Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA

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

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e N=198 “Treatment was given until disease progressed, the patient developed unacceptable toxic effects, or consent was withdrawn.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

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

8. NCCTG 9741 R A N D O M I Z E IFL N=245 FOLFOX (5-FU/LV/Oxali) N=246 Irinotecan/Oxaliplatin N=250 Goldberg JCO 2004.

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

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

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

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 Responding or stable disease after 12 weeks Maughan et al The Lancet. 2003. 361: 457-64.

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

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

18. Continuous v Intermittent Therapy:2nd 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. Continuous v Intermittent Therapy:GISCAD Trial E V A L U A T I O N E V A L U A T I O N A FOLFIRI x 2 m FOLFIRI x 2 m STOP x 2 m RANDOM CR, PR, SD B FOLFIRI x 2 m FOLFIRI x 4 m 2nd Line (OHP) Every 4 m until PD PD 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 Median OS 17 v 18 months HR 0.88 (0.69–1.14) Median chemo-free interval 3.5 months Median PFS 6 v 6 months HR 1.03 (0.81–1.29) Labianca R et al. Ann Oncol 2011;22:1236-1242

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

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

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

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

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

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

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

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

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

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

32. CONcePT TrialPrimary endpoint:TTF for CO vs IO schedule 270 pts First-line mCRC, 532 patients Primary endpoint: time to failure (TTF) Randomization (2x2): mFOLFOX7 + bevacizumab CO until Treatment Failure R +/- IV CaMg mFOLFOX7 + bevacizumabIntermittent oxaliplatin CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin Grothey et al ASCO 2008

33. CONcePT Trial: IO Arm 5-FU Cumulative oxaliplatin Months LV 200 2400 OX 85 BEV 5 x 8 680 mg/m2 4 200 2400 5 Early reintroduction of oxaliplatin if progression x 8 680 mg/m2 8 200 2400 85 5 x 8 1360 mg/m2 12 etc. Grothey et al ASCO 2008

34. CONcePT Trial Unstratified (IO relative to CO), p=0.002a Stratified by CaMg (IO relative to CO), p=0.003a a log rank test Grothey et al ASCO 2008

35. CONcePT Trial Grothey et al ASCO 2008

36. CONcePT Trial Grothey et al ASCO 2008

37. N016966 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 ] ) Saltz et al. JCO. 2008; 26: 2013-2019

38. MACRO Trial Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Capecitabine Oxaliplatin Bevacizumab until progression N=239 R Progression Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Bevacizumab until progression N=480 N=241 • 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% Taberno et al ASCO 2010

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

40. MACRO Trial Patients at risk 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