1. Have the OPTIMOX-2, CAIRO-3, COIN, DREAM and other recent trials settled the question of maintenance versus observation in advanced CRC? Yes Deborah Schrag, MD, MPH No John L. Marshall, MD

2. Maintenance Why we do it – Optimox, should we optimiri Timing of change – Switch or reduce What drugs – 5fu or capecitabine – Bev? Erlotinib, other? What if front line is an EGFR regimen? Do we build resistance vs start and stop? Other diseases- lung, breast, heme, prostate….

3. 3 Study Design and Drugs Phase III Trial of CapeOx vs. FOLFOX4 plus Bevacizumab or Placebo in First-line MCRC CapeOx + placebo (N=350) FOLFOX4 + placebo (N=351) CapeOx + bevacizumab (N=350) FOLFOX4 + bevacizumab (N=350) CapeOx (N=317) FOLFOX4 (N=317) Recruitment June 2003–May 2004 Recruitment Feb 2004–Feb 2005 Initial 2-arm open-label study (N=634) Publication of Bevacizumab Phase III data (Hurwitz H, et al. N Engl J Med 2004;350:2335-2352). Original Protocol Amended to a 2x2 placebo controlled design. Cassidy J. et al., Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006-2012.

4. PFS XELOX Non-inferiority Roche Medical Affairs. All rights reserved. Phase III Trial of XELOX vs. FOLFOX4 plus Bevacizumab or Placebo in First-line mCRC FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumabN=1017; 826 events XELOX/XELOX+placebo/XELOX+bevacizumabN=1017; 813 events Primary Objective Achieved Based on ITT Cassidy et al. ESMO 2006. Oral Presentation

5. PFS Superiority of Bevacizumab + CT Roche Medical Affairs. All rights reserved. HR=0.83 [97.5% CI 0.72–0.95] (ITT) p=0.0023 FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+ bevacizumab N=699; 513 events Primary Objective Achieved XELOX Subgroup FOLFOX Subgroup HR=0.77 [97.5% CI 0.63–0.94] (ITT) p=0.0026 XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events HR=0.89 [97.5% CI 0.73–1.08] (ITT) p=0.1871 FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events Phase III Trial of XELOX vs. FOLFOX4 plus Bevacizumab or Placebo in First-line mCRC Cassidy et al. ESMO 2006. Oral Presentation

6. Patients should remain ‘on treatment*’ to achieve the optimal clinical benefit with Bevacizumab Saltz, et al. ASCO 2007 (poster) *Preplanned analysis 05101520 Months PFS estimate FOLFOX4/XELOX + Bevacizumab FOLFOX4/XELOX + placebo 1.0 0.8 0.6 0.4 0.2 0 GENERAL: HR=0.83 (PFS 9.4 vs 8.0 months, p=0.0023) ON TREATMENT: HR=0.63 (PFS 10.4 vs 7.9 months, p<0.0001) 6 months

7. OPTIMOX Studies OPTIMOX-1: Maintenance therapy (N=620) FOLFOX 4 until progression FOLFOX 7 sLV5FU2 OPTIMOX-2: Chemotherapy-free interval (N=202) mFOLFOX 7 sLV5FU2 mFOLFOX 7 Chemotherapy- free interval Tournigand et al. J Clin Oncol. 2006;24:394. Maindrault-Goebel et al. ASCO, 2007. Abstract 4013.

8. Progression-free Survival

9. Overall Survival

10. Maughan TS et al. Lancet. 2003;361:457-464. PFS HR1.20 (0.96-1.49) favor continuous Continuous vs. Intermittent Therapy: MRC Trial Median off-treatment duration with intermittent therapy was 4.3 months – Significantly fewer adverse events Overall survival was similar in both groups Intermittent Continuous 100 75 50 25 0 OS (%) 178 (94) 176 (94) 76 (41) 74 (49) 24 (12) 17 (12)2 (0) 5 (0)3 2 PFS (%) 100 75 50 25 0 0 Months From Randomization 12243648 No. at Risk Intermittent Continuous 178 (162) 176 (152) 14 (6) 19 (15) 6 (0) 1 (1) 2 (0) 0 (0) 1 0 012243648 Months From Randomization

11. CR, PR, SD Previously Untreated mCRC R A N D O M I Z A T I O N FOLFIRI x 2 months FOLFIRI x 2 months FOLFIRI x 2 months FOLFIRI x 2 months EVALUATEEVALUATE EVALUATEEVALUATE Progression – Off Trial Continuous vs. Intermittent Therapy: GISCAD Trial 11 Break x 2 months then FOLFIRI x 2 months Break x 2 months then FOLFIRI x 2 months FOLFIRI x 4 months FOLFIRI x 4 months Labianca R et al. Ann Oncol. 2011;22:1236-1242.

12. 146 147 75 70 25 27 10 9 146 147 95 101 39 43 10 13 No. at Risk Continuous Intermittent Months 0 Patients, % 061218 Months 100 80 60 40 20 0 Patients, % 61218243036 130 124 60 68 19 29 Labianca R et al. Ann Oncol. 2011;22:1236-1242. Overall Survival Progression-Free Survival 100 80 60 40 20 0 Continuous arm Intermittent arm Events 145 143 Totals 146 147 Continuous arm Intermittent arm Events 145 143 Totals 146 147 Continuous vs. Intermittent Therapy: GISCAD Trial

13. CR, PR, SD Patients with newly diagnosed mCRC N = 480 Patients with newly diagnosed mCRC N = 480 R A N D O M I Z A T I O N Capecitabine Oxaliplatin Bevacizumab 6 cycles, q3 weeks Capecitabine Oxaliplatin Bevacizumab 6 cycles, q3 weeks Capecitabine Oxaliplatin Bevacizumab 6 cycles, q3 weeks Capecitabine Oxaliplatin Bevacizumab 6 cycles, q3 weeks EVALUATEEVALUATE EVALUATEEVALUATE Maintenance Bevacizumab: MACRO Trial 13 Diaz-Rubio E et al. Oncologist. 2012;17:15-25. Capecitabine Oxaliplatin Bevacizumab until Progression Capecitabine Oxaliplatin Bevacizumab until Progression Bevacizumab until Progression

14. MACRO: Overall Survival (ITT) XELOX-BevBev No. of Patients239241 Event175 (73%)174 (72%) Censored64 (27%)67 (28%) Median (95% CI)23.2 (19.79, 26.01) 19.99 (17.98,23.25) Time (months) XELOX-Bev Bev No. at Risk 241 239 Survival Probability 0.0 0.25 0.50 0.75 1.00 0 0 2 39 19 13 33 26 23 30 39 40 27 54 60 24 77 85 21 101 120 18 132 146 15 159 170 12 193 191 9 210 208 6 226 227 3 8 6 36 Bev XELOX-Bev Diaz-Rubio E et al. Oncologist. 2012;17:15-25. HR: 1.05 (0.851, 1.295)

15. OPTIMOX3 – DREAM protocol mFOLFOX7 + bevacizumab a XELOX2 + bevacizumab b FOLFIRI + bevacizumab c a Oxaliplatin 100 mg/m² d1 (6 cycles), 5-FU 2.4 g/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 6–12 cycles b Oxaliplatin 100 mg/m² d1 (6 cycles), capecitabine 1.25–1.5 g/m² bid d1–d8, bev 5 mg/kg d1 q2w, 6–12 cycles c Irinotecan 180 mg/m² d1, 5-FU 2.4 mg/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 12 cycles Bevacizumab (7.5 mg/kg q3w) + erlotinib (150 mg/d) until PD Bevacizumab (7.5 mg/kg q3w) + erlotinib (150 mg/d) until PD RANDOMIRANDOMISATSATIONIONRANDOMIRANDOMISATSATIONION No PD n=222 n=224 4 Jan 2007 – 13 Oct 2011 INDUCTION (N=700)MAINTENANCE (N=446) Bevacizumab (7.5 mg/kg q3w) until PD Bevacizumab (7.5 mg/kg q3w) until PD REREGGIISSTTRRAATTIIOONNREREGGIISSTTRRAATTIIOONNGISTRATION

16. Maintenance PFS (from randomization) Bevacizumab Bevacizumab + erlotinib No. of patients224222 Events177 (79%)150 (68%) Censored47 (21%)72 (32%) Median [95% CI] 4.57 [4.1 – 5.5]5.75 [4.5 – 6.2] HR [95% CI] 0.73 [0.59 – 0.91] p-value0.0050 Maintenance PFS (%) 0 20 40 60 80 100 Time (months) 26 0 4 8 10 12 Bevacizumab Bevacizumab + erlotinib No. at risk: Bevacizumab Bevacizumab + erlotinib 224 222 172 176 110 116 67 73 40 53 26 37 15 28

17. PFS from registration (randomised population) Bevacizumab Bevacizumab + erlotinib No. of patients224222 Events177 (79%)150 (68%) Censored47 (21%)72 (32%) Median [95% CI] 9.23 [8.5 – 10.1]10.22 [9.6 – 11.1] HR [95% CI] 0.73 [0.59 – 0.91] p-value0.0045 Maintenance PFS (%) 0 20 40 60 80 100 Time (months) 26 0 4 8 10 12 Bevacizumab Bevacizumab + erlotinib No. at risk Bevacizumab Bevacizumab + erlotinib 224 222 224 222 216 218 185 193 76 90 42 58 20 27 15 19 14 16 18 30 39 123 136

18. Overall survival (all patients, from registration) Overall survival (%) Time (months) 48 0 12 Median overall survival 25.4 months [95% CI 22.96–28.19] (n=700) No. at risk: 700 660 580 469 384 231 16 20 24 313 0 20 40 60 80 100

19. Study design SD or better after 6 cycles CAPOX- B observation R capecitabine + bevacizumab PD Re-introduction CAPOX-B PFS1 PFS2

20. Median PFS1 Observation4.1 m[95%CI: 3.9-4.4] Maintenance8.5 m[95%CI: 6.9-10.2] Stratified HR0.44[95%CI: 0.36-0.53] p value< 0.00001 PFS1 adjusted HR 0.41, p <0.001

21. TT2PD Median TT2PD Observation15.0 m[95%CI:13.6-16.4] Maintenance19.8 m[95%CI: 18.0-21.9] Stratified HR0.67[95%CI: 0.55-0.81] p value< 0.00001 adjusted HR 0.63, p <0.001

22. Overall Survival Median OS Observation18.2 m[95%CI: 16.3-20.8] Maintenance21.7 m[95%CI: 19.4-24.0] Stratified HR0.87[95%CI: 0.71-1.06] p value0.156 adjusted HR 0.80, p 0.035 preliminary survival analysis

23. Work to be done Agree to establish cape and bev as the standard arm Now we must do the studies –EGFR/VEGF –Immune therapies –Regorafanib, others