Metastatic Colorectal Cancer. Update 2015

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1 Metastatic Colorectal Cancer Update 2015 A/Prof Jeremy Shapiro GI Medical Oncologist Cabrini Hospital, Melbourne 1

2 Not all pts with metastatic CRC are equal

3 1 st consideration can patient be cured by resection of metasatic disease? 3

4 Metastatic colorectal cancer Unresectable 66% 48% Resectable --- Best supportive care --- 5FU --- Resectable liver mets % Colon Cancer Collaborative Group, BMJ 2000 and Adam, Ann Surg 2004

5 Liver resection can cure some pts Refs Colon Ca Collab. Group, BMJ 2000 / Tournigand, JCO 2004 / Adam, Ann Surg % --- BSC FU --- FOLFIRI/FOLFOX6 --- FOLFOX6/FOLFIRI --- resectable 40 30% years

6 Is metastatic disease resectable? Full CT staging, PET +/- liver MRI And if it is, is pt fit enough for surgery? sometimes, I can make the call. 20 % pts suitable, 50 % clearly not Perhaps 30% or so unsure => Best to assess all pts with liver limited disease in MDT.. NB Bilobar disease, not necessarily a contra-indication

7 2 nd consideration understanding what you can/ can t do with chemo

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9 Pts diagnosed with met CRC in can t be cured with chemo alone - can expect (on average) to live about 2.5 years % chance of living beyond 5 years

10 Managing Colorectal Cancer in the clinic Traditional Same treatment for all Limited options Treating doctor only 2015 Individualised treatment plan Large treatment menu Multi-disciplinary care

11 CRC Menu Chemotherapy 5FU Capecitabine Raltitrexed S1 Oxaliplatin Irinotecan Mitomycin C Primary tumour Leave in situ Stent Surgery Radiotherapy Biologic agents Bevacizumab Cetuximab Panitumumab Aflibercept Ramucirumab Supportive Symptom control Palliative services Clinical trial Surgery Liver Lung Peritonectomy Liver directed therapy Sirt RFA DC beads FUDR (HAI) Biomarkers

12 All pts suitable for Rx should have a RAS test at diagnosis of metastases (altho RAS test will not necessarily determine initial Rx..)

13 RAS a new predictive biomarker -a gene that encodes one of the proteins in the epidermal growth factor receptor (EGFR) signaling pathway -important in the development and progression of cancer - 40% CRC pts have a KRAS exon 2 mutation and don t benefit from EGFR-ab Rx - ** another 10-15% have a NRAS or rare type of KRAS mutation => Near perfect negative predictor of resistance

14 Distribution of mutations in mcrc KRAS mt (non exon 2 KRAS mt) & NRAS mt ~10% RAS wt ~50% KRAS mt (exon 2) ~40% Douillard JY. ASCO Abstract 3620; Oliner KS. ASCO Abstract 3511.

15 KRAS testing A revolution in the clinical care of met CRC pts % met CRC pts being KRAS tested in USA (n=1188) Before EGFR inhibitor treatment At any time during clinical care Webster J Cancer Epidemiol Biomarkers Prev 2013

16 Which chemotherapy? Disease factors Curative v Non-curative Symptoms Burden of metastatic disease Clinical course - ie pace of disease

17 Which chemotherapy? Patient factors Age Performance Status Co-morbidities Patient wishes

18 Which chemo? Cure Aggressive Rx Rapid PD / Significant Sx Aggressive Rx No cure / no rapid PD or signif Sx (majority) Can use milder approaches

19 First line therapy

20 systemic therapy cards Additional Australian (PBS) Rules: - Can substitute X card in place of F - Must play B at start or not at all - A can not be played at all - Can only play C after O or I has been played - Only some players are given the C or P cards and they are interchangeable - New cards cannot be used without lengthy application to rules committees

21 First line therapy Non-intensive initial approach (suitable for > 50% but in practice used less often)

22 Overall survival CAIRO study: median overall survival 1.0 sequential Rx 16.3 m ( ) combination Rx 17.4 m ( ) st line sequential capecitabine Randomisation combination capecitabine + irinotecan nd line Combination (Arm B) irinotecan capecitabine + oxaliplatin 0.2 Sequential (Arm A) p = rd line capecitabine + oxaliplatin n = Months from randomisation Koopman et al. Lancet 2007

23 Oral Capecitabine 5FU pro-drug, with equivalent efficacy usually well tolerated Patients like the freedom! (no IV / can travel) still need regular monitoring Especially in initial stages as dose is adjusted Side effects slowly accumulate with each course Dose delays between cycles often required Compliance issues

24 Cape + Bev better than Cape Cape best option for most monotherapy pts can still use IV 5FU schedules if you want Concerned re compliance Unable to swallow/absorb talblets Troublesome HF syndrome adding Bev increases RR, PFS and possibly OS

25 AVEX Phase III Study Design Patients Previously untreated mcrc Age 70 yr Adjuvant chemo if >6 mo prior Not optimal candidates for irinotecan or oxaliplatin No cardiovascular disease, recent aspirin/nsaid use, or full-dose anticoagulants or thrombolytics N=280 Capecitabine 1000 mg/m2 BID days Bev 7.5 mg/kg day 1 every 3 weeks 1:1 Randomization Capecitabine 1000 mg/m2 BID days 1-14 every 3 weeks Treat to progression Cunningham et al: The Lancet Oncology, Volume 14, Issue 11, Pages , October 2013

26 AVEX: Progression-Free Survival Cunningham et al: The Lancet Oncology, Volume 14, Issue 11, Pages , October 2013

27 AVEX: Outcomes by Age years years 80 years Cape + Bev (n=55) Cape (n=46) Cape + Bev (n=57) Cape (n=66) Cape + Bev (n=28) Cape (n=28) Median PFS, mos PFS HR (P value) 0.52 (p<0.001) 0.60 (p=0.016) 0.36 (p=0.003) Median OS, mos OS HR (P value) 0.91 (p=0.55) 0.79 (p=0.37) 0.62 (p=0.24) Best ORR, % ORR P value Grade 3 AEs, % Saunders M. ESMO Abstract O-0030.

28 Proportion not progressed AGITG MAX: Bev increases PFS Capecitabine + Bevacizumab + Mitomycin C Median PFS C: 5.7 months CB: 8.5 months CBM: 8.4 months 0.6 Capecitabine Capecitabine + Bevacizumab Hazard ratios C vs CB: 0.63, P<0.001 C vs CBM: 0.59, P< Months from randomisation 24 Tebbutt, MAX AGITG study ESMO 2009

29 First line therapy More intensive initial approach

30 Oxaliplatin and Irinotecan are the most active drugs, and are similar in efficacy (when used optimally in 1st-line advanced disease)

31 Equivalent survival if both drugs combined with infusional 5FU in 1 st line Colucci et al. JCO Aug 2005 Tournigand et al. JCO 2004 RR 31% v 34% (NS) RR (1 st line) 56% v 54% (NS) TTP 7 m v 7 m (NS) TTP (1 st line) 8 m v 8.5 m (NS) Med survival 14 m v 15 m (NS) Med survival 21.5 m v 20.6 m (NS)

32 Capecitabine can replace 5FU doublet backbone Overall Survival XELOX v FOLFOX Cassidy ASCO 2007

33 order not important, as long as all the active drugs are used

34 Best survival if exposed to all active agents Median OS (mos) p = Patients With Three Drugs (%) 11 phase III trials: 5,768 patients OS (mos) = (% 3 drugs x 0.1); R^2 =.85 1st-line therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV/5-FU2 FOLFOXIRI CAIRO-1 Grothey & Sargent, 2005; Falcone et al., 2007; Koopman et al., 2007.

35 Oxaliplatin Mode of action Oxaliplatin causes inter- and intra-strand cross-links in DNA, inhibiting DNA synthesis and cell proliferation Lesions per Mbp Monoadducts Interstrand Protein cross-links Breaks Oxaliplatin Cisplatin

36 Irinotecan Mode of action Irinotecan is a topoisomerase I inhibitor, this causes DNA double strand breaks and S-phase specific cytotoxicity

37 5-Fluorouracil (5-FU) Mode of action 5-FU inhibits thymidylate synthase (TS) and the synthesis of thymidine nucleotides required for DNA replication It prevents cell division and is S-phase specific

38 Folfiri FOLFOX v FOLFIRI: different toxicity profiles nausea, diarrhoea, mucositis, alopecia fatigue Mild-moderate cytopenias low rates of hospital admission Folfox neurotoxicity is the major toxicity and is usually dose-limiting fatigue Mild-moderate cytopenias low rates of hospital admission

39 Biologic agents VEGF-ab (bevacizumab / aflibercept / ramucirumab) EGFR-ab (cetuximab / panitumumab)

40 Angiogenesis is critical for tumour growth, development, and spread Pre-malignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumour progression Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:

41 Bevacizumab (Avastin ) Blocks VEGF a key mediator in angiogenesis Recombinant humanized monoclonal IgG 1 antibody Half-life is approximately 20 days (range, 11 to 50 days) Avastin (bevacizumab) PI. October 2006; 2. Presta et al. Cancer Res. 1997;57:4593.

42 Proportion surviving Bevacizumab Increases OS in 1st-line mcrc HR=0.66, P= Med OS : 15.6 v 20.3 months 0.2 IFL + placebo IFL + bevacizumab survival (mo) Hurwitz et al. NEJM 2004

43 Proportion of patients NO16966: Bev did not significantly improve OS 1.0 XELOX / FOLFOX4 + Bev XELOX / FOLFOX4 + Placebo HR=0.89 [ ] p= Time [months] Cassidy JCO 2008

44 Several studies now reported, and ALL show some benefit BUT - not as effective as we had initially thought - not as toxic as we had feared - costly - no sub-group identified that derive greater (or lesser) benefit - Doesn t work as monotherapy

45 Aflibercept VEGFR-1 VEGFR-2 IgG Fc Aflibercept Soluble fusion protein Consists of portion of extracellular domains of human VEGF receptors 1 and 2 fused to human IgG1 Fc portion Binds all VEGF-A isoforms, VEGF-B and PlGF High affinity: binds VEGF-A and PlGF more tightly than native receptors Half-life in humans ~17 days

46 VELOUR Study (World GI and ESMO 2011) R A N 600 Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Metastatic CRC with PD post oxaliplatin Stratification factors: - ECOG PS (0 vs 1 vs 2) - Prior bevacizumab (Y/N) D O M I Z E 1:1 600 Placebo IV, day 1 + FOLFIRI q2 weeks Primary endpoint: OS Sample size: HR 0.8, 90% power and a 2-sided type I error 0.05

47 Overall Survival - ITT Population Cut-off date = February 7, 2011; Median follow-up = months

48 Ramucirumab RAISE (n=1072) : Ph3: FOLFIRI + Ramucirumab/Placebo Med OS 13.3 v 11.7m HR 0.84 p=.02 Med PFS 5.7 v 4.5m HR 0.79 p <.05 Gr 3 toxicity increase: Neut 38 v 23%, HPT 11%v 3%

49 Adding EGFRab to chemo (in RAS WT patients only) Refractory pts work best in this setting either as monotherapy (OS benefit) (often given with irinotecan based on an old phii study in pts unselected for KRAS) Second line improves RR and PFS in all studies but not OS (? cross over effect) First line more consistent improvement in RR cf Bevacizumab -? a better debulker Generally improves PFS v doublet alone Crystal and PRIME studies +ve for OS (modest in KRAS popn) but also 2 ve studies (COIN, NORDIC) (?oxali?cape)

50 OS estimate OS estimate Crystal 1 st line: all RAS: Cetuximab improves OS Overall patient population (ITT) Cetuximab + FOLFIRI (n=599) FOLFIRI (n=599) HR 0.88 p= Months RAS wt population Cetuximab + FOLFIRI (n=178) FOLFIRI (n=189) 28.4 HR 0.69 p= Months Adapted from Van Cutsem E, et al. J Clin Oncol 2011 and Ciardiello F, et al. ASCO 2014 (#3506)

51 Prime (FOLFOX+/-Pan) all RAS WT HR 0.83 med OS 23.9 v 19.7 p=.07 OS BENEFIT months RAS WT (both) => greater OS benefit (Post removal 17% pts with mnras) HR 0.78 medos 26.0 v 20.2 p=.04 OS BENEFIT months

52 Prime (FOLFOX+/-Pan) mutant (all) RAS Mutant RAS pts may be harmed by Panitumumab

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54 1 NCIC CTG C0.17: Overall survival in K-ras Mutant patients Study arm MS (months) 95% CI 0.8 Cetuximab + BSC BSC alone Proportion Alive HR % CI (0.70,1.37) Log rank p-value: Cetuximab BSC Cetuximab BSC Time from Randomisation (Months)

55 1 NCIC CTG C0.17: Overall survival in K- ras Wild-Type patients Study arm MS (months) 95% CI Proportion Alive Cetuximab + BSC BSC alone HR % CI (0.41,0.74) Log rank p-value: < Cetuximab BSC Time from Randomisation (Months) Cetuximab BSC

56 Biologics - toxicity Bevacizumab Cetuximab/Panitumumab Hypertension gr3/4 (10-15%) Proteinuria gr3 (0-2%) Arterial thrombosis (2-3%) wound healing (1-2%) Bleeding (1-2%) GI perforation (1-2%) acne-form rash (>70%) paronychia Dyspnoea - rare Infusion reaction (0-3%) No effects on wound healing/bleeding reported Long half life

57 EGFr Inhibitor-mediated Skin Toxicity

58 Proportion Alive CO17: Suvival by Worst Grade of Rash Grade HR 95%CI p-value 2+ vs (0.22, 0.50) < vs (0.40, 0.93) vs (0.41, 0.72) < Grade n Median Survival mo mo mo 20 0 Landmark-type analysis excluding all pts dying within 28 days of entry 90% experienced rash by 29 days, Median time to rash = 10 days Months 18

59 head to head comparison (only in the 40-50% of pts all RAS WT)

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61 Primary Endpoint of FIRE-3: Overall Response Rate Endpoint FOLFIRI + Cetuximab FOLFIRI + Bevacizumab OR P Value ORR, intent-to-treat (ITT) population (N=592) 62.0% 58.0% 1.18 ( ) Complete response 4.4% 1.4% Partial response 57.6% 56.6% Stable disease 17.5% 28.8% Progressive disease 7.1% 5.4% Not evaluable 13.1% 7.8% ORR, Evaluable (N=526) 72.2% 63.1% 1.52 ( ) Heinemann V. ASCO Abstract LBA3506.

62 FIRE-3: Progression Free Survival Stintzing S. ASCO Abstract LBA3506

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65 This data rocked GI oncology in 2013/ 2014 Was it true? How could a drug not increase RR (primary end point), or PFS, yet increase OS..?? large US trial (80405) eagerly anticipated

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69 PBS Logistics 2015 PBS reimbursement dictates order of use: => Bevacizumab then Cetuximab/Panitumumab Bev PBS funded only for 1 st line Cetux/Pan PBS funded only after progression (RAS WT only) Bevacizumab not funded if given after Cetuximab

70 First line therapy Even more intensive initial approach FOLFOXIRI +/- biologics

71 Even more intensive Advantages Most like to induce a rapid and more dramatic responses Rapid symptom relief Longer disease control conversion therapy unresectable to resectable

72 Even more intensive Disadvantages Toxicity Played all cards upfront?? salvage Not clear that this will result in OS advantage

73 FOLFIRI vs FOLFOXIRI: GONO STUDY FOLFIRI (122 pts) FOLFOXIRI (122 pts) P value RR 34% 60% < R0 surgery 6% 15% Liver only 12% 36% mpfs (mos) mos (mos) A. Falcone et al. JCO 2007 and ASCO 2007

74 FOLFIRI vs FOLFOXIRI: GONO STUDY Largely ignored! (TOXICITY CONCERNS) Gr 3-4 toxicity Triplet % Doublet % neutropenia diarrhoea vomiting 7 2 Neuro (gr 2/3) 20 0 => DOUBLET + BIOLOGICS PREFERRED IF AVAILABLE A. Falcone et al. JCO 2007 and ASCO 2007

75 Since 3 drugs are better than 2... How about 4??...? Triple chemo with one biologic? Doublet chemo with 2 biologics

76 TRIBE Phase III Study ( 4 v 3 drugs) Patients Unresectable mcrc No prior mcrc treatment Adjuvant oxali-containing chemotherapy allowed if >12 mo between tx and relapse FOLFIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) 1:1 Randomization FOLFOXIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) Treat to progression Falcone A. ASCO Abstract 3505.

77 TRIBE: PFS (ITT Population) Falcone A. ASCO Abstract 3505.

78 TRIBE: Secondary Endpoint (OS) Falcone A. ASCO Abstract 3505.

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80 Combination EGF and VEGF Abs. Seemed a good idea...pre-clinical rationale, clinical data (BOND2)... But PACCE (2007) Increased toxicity Inferior PFS Phase III ChemoBev +/- panitumumab in arm with chemo and doublet antibody trend to worse OS at interim analysis => TRIAL STOPPED CAIRO 2 (2008) Phase III XeloxBev +/- cetuximab Increased toxicity in arm with chemo and doublet antibody Inferior PFS 9.6 v 10.7 m [p=0.018]

81 Maintenance therapy

82 Chemotherapy Free Intervals - CFIs OPTIMOX 1 (JCO 06) - Similar outcomes - arm2 better tolerated FOLFOX7 x 6 FOLFOX4 until progression 5FU FOLFOX7 OPTIMOX 2 (ASCO 07) - inferior outcome in arm2 - (av break 4 mths?too long) FOLFOX7 x 6 FOLFOX7 x 6 5FU FOLFOX7 FOLFOX7 GISCAD (ASCO 06) - Similar outcomes - Less toxicity - 2 months on/off Irinotecan - continuous Irinotecan Irinotecan Irinotecan Irinotecan

83 Koopman, et al. ASCO 2013 CAIRO3: maintenance bev+cape v observation PFS1 PFS2 Arm A Previously untreated mcrc (n=558) bevacizumab + XELOX (x6) CR PR SD R Observation bevacizumab + capecitabine PD1 PD1 bevacizumab + XELOX bevacizumab + XELOX PD2 PD2 Arm B Primary endpoint: PFS after re-introduction = PFS2 Capecitabine 625 mg /m2 bd continuously (Bev 7.5 mg/kg q3 wks) Upon PD1, only 75% in ARM A and 47% arm B received XELOXbev

84 PFS1 estimate CAIRO3: PFS1 significantly improved with maintenance Maintenance Observation Median PFS1, months Stratified HR (95% CI) 0.44 ( ) p< Adjusted* HR 0.41 p < Time (months) Observation Maintenance *Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013

85 PFS2 estimate CAIRO3: PFS2 (1 o end point) improved with maintenance Maintenance Observation Median PFS2, months Stratified HR (95% CI) 0.81 ( ) p=0.028 Adjusted* HR 0.77 p= Time (months) Observation Maintenance *Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013

86 OS estimate CAIRO3: OS improved* with maintenance bevacizumab (preliminary analysis) Maintenance Observation Median OS, months Stratified HR (95% CI) 0.87 ( ) p=0.156 Adjusted* HR 0.80 p= Time (months) Observation Maintenance *Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013

87 CAIRO3: safety profile during observation/ maintenance Grade 3/4 adverse event, % Observation (n=279) Maintenance (n=279) Hypertension Neutropenia 0 2 Thrombocytopenia 0 1 Diarrhoea 1 3 Vomiting Nausea 0 2 Hand-foot syndrome 0 22 Neurotoxicity 5 10 GI perforation 0 1 Venous thromboembolic events 2 3 Fatigue 2 4 Red box indicates a difference in incidence between treatment arms of 5% NB also - no drop off in % pts receiving all 4/5 drugs - reassuring

88 Maintenance therapy No significant survival benefit can t be too dogmatic! Does delay progression modestly (CAIR03 HR 0.44) If having breaks, need to monitor closely A FP + bev is optimal. (No role Bev mono) however 22% gr3+ HF syndrome is unacceptable Which subgroup benefit most from this approach??

89 Second line therapy? chemo + antivegf (more bev/aflib/ram?)? chemo + EGFR (WT)? chemo alone

90 Decision 1 is more systemic Rx needed? Progression may be very slow? continue to observe Sometimes non-systemic Rx is appropriate Radiotherapy for local PD Liver directed therapy

91 Decision 2: which chemo backbone? Change doublet Restart 1 st line Rx if did not progress on Rx. (if Optimoxing, or if on a chemo-break)

92 Decision 3: to add a biologic? Continue Bevacizumab Beyond Progression New data re aflibercept/ramucurimab to consider too Switch from Bev to EGFRab if WT (or vice versa) Chemo alone, (keep EGFRab in reserve for 3 rd line) NB If FOLFIRI alone in 1 st line => FOLFOX + Bev (e3200 data, but not PBS)

93 What about using EGFR Abs in second line

94 2 nd line regimens -EGFRAb Increased RR and PFS when C-Mab / P-Mab added to Irinotecan-based chemo EPIC trial - cetux Sobrero JCO trial - p mab Peeters ESMO 2009 BUT no survival benefit (? due to crossover)

95 ECCO 2011: PICCOLO: efficacy data KRAS WT Irinotecan (n=230) Irinotecan + panitumumab (n=230) Median OS (months) HR (95% CI) 0.91 ( ) p value 0.44 Median PFS (months) HR (95% CI) 0.78 ( ) p value 0.01 ORR (%) p value < Seymour, et al. ECCO-ESMO 2011 (abstract 6007)

96 ECCO 2011: PICCOLO trial Irinotecan +/- P mab in 2 nd line adv CRC Again no overall survival benefit with EGFR in 2 nd line but Not due to crossover only 6% in this study => Strengthens argument to hold EGFRAb for 3 rd line - delay toxicity - use where survival benefit clearly documented

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98 Proportion of pts receiving Rx diminishes with subsequent lines 1st line 2nd line 3rd line

99 Refractory patients No significant advances for several years now modest benefit at best: Regorafenib/TAS102 several ve phase III trials: Brivanib, BBI Don t always need to rush into next line of Rx consider liver directed Rx if suitable.. consider Rx breaks if asymptomatic/slow paced

100 Regorafenib (BAY ), an oral multikinase inhibitor targeting multiple tumor pathways 1-3 Biochemical activity Regorafenib IC 50 mean ± SD nmol/l (n) Regorafenib VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Inhibition of proliferation KIT PDGFR RET Inhibition of tumor microenvironment signaling PDGFR-β FGFR Inhibition of neoangiogenesis VEGFR1-3 TIE2 Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAF V600E 19 ± 6 (6) 1. Wilhelm SM et al. Int J Cancer Mross K et al. Clin Cancer Research Strumberg D et al. Expert Opin Invest Drugs 2012.

101 Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p< at approximately 74% of events required for final analysis)

102 Drug-related treatment-emergent adverse events occurring in 10% of patients Adverse event, % All grades Regorafenib N=500 Grade 3 Grade 4 Grade 5* All grades Grade 3 Placebo N=253 Grade 4 Hand-foot skin reaction Fatigue Hypertension Diarrhea Rash / desquamation Anorexia Mucositis, oral Thrombocytopenia Fever Nausea Bleeding Voice changes Weight loss * Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm Grade 5*

103 What about SIR Spheres? ASX: post SIRFLOX press release 17/3/15

104 Conclusions (1) consider if your stage IV pt could be resectable Even if not, med OS 2.5 yrs, 15% > 5 years. A large array of treatment options now available Early review of these patients in MDM setting

105 Conclusions (2) Treatment Goal Treatment Intensity Develop chemo strategy (cure v palliative v decide in 3months) (aggressive v mono v observ) (OPTIMOX/?maintenance/?CFI) Determine biologic strategy

106 Play your systemic therapy cards cleverly know when to hold them..

107 For RAS WT pts refractory to Irinotecan.. The Irinotecan Cetuximab Evaluation and the Cetuximab Response Evaluation Among Mutants (ICE CREAM) study MONO V COMBO cetux cetux + irino Study recruitment 89/100, g13d arm closed WT arm : all RAS WT now acceptable for study entry..