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Deb Schrag, MD, MPH Presentation in “Great Debates” Symposium March 28 th , 2014

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

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Deb Schrag, MD, MPH Presentation in “Great Debates” Symposium March 28 th , 2014

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  1. Intermittent versus Continuous Systemic Therapy for Metastatic Colorectal CancerPRO: Continue Systemic Therapy Deb Schrag, MD, MPH Presentation in “Great Debates” Symposium March 28th, 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. 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 • 1st PFS interval, 2nd 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 Responding or stable disease after 12 weeks Maughan et al The Lancet. 2003. 361: 457-64.

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

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

  9. OPTIMOX 1: Hold the oxaliplatin post-induction 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

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

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

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

  13. 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 chemotherapy free interval = 3.9 months in arm 2. Chibaudel B et al. JCO 2009;27:5727-5733

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

  15. 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 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

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

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

  18. The GERCOR DREAM phase III trial: Bevacizumab with or without erlotinib maintenance following induction 1st-line chemotherapy plus bevacizumab, in patients with metastatic CRCCC. 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 ResultsBev vs. Bev/Erlotinib maintenance 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 BEV continuation (7.5 mg/kg q 3 w) until PD No PD First-linechemo-therapy + BEV for 4-6 months Randomization 1: 1 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-BTTP (from randomization) TTP Trend favors continued Bev Koeberle ASCO 2013

  22. SAKK: Induction +/- Maintenance-B PFS (from start of first-line therapy) PFS Trend favors continued Bev Koeberle ASCO 2013

  23. SAKK: Induction +/- Maintenance-B Overall Survival (from start of first-line therapy) OS Trend favors continued Bev Koeberle ASCO 2013

  24. CAIRO-3: Study design PFS1 PFS2 capecitabine + bevacizumab observation Re-introduction CAPOX-B SD/PR/CR post CAPOX-B x 6 PD PD R 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 Koopman: ASCO 2013 for Dutch Colorectal Study Group

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

  26. CAIRO-3 Primary endpoint PFS2 adjusted HR 0.77, p 0.007

  27. CAIRO-3 TT2PD adjusted HR 0.63, p <0.001

  28. CAIRO-3 Overall Survival 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 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. Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493

  32. Factors to Consider in Counseling mCRC patients about “Chemo Holidays” Tilt towards maintenance: 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 • 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

  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

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