1. Standard Management of Stage IV Colorectal Cancer: Start and Stop, Maintenance, Chemotherapy Holidays Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA

2. Disclosures Consultant: Sanofi-aventis Research funding (to DFCI or CALGB) – Pfizer, BMS, Astra Zeneca NCI research funding

3. Outline for this segment Continuous treatment for metastatic colorectal cancer – how we got here 3 strategies besides continuous –Full chemotherapy holiday –Maintenance –Start and stop (some twist of above 2)

4. 5-Fluorouracil First introduced by Heidelberger & colleagues 1957 (J Am Chem Soc 1957; Nature 1957) While toxic, it does not have cumulative dose limiting toxicities –Rare patients with relative DPD deficiency have severe bone marrow suppression – else, most do not bone marrow limitations

5. Chemotherapy versus Best Supportive Care TrialNTreatmentsDurationResult NORDIC trial133 Advanced, asymptomatic Immediate v delayed MLF Up to 6 monthsOS: 14 m v 9 m (p log rank 0.14; p Breslow-Gehan <0.02 Scheithauer et al 40 Advanced, symptomatic 5-FU, LV, CDDP v BSC only Up to 6 monthsOS: 11 v 5 months Yorkshire GI Tumour Group 57 residual disease after palliative surgery Methyl CCNU, 5-FU v BSC only Up to 2 years1 yr OS: 74 v 57%

6. RANDOMIZeRANDOMIZe Irinotecan IFL(bolus 5-FU/LV/ Irinotecan) IFL(bolus 5-FU/LV/ Irinotecan) 5-FU/LV (Mayo Clinic) Saltz LB et al. N Engl J Med. 2000;343:905; N=226 N=231 Irinotecan/5-FU/LV (AIO or de Gramont regimen) Irinotecan/5-FU/LV (AIO or de Gramont regimen) 5-FU/LV (AIO or de Gramont regimen) 5-FU/LV (AIO or de Gramont regimen) Douillard JY et al. Lancet. 2000;355:1041. N=198 N=187 RANDOMIZeRANDOMIZe First-Line Irinotecan “Treatment was given until disease progressed, the patient developed unacceptable toxic effects, or consent was withdrawn. “ “Treatment was continued until one of the following occurred: disease progression, unacceptable adverse effects, or the withdrawal of consent by the patient. “

7. RANDOMIZERANDOMIZE De Gramont 5-FU/LV FOLFOX De Gramont et al. JCO. 2000; 18: 2938-47; Giacchetti et al. JCO. 2000; 18: 136-47; N=210 First-Line Oxaliplatin “Treatment was continued until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue treatment. “ RANDOMIZERANDOMIZE Chronomodulated 5-FU/LV Oxaliplatin + Chrono 5-FU/LV N=100 Treatment continued until toxicity limited, patient became surgical candidate, patient refusal, loss to f/u, death

8. RANDOMIZERANDOMIZE IFL Irinotecan/Oxaliplatin FOLFOX (5-FU/LV/Oxali) Goldberg JCO 2004. N=245 N=246 N=250 Response rate Time to Progress Median Overall Survival Grade 3/4 Neutropenia Grade 3/4 Diarrhea Grade 3/4 Neuropathy IFL33 %6.9 m14.8 m 40 %28 %3 % FOLFOX45 %8.7 m19.5 m 50 %12 %18 % IROX35 %6.5 m17.4 m 36 %24 %7 % NCCTG 9741

9. Goldberg JCO 2004. NCCTG 9741 IFL  67% ceased treatment due to disease progression or FOLFOX  42% IROX  55%

10. Log Kill Kinetics Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493 Rate of tumor volume regression is proportional to the rate of growth.

11. Gompertzian Model of Tumor Growth and Norton–Simon hypothesis Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493 Rate of tumor volume regression is proportional to the rate of growth.

12. Lung Cancer Experience Continuation of 2 and 3 drug combinations beyond 4-6 cycles does not improve survival Socinski M A et al. JCO 2002;20:1335-1343

13. Lung Cancer Experience Maintenance with non-cross resistant agents likely helpful –Docetaxel – PFS significant; OS trend –Pemetrexed – PFS and OS significant –EGFR TKIs – PFS significant; OS mixed data

14. Continuous v Intermittent Therapy: MRC Trial Maughan et al The Lancet. 2003. 361: 457-64. Responding or stable disease after 12 weeks

15. Continuous v 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 Maughan et al The Lancet. 2003. 361: 457-64. PFS HR 1.20 (0.96-1.49) favor continuous

16. Continuous v Intermittent Therapy: MRC Trial Selection bias – randomization after known disease control to therapy –Included and not included patients similar baseline characteristics Only 37% in intermittent group resumed scheduled treatment at progression Maughan et al The Lancet. 2003. 361: 457-64.

17. Continuous v Intermittent Therapy: 2 nd Line Irinotecan Lal R et al. JCO 2004;22:3023-3031 Progressed on fluoropyrimidine therapy

18. Continuous v Intermittent Therapy: 2 nd Line Irinotecan No differences in failure-free survival (P =.999) or overall survival (P =.11) No difference in mean global health status QOL score Lal R et al. JCO 2004;22:3023-3031

19. FOLFIRI x 2 m EVALUATIONEVALUATION PD STOP x 2 m A B 2 nd Line (OHP) CR, PR, SD RANDOM FOLFIRI x 2 m FOLFIRI x 2 m FOLFIRI x 4 m Every 4 m until PD EVALUATIONEVALUATION Continuous v Intermittent Therapy: GISCAD Trial Labiana ASCO 2006

20. Continuous v Intermittent Therapy: GISCAD Trial Labianca R et al. Ann Oncol 2011;22:1236-1242

21. Continuous v Intermittent Therapy: GISCAD Trial Labianca R et al. Ann Oncol 2011;22:1236-1242 Median OS 17 v 18 months HR 0.88 (0.69–1.14) Median PFS 6 v 6 months HR 1.03 (0.81–1.29) Median chemo-free interval 3.5 months

22. OPTIMOX 1: Trial of Maintenance Tournigand et al. JCO 2006;24:394-400 FOLFOX7 x 6 cycles sLV5FU2 x up to 12 cycles FOLFOX7 x 6 cycles sLV5FU2 x up to 12 cycles FOLFOX7 x 6 cycles FOLFOX4 until Progression N=311 N=309 RANDOMIZeRANDOMIZe Only 40% reintroduced oxaliplatin 18.5% early progression/death 18.4% toxicity (including neuropathy) 5.5% surgery 17.5% unknown

23. OPTIMOX 1: Trial of Maintenance Tournigand et al. JCO 2006;24:394-400

24. OPTIMOX 1: Trial of Maintenance Tournigand et al. JCO 2006;24:394-400 Duration of Disease Control

25. OPTIMOX 1: Trial of Maintenance Tournigand et al. JCO 2006;24:394-400 PFSOS

26. OPTIMOX 1: Trial of Maintenance Tournigand et al. JCO 2006;24:394-400 Grade 3 / 4 Toxicity Grade 3 Neurotoxicity

27. OPTIMOX 2: Go and Full Stop Chibaudel B et al. JCO 2009;27:5727-5733

28. OPTIMOX 2: Go and Full Stop A FOLFOX7 x 6 cy AAAAA FOLFOX7 x 6sLV5FU2 Baseline progression FOLFOX7 x 6 cy AAAA FOLFOX7 x 6 Chemotherapy-free interval Baseline progression LV 400 5-FU 3000 mFOLFOX7 Oxali 100 H0 H2 H24 H48 LV 400 5-FU 3000 sLV5FU2 H0 H2 H24 H48 5FUb 400 Cycles every 14 days, d ose mg/m² OPTIMOX 1 OPTIMOX 2 A A Maindrault-Goebel ASCO Presentation 2006

29. OPTIMOX 2: Go and Full Stop t T size FOLFOX ProgressionBaseline progression Progression at reintroduction Chemotherapy-free Interval Maindrault-Goebel ASCO Presentation 2006

30. OPTIMOX 2: Go and Full Stop Chibaudel B et al. JCO 2009;27:5727-5733 HR= 0.71 (95% CI, 0.51 to 0.99; P =.046 Median duration of maintenance therapy = 4.8 months in the arm 1 Median duration of CFI = 3.9 months in arm 2.

31. OPTIMOX 2: Go and Full Stop Chibaudel B et al. JCO 2009;27:5727-5733 PFS HR = 0.61; P =.0017 OS HR = 0.88; P = 0.42

32. CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin CONcePT Trial Primary endpoint: TTF for CO vs IO schedule 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 Grothey et al ASCO 2008

33. 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 CONcePT Trial: IO Arm Grothey et al ASCO 2008 Early reintroduction of oxaliplatin if progression

34. 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 CONcePT Trial Grothey et al ASCO 2008

35. CONcePT Trial PFS (mos) 95% CI CO7.36.9 - NE IO12.08.2 - NE Grothey et al ASCO 2008

36. 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) CONcePT Trial Grothey et al ASCO 2008

37. N016966 Saltz et al. JCO. 2008; 26: 2013-2019 Treatment d/c due to PD in 29% in the bevacizumab-containing arms and 47% in the placebo-containing arms Prespecified secondary analysis, median on-rx PFS = 10.4 vs 7.9 months (HR, 0.63 [ 0.52 to 0.75 ] )

38. MACRO Trial Progression R Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Bevacizumab until progression N=480 N=239 N=241 Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Capecitabine Oxaliplatin Bevacizumab until progression Taberno et al ASCO 2010 Non-inferiority design Sample Size: 470 patients; 235 per arm Assuming 10 months as median PFS Non-inferiority limit of 7.6 m (HR=1.32) One sided alpha = 0.025, one side; Power = 80%

39. LNI: 1.32 Patients at risk MACRO Trial Taberno et al ASCO 2010

40. Patients at risk MACRO Trial Taberno et al ASCO 2010

41. Some Ongoing Trials AIO-Studien-gGmbH (n = 760) –FOLFOX / Bevacizumab x 24 week then maintenance with fluoropyrimdine / bevacizumab OR bevacizumab alone OR full treatment holiday Dutch Colorectal Cancer Group (n = 635) –XELOX / Bevacizumab x 6 months then capecitabine / bevacizumab OR full treatment holiday Spanish Cooperative Group (n = 192) –FOLFOX / Cetuximab x 18 weeks then continuation OR cetuximab only Swiss Group (n = 238) –Chemotherapy / Bevacizumab x 16-24 weeks then bevacizumab OR full treatment holiday

42. Some Ongoing Trials FFCD (n = 188) –FOLFIRI / Bevacizumab x 24 week then maintenance bevacizumab alone OR full treatment holiday Lund University Hospital (n = 240) –Chemotherapy / Bevacizumab x 4 months then bevacizumab / erlotinib OR bevacizumab only DREAM / OPTIMOX 3 (n = 640) –FOLFOX or XELOX / Bevacizumab then bevacizumab / erlotinib OR bevacizumab only

43. What To Do? Data can be seen as favoring any approach –Continuing combination therapy til progression –Maintenance with some of the agents –Full treatment holidays Don’t forget about surgery if inoperable  operable One size (or at least strategy) doesn’t fit all –Patient preferences, goals, quality of life –Low burden disease / asymptomatic versus symptomatic or high burden of disease –Consider initial response to therapy Consider a clinical trial for your patient