What s New? Dr. Barbara Melosky

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1 Metastatic Colorectal o Carcinoma a What s New? Dr. Barbara Melosky

2 Objectives Review any recent changes regarding treatment t t options for mcrc Discuss the common and expected toxicities of treatment Discuss new targeted therapies that will be seen in the clinic in the future

3 Conflict of Interest I have received honorariums from Roche Sanofi-Aventis Amgen

4 Metastatic Colorectal Cancer Completely Unresectable Resectable Potentially Resectable

5 mcrc Resectable 15% Unresectable 85% Preoperative Therapy Resectable First-Line 2-3 months 15-30% Chemotherapy 2-3 months Hepatectomy (One-stage or Two-stage) ± PVE* CONVERSION Second-Line Chemotherapy Postoperative Therapy 3-4 months Third-Line Chemotherapy Kopetz S and Vauthey JN Lancet 2008

6 Metastatic Colorectal Cancer Completely Unresectable

7 mcrc Resectable 15% Unresectable 85% Preoperative Therapy Resectable First-Line 2-3 months 15-30% Chemotherapy 2-3 months Hepatectomy (One-stage or Two-stage) ± PVE* CONVERSION Second-Line Chemotherapy Postoperative Therapy 3-4 months Third-Line Chemotherapy Kopetz S and Vauthey JN Lancet 2008

8 Lines of Therapy Today First Line FOLFIRI + Bevacizumab FOLFOX + Bevacizumab Optimox or Drug Holidays Capecitabine Second Line FOLFOX or FOLFIRI No Bevacizumab is allowed Third Line Kras WT: Panitumumab or Cetuximab

9 Treatment Options in mcrc Monotherapy RR 15-30% MS months Combination therapy RR 30-50% MS months Sequential therapy incorporating different combination therapy and single agents MS months

10 5FU the Drug of Choice for over 30 Years! Nature, March 30, 1957

11 First Line FOLFOX or FOLFIRI?

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16 Why the bevacizumab?

17 VEGF Angiogenesis

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19 IFL and Avastin: OS HR=0.66 (95% CI: ) 1.0 p< Estimated probabil lity IFL + Avastin IFL + placebo Months ITT population Hurwitz et al. NEJM 2004

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21 Safety of bevacizumab

22 Bevacizumab Safety profile Most common Hypertension, proteinuria, fatigue, Most Serious GI perforation, bleeding, ATE Special Interest Wound-healing, epistaxis, VTE, fistula

23 Overview of grade 3 adverse events of special interest in randomised trials in mcrc AVF2107g E NO Patients (% %) Hurwitz NEJM 2004; 2. Giantonio JCO 2007; 3. Saltz JCO 2008

24 Treatment to Progression?

25 Optimox 1

26 OPTIMOX Continous vs Stop and Go FOLFOX OPTIMOX 600+ patients FOLFOX x6 cycles 5FU/LV x 12 cycles FOLFOX Andre T et al. Proc ASCO. 2003;23 (abstr 1016).

27 OPTIMOX R 620 pts FOLFOX 6x FOLFOX- 12x slv5fu2-6x FOLFOX (%) Continuous Stop and Go RR PFS DDC OS G3/4 NTox Primary endpoint Tournigand et al, JCO 2006

28 OPTIMOX 1: neurotoxicity 25 Grade 3 neurotoxicity Continous Stop and Go Cycles Tournigand et al, JCO 2006

29 Acute Neuropathy Hg 2+ + TTX oxaliplatin EXTRA Membrane Na + INTRA ATP ATP oxalate Ca 2+ Dach-Pt

30 Acute Neuropathy Transient Cold-triggered paresthesia/dysesthesia Frequent (85-95%) Not dose-limiting Treatment: Prolong the infusion

31 Oxaliplatin Neurotoxicity

32 Chronic Neuropathy Cumulative dose Frequency of grade 3: 15-20% Dose-limiting toxicity of Oxaliplatin Treatment: Dose reduction

33 What about prevention of the neuropathy? The Calcium and Magnesium Story

34 Concept

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38 However. Independent Radiological Review e

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41 Elderly/ PS poor Single Agent Capecitabine

42 Fluoropyrimidines in Metastatic Disease Median survival: ~ 12 months Infusional 5FU better than bolus Capecitabine oral 5FU Regimen Response, % Bolus 5-FU 7-15 Infusional 5-FU FU/LV Mayo, Roswell schedules de Gramont (LV5-FU2) AIO (once weekly, 24-hour infusion) M R ll h d l Capecitabine 20-25

43 Enzymatic activation of Xeloda Intestine Liver Xeloda Xeloda CE Tumour 5 -DFCR CyD 5 -DFCR CyD 5 -DFUR 5 -DFCR = 5 -deoxy-5-fluorocytidine; 5 -DFUR = 5 -deoxy-5-5 -DFCR = 5 -deoxy-5-fluorocytidine; 5 -DFUR = 5 -deoxy-5- fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase 5 -DFUR Thymidine phosphorylase (TP) 5-FU

44 Xeloda: Phase III-results in metastatic CRC Pooled Data Arms: no. % RR TTP/m Med. Surv/ m Xeloda: * FU/LV:

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48 Second Line? What ever you didn t use first line

49 Concept of All-3-Drugs 11 Phase III Trials, 5768 Patients (mo) Me edian OS First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + ii irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU FOLFOXIRI Patients with 3 drugs (%) CAIRO 2007 Grothey & Sargent, JCO 2005

50 What s New? Continuous Inhibition of VEGF

51 ASCO 2012 TML Study Bevacizumab beyond progression R A Standard N second-line D chemotherapy Standard O M first-line Progression I chemotherapy S + bevacizumab A Standard T second-line I chemotherapy O N + bevacizumab First-line (n=820) Primary endpoint = OS Second-line

52 OS 1.0 CT (n=410) BEV + CT (n=409) OS estima ate HR: 0.81 (95% CI: ) p= (log-rank test) mo 11.2 mo Time (months)

53 Aflibercept Aflibercept Blocks all human VEGF-A isoforms, VEGF-B and placental growth factor (PlGF)²

54 VELOUR mcrc Previously Treated FOLFOX +/- Bevacizumab R A N D O M I Z E Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Placebo IV, day 1 + FOLFIRI q2 weeks Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

55 Overall Survival, ITT Population Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

56 Overall Survival Placebo/ FOLFIRI Median (mos) N = 614 Aflibercept/FOLFIRI Median (mos) N = 612 P-value for interaction All Patients All Patients Prior BEV No Yes Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

57 Third LIne Kras Wild Type: EGFR Inhibitors Kras Mutation: Clinical Trial

58 mcrc EGFR (Epidermal Growth Factor Receptor) Cell Membrane TK P TK P STATs PI3 kinase Ras/Raf Akt P PTEN MAPK/ERK Angiogenesis Apoptosis Proliferation Invasion & metastasis

59 Panitumumab Cetuximab EGFR (Epidermal Growth Factor Receptor) Cell Membrane TK P TK P STATs PI3 kinase Ras/Raf Akt P PTEN MAPK/ERK Angiogenesis Apoptosis Proliferation Invasion & metastasis

60 Panitumumab Cetuximab EGFR (Epidermal Growth Factor Receptor) Cell Membrane TK P TK P STATs PI3 kinase Ras/Raf Akt P PTEN MAPK/ERK Angiogenesis Apoptosis Proliferation Invasion & metastasis

61 Nomenclature No mutation in Kras= Wild type Kras= Treatment with EGFR MOA

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64 NCIC CTG CO.17 Failed all recommended therapies R E G I S T E R R A N D O M I Z E Cetuximab* + BSC BSC alone Disease Progression or Unacceptable Toxicity

65 NCIC CTG C0.17: Overall survival in K-Ras Wild-Type patients 1 Study arm MS (months) 95% CI roportion Aliv ve P Cetuximab + BSC BSC alone HR % CI (0.41,0.74) Stratified Log rank p-value: < Cetuximab BSC Time from Randomisation (Months) Cetuximab BSC

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68 Mild Grade 1 may not need treatment Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice daily

69 Moderate Minocycline 100 mg bid for 4 weeks Topical clindamycin 2% with hydrocortisone 1% in lotion base bid Scalp lesions: Clindamycin 2%, Triamcinolone acetonide 0.1% in equal parts of propylene glycol and water

70 Grade 3 Stop drug therapy for 1 week and restart at lower dose Minocycline 100 mg bid for 4 weeks Topical clindamycin 2% with hydrocortisone 1% in lotion base bid Scalp lesions: Clindamycin 2%, Triamcinolone acetonide 0.1% in equal parts of propylene glycol and water

71 What about Preventing the Rash? Prophylactic Minocycline

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73 Patient Assignments: Treatment Arm and Randomization 2 nd nd LINE TREATMENT FOLFIRI Q2W + IRINOTECAN Q3W + PANITUMUMAB THERAPY* PANITUMUMAB THERAPY n = 48 n = 47 RANDOMIZATION PRE-EMPTIVE EMPTIVE SKIN TREATMENT REACTIVE SKIN TREATMENT Doxycycline 100 mg BID

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75 STEPP Subsets: Summary of Efficacy By Central Review ITT WT KRAS Mutant KRAS Pre-emptive Reactive Pre-emptive Reactive Pre-emptive Reactive n ORR (%) Median PFS (months) Do Not Copy or Distribute Amgen Canada 2008

76 Overall Survival for Panitumumab Patients by Grade of Skin Toxicity it

77 Overall Survival by Worst Grade of Rash NCIC CTG CO Grade HR 95%CI p-value 2+ vs (0.22, 0.50) < ive Prop portion Al vs (0.40, 0.93) vs (0.41, 0.72) < Grade n Median Survival mo mo mo Survival (months) Grade 0 Grade 1 Grade 2+ Jonker DJ et al. N Engl J Med 2007;357:

78 What is new? Regorafinib

79 Mode of action of regorafenib (BAY ) Regorafenib inhibits multiple cell-signaling kinases: Angiogenic VEGFR1 3, TIE2 Stromal PDGFR-β, FGFR Oncogenic KIT, PDGFR, RET T 1/2 in man: approx hrs Two major metabolites (M2, M5) are pharmacologically active Wilhelm SM et al. Int J Cancer 2011

80 CORRECT mcrc after standard therapy R A N D O M I Z AT T I O N Z AT 2 : 1 Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Placebo + BSC 3 weeks on, 1 week off Primary Endpoint: OS

81 Overall response and disease control rates Best response, % Regorafenib N=505 Placebo N=255 Complete response 0 0 Partial response Stable disease Progressive disease Disease control rate,,%* *DCR = PR + SD; p<

82 Progression-free survival Su urvival dis stribution fu unction Regorafenib Placebo Median 1.9 mos 1.7 mos 95% CI Hazard ratio: 0.49 (95% CI: ) 1-sided p-value: < Placebo N=255 Regorafenib N= Days from randomization

83 Overall survival Survival distributio on function n Placebo N=255 Regorafenib N=505 Regorafenib Placebo Median 6.4 mos 5.0 mos 95% CI Hazard ratio: 0.77 (95% CI: ) 1-sided p-value: Days from randomization

84 O 2012

85 Lines of Therapy Today (Yesterday) First Line FOLFIRI + Bevacizumab FOLFOX + Bevacizumab Optimox or Drug Holidays Capecitabine Second Line FOLFOX or FOLFIRI No Bevacizumab is allowed Third Line Kras WT: Panitumumab or Cetuximab

86 Lines of Therapy Tomorrow First Line FOLFIRI + Bevacizumab FOLFOX + Bevacizumab Optimox or Drug Holidays Capecitabine Second Line FOLFOX or FOLFIRI + Bevacizumab is allowed + Aflibercept (with FOLFIRI) Third Line Kras WT: Panitumumab or Cetuximab End of Line Regorafinib

87 Each month, the Canadian Oncology Societies es produces live, interactive e educational webinars aimed at oncology professionals. Programs are archived on the COS website ca Your input and suggestions would be welcome. For information: info@cos.ca or

88 Thank you