1. Intermittent versus Continuous Systemic Therapy for Metastatic Colorectal Cancer PRO: Continue Systemic Therapy Deb Schrag, MD, MPH Presentation in “Great Debates” Symposium March 28 th, 2014 Attending Physician, Dana-Farber Cancer Institute Professor of Medicine, Harvard Medical School Boston MA, USA

2. Overview Brief review of stop versus go trials –COIN –OPTIMOX1 and 2 –DREAM –CAIRO-3 Challenges to interpretation of these studies Strategies for clinical decision making

3. Common Clinical Decisions What is optimal management of mCRC post-induction chemo? How long to continue induction systemic rx? Should maintenance therapy: –Be identical to induction? –Drop oxaliplatin? –Include 5FU/Bev? –Bev alone, Bev/erlotinib? –No maintenance? How long is it reasonable to continue chemo breaks?

4. Strategy for post-induction systemic treatment for mCRC patients who do not have PD Example trial that uses this strategy Plan to alternate intense/light phases of treatment..eg 2 months on 2 months off systematically GISCAD Eliminate the most toxic ingredient eg oxaliplatin or irinotecan but restart the more intense regimen at progression OPTIMOX-1 Eliminate cytotoxics and continue biologics DREAM/OPTIMOX-3, SAKK Eliminate all therapy….true “holiday”OPTIMOX 2, CAIRO-3 Stop and Go Strategies for Post- Induction Systemic Therapy Are Not All Created Equal

5. Stop and Go Trials’ Heterogeneity Makes them Challenging to Compare Different induction regimens/durations Different maintenance regimens/durations Various endpoints 1 st PFS interval, 2 nd PFS interval Duration of disease control OS Monitoring strategy influences PFS assessment CEA frequency Scan frequency

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

7. Continuous v Intermittent Therapy: MRC COIN Trial CAPOX or FOLFOX until PD vs. CAPOX/FOLFOX for 12 weeks with re- initiation of same chemo at progression for another 12 weeks Median off-treatment duration with intermittent therapy was 4.3 months Significantly fewer adverse events Overall survival was similar in both groups Intermittent strategy didn’t meet non-inferiority threshold Maughan et al The Lancet. 2003. 361: 457-64. PFS HR 1.20 (0.96-1.49) favors continuous

8. OPTIMOX Studies OPTIMOX-1 N = 620 FOLFOX4 until TF FOLFOX7 sLV5-FU2 OPTIMOX-2 N = 202 mFOLFOX7 sLV5-FU2 mFOLFOX7 CFI Tournigand et al, JCO 2006 Maindrault-Goebel et al, ASCO 2007 Abstract #4013

9. OPTIMOX 1: Hold the oxaliplatin post-induction 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

10. OPTIMOX 1: Maintenance 5FU Alone Tournigand et al. JCO 2006;24:394-400 PFSOS No meaningful benefit is clearly evident from continuation of oxaliplatin without a break Caveat: most of us don’t use FOLFOX4 or 7

11. OPTIMOX 1: Maintenance 5FU alone Tournigand et al. JCO 2006;24:394-400 Grade 3 / 4 Toxicity Grade 3 Neurotoxicity Continuous therapy has: higher overall toxicity substantially higher late neurotoxicity

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

13. 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 chemotherapy free interval = 3.9 months in arm 2.

14. 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 A chemotherapy holiday with no maintenance therapy has significantly worse PFS compared to maintenance therapy (allowing for attenuating oxaliplatin). Overall survival trend also favors maintenance therapy but is not significant

15. 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 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%

16. LNI: 1.32 Patients at risk MACRO Trial: Non-significant PFS trend favors continuation of XELOX Taberno et al ASCO 2010

17. Patients at risk MACRO Trial No difference in overall survival Taberno et al ASCO 2010

18. The GERCOR DREAM phase III trial: Bevacizumab with or without erlotinib maintenance following induction 1 st -line chemotherapy plus bevacizumab, in patients with metastatic CRC CC. Tournigand et al ASCO 2012 6-12 cycles of Induction Chemotherapy –EITHER FOLFOX-7 or XELOX or FOLFIRI all with Bev If no Disease Progression then randomize 1:1 to Maintenance Bev and Erlotinib or Maintenance Bev alone

19. DREAM Results Bev vs. Bev/Erlotinib maintenance B 222 B+E 223 HRP value PFS from randomization 4.65.80.73P=.005 PFS from registration 9.210.20.75P=.005 Grade 3 skin toxicity 0%20%-- Overall survival no difference: 25.4 months [95% CI 22.9–28.2] TAKE HOME: Marginal survival benefit and excess toxicity for Bev/Erlotinib

20. SAKK: Induction +/- Maintenance Bev First-line chemo- therapy + BEV for 4-6 months No PD Randomization 1: 1 BEV continuation (7.5 mg/kg q 3 w) until PD No antitumor treatment (no BEV) until PD Stratification factors: Best response during first-line chemotherapy + BEV (CR/PR vs SD) Duration of first-line chemotherapy + BEV (16-20 vs 21-24 weeks) Type of chemotherapy (Irinotecan + 5-FU vs Oxalipaltin + 5-FU vs Fluoropyrimidine mono) Disease burden (metastases in one organ vs multiple organs) Study conducted in 26 sites in Switzerland (accrual period 2007-2012)

21. SAKK: Induction +/- Maintenance-B TTP (from randomization) BEVno BEV No. of events124123 Median (95%CI) 4.1 months (3.1-5.4) 2.9 months (2.8-3.8) HR 95% CI 0.74 (0.57-0.95) Non-inferiorityp = 0.47 Koeberle ASCO 2013 TTP Trend favors continued Bev

22. SAKK: Induction +/- Maintenance-B PFS (from start of first-line therapy) BEVno BEV No. of events125124 Median (95%CI) 9.5 months (8.6.-10.2) 8.5 months (8-8.9) HR 95% CI 0.75 (0.58-0.96) Differencep = 0.021 Koeberle ASCO 2013 PFS Trend favors continued Bev

23. SAKK: Induction +/- Maintenance-B Overall Survival (from start of first-line therapy) BEV no BEV No. of events84 Median (95%CI) 25.1 months (22-28.9) 22.8 months (20.3-26.1) HR 95% CI 0.83 (0.61-1.12) Differencep = 0.218 OS Trend favors continued Bev Koeberle ASCO 2013

24. CAIRO-3: Study design SD/PR/CR post CAPOX-B x 6 observation R capecitabine + bevacizumab PD Re-introduction CAPOX-B PFS1 PFS2 Koopman: ASCO 2013 for Dutch Colorectal Study Group Primary endpoint: PFS2 time from randomization to progression upon re-introduction of CAPOX- B PFS2 is considered to be equal to PFS1 for patients in whom CAPOX- B is not reintroduced after PFS1 for any reason

25. CAIRO-3: Study design SD/PR/CR post CAPOX-B x 6 observation R capecitabine + bevacizumab PD Any further Rx Including CAPOX-B PFS1 TT2PD Koopman: ASCO 2013 for Dutch Colorectal Study Group TT2PD = time to second progression of disease = time from randomization to progression after any post PFS1 Rx including CAPOX-B

26. CAIRO-3 Primary endpoint PFS2 Median PFS2 Observation10.5 m[95%CI: 9.3-12.3] Maintenance11.8 m[95%CI: 10.2-13.3] Stratified HR0.81[95%CI: 0.67-0.98] p value0.028 adjusted HR 0.77, p 0.007

27. CAIRO-3 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

28. CAIRO-3 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

29. Cancer Care Ontario Metanalysis Includes 10 trials, but not CAIRO3 Notes heterogeneity of stop/go strategies Variation in maintenance regimens Inconclusive as to benefits

30. Evidence Summary from Trials No strategy is clearly superior The preponderance of evidence favors some form of maintenance therapy Reasonable to drop the oxaliplatin (OPTIMOX-1)—low threshold to do so Reasonable to continue 5FU-B (CAIRO)

31. Gompertzian Model of Tumor Growth and Norton–Simon hypothesis Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493 The Norton-Simon hypothesis states that the rate of cancer cell death in response to treatment is directly proportional to the tumor growth rate at the time of treatment. response to treatment

32. Factors to Consider in Counseling mCRC patients about “Chemo Holidays” Tilt towards maintenance: Continued response could result in candidacy for R0 resection Major/brisk/ongoing response More symptoms from cancer than from chemotherapy Easy to track disease status— CEA or measurable disease mCRC is primary threat to survival Tolerates chemotherapy well Prefers intensive management Tilt towards true holiday Will never be a candidate for R0 resection Stable disease/slow response Minimal disease burden Tolerates therapy poorly Major comorbidity Prefers less intensive/interventionist management

33. Viewpoint We are saturated on maintenance regimen trials Time to tailor strategies to disease biology If biology doesn’t provide a clear cut signal-- patient preference is the key issue Better understanding of resistance mechanisms and genomics should enable us to distinguish low vs. high grade tumors with greater accuracy

34. Are further trials of continuous versus intermittent treatment important? With current agents, seems unlikely that additional trials will provide greater clarity May yield some insight from subgroup analyses based on genomic charachteristics of mCRC genomic analyses of olecular subtypes by continuous vs. intermittent strategy neede