREE-2 mFOLFOX bFOL CapeOx mFOLFOX + bevacizumab bFOL + bevacizumab CapeOx + bevacizumab CapeOx (n=48) bFOL (n=50) mFOLFOX (n=49) 4.44.96.5 Median (months) 3.0–5.83.5–6.15.4–8.395% CI mFOLFOX + bev (n=71) 4.9–6.7 5.8 bFOL + bev (n=70) 4.0–6.6 5.5 CapeOx + bev (n=72) 4.7–6.5 5.5 Median (months) 95% CI

15. Time to tumor progression a a With censoring for second-line treatment CapeOx + bev (n=72) bFOL + bev (n=70) mFOLFOX + bev (n=71) 8.6–12.56.6–9.97.9–11.795% CI 10.38.39.9 Median (months) CapeOx (n=48) bFOL (n=50) mFOLFOX (n=49) 5.1–7.4 4.2–8.0 6.5–9.8 95% CI 5.96.98.7 Median (months) 1.0 0.8 0.6 0.4 0.2 0510 Time to tumor progression (months) 152025 0 Probability 1.0 0.8 0.6 0.4 0.2 0510 Time to tumor progression (months) 152025 0 Probability TREE-1TREE-2 mFOLFOX bFOL CapeOx mFOLFOX + bevacizumab bFOL + bevacizumab CapeOx + bevacizumab

16. Survival: TREE-1 CapeOx mFOLFOX bFOL 1.0 0.8 0.6 0.4 0.2 0.1 0.3 0.5 0.7 0.9 0510 Survival time (months) 152025303540 0 Probability CapeOx (n=48) bFOL (n=50) mFOLFOX (n=49) 12.5–22.311.5–24.6 14.2 – 24.2 95% CI 17.217.919.2 Median (months)

17. Survival: TREE-2 CapeOx + bevacizumab mFOLFOX + bevacizumab bFOL + bevacizumab 1.0 0.8 0.6 0.4 0.2 0.1 0.3 0.5 0.7 0.9 0510 Survival time (months) 152025303540 0 Probability CapeOx + bev (n=72) bFOL + bev (n=70) mFOLFOX + bev (n=71) 21.8–NE18.8–25.3 18.0 – NE 95% CI 27.020.726.0 Median (months) NE, not evaluable

18. Survival: chemotherapy regimens combined TREE-1 (n=147) TREE-2 (n=213) Patients who have died, n (%)101 (69)111 (52) Patients alive at last follow-up, n (%)46 (31)102 (48) Median survival time, months [95% CI] 18.2 [14.5 –21.6] 24.4 [21.4 –26.8] Survival probability, % [95% CI] 12 months 18 months 24 months 67.3 [58.9 – 74.3] 50.1 [41.5 – 58.1] 35.8 [27.6 – 44.1] 79.1 [73.0 –84.0] 64.7 [57.8–70.8] 50.7 [43.6–57.4]

19. Survival: oxaliplatin-based regimens combined a 21.4–26.814.5–21.695% CI 24.418.2 Median survival (months) TREE-2 (n=213) TREE-1 (n=147) 1.0 0.8 0.7 0.5 0.3 0.1 0.9 0.6 0.4 0.2 051015202530 Survival time (months) 3540 0 Probability TREE-1 TREE-2 a Sequential cohorts without (TREE-1) and with bevacizumab (TREE-2)

20. Efficacy summary TREE-1TREE-2 ORR a (% patients)22 – 4341 – 53 TTP b (months)6.1 – 8.78.3 – 10.3 TTF (months)4.4 – 6.55.5 – 5.8 Median survival time (months) c 18.224.4 a Per-protocol population. b Censored for second-line therapy. c All three treatment arms combined

21. Conclusions (1) Oxaliplatin, in combination with bolus, infusional, or oral fluoropyrimidine regimens, is active and well tolerated in previously untreated mCRC No major differences in activity were observed between the three fluoropyrimidine regimen, but bFOL may be the least efficacious (response and TTP in both cohorts) With dose reduction a of capecitabine, CapeOx with bevacizumab was tolerated much better (compared with CapeOX in TREE-1)  equivalent activity to FOLFOX with bevacizumab a From 1000 mg/m 2 (TREE-1) to 850 mg/m 2 orally bid (TREE-2),

22. Conclusions (2) Bevacizumab, when added to oxaliplatin –f luoropyrimidine regimens results in increased efficacy with the expected toxicity profile  Addition of bevacizumab did not change TTF but improved TTP Overall survival was improved with the addition of bevacizumab (sequential historical cohorts)  Median survival time was: 18.2 months in TREE-1 a (95% CI:14.5–21.6 months) 24.4 months in TREE-2 a (95% CI: 21.4–26.8 months) a All three treatment arms combined

23. Acknowledgment Investigators  Lowell Hart, Florida Cancer Specialists  R. Ramanathan, Univ Pittsburgh  John Hainsworth, Sarah Cannon Cancer Center  Louis Fehrenbacher, Kaiser Permanente  Yusif Abubakr, Florida Oncology  Lee Schwartzberg, West Cancer Clinic  Peter Eisenberg, California Cancer Care  James Atkins, Southeastern Medical Oncology  Maunuel Modiano, Arizona Clinical Research Center  Marshall Levine, Greater Baltimore Medical Center  Joaquina Veranda, Kansas City VA Hospital  Gladys Rodriguez, South Texas Oncology  Michael Wertheim, Treasure Coast  George Geils, Charleston Hematology Oncology  Margaret Deutsch, Raleigh Hematology Oncology  Renato LaRocca, Kentuckiana Cancer Institute  David Mintzer, Pennsylvania Hematology Oncology  Other investigators sanofi aventis  Gilbert Jirau-Lucca, MS  Arkady Shpilsky, PhD  Yasir Nagarwala  Lauri Wells, MD  Barry Childs, MD Genentech  Robert Mass, MD  Eric Hedrick, MD  David Emanuel, MD OTHERS  Nursing personnel  Data Personnel  Research Staff  PATIENTS