Ο ξόινο ηωλ anti-eg/fr ζηε ζεξαπεία 1εο γξακκήο ζην κεηαζηαηηθό θαξθίλν ηνπ παρένο εληέξνπ.

Transcript

1 Κιηληθό Φξνληηζηήξην: «Καξθίλνο Παρένο Εληέξνπ» Ο ξόινο ηωλ anti-eg/fr ζηε ζεξαπεία 1εο γξακκήο ζην κεηαζηαηηθό θαξθίλν ηνπ παρένο εληέξνπ. Α. Σδνβάξαο

2 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology ΕΠΙΔΗΜΙΟΛΟΓΙΑ ΚΑΡΚΙΝΟΤ ΠΑΥΕΟ ΕΝΣΕΡΟΤ EGFR /K-RAS. ANTI EGFR ΠΑΡΑΓΟΝΣΕ ΚΛΙΝΙΚΕ ΜΕΛΕΣΕ

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5 Colorectal Cancer: Stage at Diagnosis Stage IV 19% Stage III 25% Stage 0 7% Stage I 24% Stage II 25% National Cancer Database.

6 Median Overall Survival in First-Line mcrc: The Golden Age BSC ~ 4-6 mos 5-FU/LV IFL or FOLFIRI FOLFOX4 or CAPEOX IFL + Bevacizumab FOLFOX6 FOLFIRI + Bevacizumab mos ~ mos mos 20.3 mos 21.5 mos 24 mos Gallagher DJ, et al. Oncology. 2010;78: Median OS (Mos)

7 Overall survival in phase III trials 1997 ~12 months 1* 2007 >20 months >30 months 6,7 *Based on a meta-analysis of >19 trials of 5-FU/LV 1. Thirion, et al. JCO 2004; 2. Hurwitz, et al. NEJM Van Cutsem, et al. NEJM 2009; 4. Van Cutsem, et al. JCO Goldberg, et al. Oncologist 2007; 6. Falcone, et al. ASCO 2013; 7. Takahari, et al. ASCO 2013

8 Epidermal Growth Factor Receptor (EGFR)

9 EGFR Structure Extracellular Domain Transmembrane Domain TK Intracellular Domain

10 Human Epidermal Growth Factor Receptor Family EGF, TGFa, b Cellulin Amphiregulin, HB-EGF No specific ligands - often acts as dimer partner Heregulins NRG2 NRG3 Heregulins β-cellulin TK TK TK erbb1 HER1 EGFR erbb2 HER2 neu erbb3 HER3 erbb4 HER4

11 Some Landmarks in EGFR Signalling Stanley Cohen EGF in mice (1960 s) Human EGF (1970 s) Isolation and cloning of EGFR (1980 s). Link between EGFR and malignant transformation of cells demonstrated Mendelsohn et al., Blocking EGFR signalling to treat cancer Murine monoclonal antibodies targeting EGFR-TK Human:murine chimeric version More than 20 anti-egfr agents in development

12 Tumour EGFR Expression Rate Breast 14 % - 91 % Colon 25 % - 77 % Lung Cancer 40 % - 80 % (Non small cell) Head & Neck 80 % - 95 % Ovarian 35 % - 70 % Pancreatic 30 % - 50 %

13 EGFR Function in Normal Cell ATP TK TK ATP + Gene Transcription Cell Proliferation Cell Cycle Progression Antiapoptosis Angiogenesis

14 Strategies to inhibit EGFR signaling EGFR tyrosine Anti-ligand Anti-EGFR mabs mabs kinase inhibitors Bispecific Abs Immune effector cell ATP TK TK TK TK

15 EGFR Best Options activation Across the Continuum may of Care involve for mcrc downstream signalling clinicaloptions.com/oncology pathways that include RAS proteins EGF EGFR EGFR Homodimer TGF-α EGF RAF RAS GTP RAS GDP EGFR MEK ERK JNK Nck JNKK PAK Rac PKC PLCγ PI3K S6K PTEN AKT mtor Proliferation Anti-apoptosis Angiogenesis Survival Metastasis Elk Myc Jun Fos Berg M, Soreide K. Discovery medicine 2012; 14:207-14; Di Fiore F, et al. Br J Cancer 2010; 103: ; Han W, Lo HW. Cancer Lett 2012; 318:124-34; Herbst RS, Shin DM. Cancer 2002; 94:

16 Best Options Across the Continuum of Care for mcrc EGFR inhibitory Mabs inhibits EGFR dimerisation and subsequent downstream signalling clinicaloptions.com/oncology EGF EGFR EGFR Homodimer TGF-α Panitumumab RAF RAS GTP RAS GDP EGFR MEK ERK JNK Nck JNKK PAK Rac PKC PLCγ PI3K S6K PTEN AKT mtor Proliferation Anti-apoptosis Angiogenesis Survival Metastasis Elk Myc Jun Fos

17 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology

19 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology EGFR inhibitors in 1 st line treatment Cetuximab Panitumumab

20 Monoclonal Antibodies as Targeted Therapy: Evolution to Fully Human Antibody Humanized Fully Human Chimeric Mouse 100% Mouse Protein 34% Mouse Protein 10% Mouse Protein 100% Human Protein mouse human cetuximab matuzumab panitumumab

21 CRYSTAL study design

22 Other RAS mutations: CRYSTAL

23 Progression-free survival

24 Progression-free survival

25 Overall survival

26 Overall survival

27 Efficacy: RAS subgroups

28 Safety: grade 3/4 adverse events

29 Conclusions

30 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology Panitumumab a fully human anti-egfr mab inhibits ligand binding and EGFR dimerisation Panitumumab Fully human, monoclonal IgG2 antibody Binds with high affinity and specificity to the extracellular domain of the human EGFR EGFR Dissociation constant: K D =0.05 nm 1 Inhibits receptor activation of all known EGFR ligands 2 1. Freeman D, et al. J Clin Oncol 2008; 26(15S):14536; 2. Yang XD et al. Cancer Res 1999; 59: ; 3. Foon KA, et al. Int J Radiat Oncol Biol Phys 2004; 58:984-90; 4. Hecht JR, et al. Proc Am Soc Clin Oncol 2004; 22:A3511; 5. Crawford J, et al. Proc Am Soc Clin Oncol 2004; 22:A7083. Inhibits EGFR-dependent activity including cell activation and cell proliferation in various tumours 2-5

31 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study FOLFOX4 ± panitumumab in 1 st -line treatment of metastatic CRC Metastatic CRC (n = 1183) R 1:1 FOLFOX4 (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFOX4 (Q2W) Disease assessment every 8 weeks E n d o f t r e a t m e n t L o n g t e r m f o l l o w u p Study endpoints: PFS (1 ); OS, ORR, safety, HRQoL KRAS status was prospectively analysed

32 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis KRAS, NRAS and BRAF mutation hotspots EXON 1 KRAS EXON 2 EXON 3 EXON % 5% 6% EXON 1 NRAS EXON 2 EXON 3 EXON % 4% 0% EXON 1 BRAF EXON 15 EXON 16 9% 600 Overall RAS ascertainment rate: 90% Overall RAS and BRAF ascertainment rate: 89% Among WT KRAS exon 2 patients, an additional 17% of tumours with RAS mutations were found Based on Douillard JY, et al. N Engl J Med 2013; 369: ; Oliner KS, et al. EJC 2013; 49 (suppl 3):abstract 2275 (and poster). Percentages have been rounded; 7 patients harboured either KRAS or NRAS codon 59 mutations

33 Proportion event-free (%) Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis PFS (primary analysis) WT RAS Months Douillard JY, et al. N Engl J Med 2013; 369: Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 156 (60) 10.1 ( ) FOLFOX4 (n = 253) 170 (67) 7.9 ( ) HR = 0.72 (95% CI, ) P = WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

34 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis PFS subgroup analysis (primary analysis) Favours panitumumab Favours FOLFOX Efficacy analysis sets N HR 95% CI Primary analysis WT KRAS exon MT KRAS exon RAS analysis WT RAS MT RAS WT KRAS exon 2 / MT other RAS Douillard JY, et al. N Engl J Med 2013; 369: WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

35 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis OS subgroup analysis (primary analysis) Favours panitumumab Favours FOLFOX Efficacy analysis sets N HR 95% CI Primary analysis WT KRAS exon MT KRAS exon RAS analysis WT RAS MT RAS WT KRAS exon 2 / MT other RAS Douillard JY, et al. N Engl J Med 2013; 369: WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

36 PRIME study RAS analysis OS by age subgroup (Age, updated analysis) WT RAS Favours Panitumumab Favours FOLFOX4 Factors N HR 95% CI All patients , 0.92 Age < , 0.94 Age , 1.09 Age >65 and age , 1.06 Age > , Hazard ratio (Panitumumab + FOLFOX4 / FOLFOX4 alone) Douillard JY et al. Ann Oncol 2014;25(Suppl 4);iv187 (poster 547P).

37 Proportion alive (%) Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis OS (primary analysis) WT RAS Months Douillard JY, et al. N Engl J Med 2013; 369: Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 128 (49) 26.0 ( ) FOLFOX4 (n = 253) 148 (58) 20.2 ( ) HR = 0.78 (95% CI, ) P = WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

38 Proportion alive (%) Proportion alive (%) Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis OS (primary analysis) WT KRAS exon 2 / MT other RAS HR = 1.29 (95% CI, ) P = Months Months MT RAS HR = 1.25 (95% CI, ) P = Panitumumab + FOLFOX4 (n = 51) Events n (%) Median (95% CI) months 35 (69) 17.1 ( ) FOLFOX4 (n = 57) 33 (58) 18.3 ( ) Panitumumab + FOLFOX4 (n = 272) Events n (%) Median (95% CI) months 187 (69) 15.6 ( ) FOLFOX4 (n = 276) 175 (63) 19.2 ( ) Douillard JY, et al. N Engl J Med 2013; 369: , supplements at: appendix.pdf. MT RAS, MT in any KRAS or NRAS exon 2, 3, or 4 (excludes 7 patients harbouring KRAS/NRAS codon 59 mutations)

39 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PRIME study RAS analysis Conclusions Prospective-retrospective analysis of PRIME Clinically significant 5.8 month improvement in OS observed in the WT RAS subgroup treated with panitumumab + FOLFOX4 vs. FOLFOX4 OS HR = 0.78 (95% CI, ; P = 0.043) PFS HR = 0.72 (95% CI, ; P = 0.004) Mutations in RAS beyond KRAS exon 2 may be predictive of adverse outcomes for panitumumab + FOLFOX4 treatment OS HR = 1.25 (95% CI, ; P = 0.03) PFS HR = 1.31 (95% CI, ; P = 0.008) The benefit-risk profile of panitumumab + FOLFOX4 was improved by excluding patients with MT RAS mcrc tumours Douillard JY, et al. N Engl J Med 2013; 369: RAS ascertainment rate was 90%

40 Median OS/PFS (months) 9.9 vs vs vs vs vs vs vs vs 19.7 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology Phase III studies of EGFR inhibitors in 1L KRAS WT mcrc Irinotecan-based regimens Oxaliplatin-based regimens 30 CRYSTAL 1 * (n=316) NORDIC VII 2 (n=97) COIN 3 (n=362) PRIME 4 (n=325) OS PFS Cetuximab + FOLFIRI OS PFS OS PFS OS PFS Cetuximab + FLOX Cetuximab + XELOX/FOLFOX Panitumumab + FOLFOX4 + = significant compared to chemotherapy alone = not significant compared to chemotherapy alone *Data based on retrospective analyses Data obtained following protocol amendment 1. Van Cutsem, et al. JCO 2011; 2. Tveit, et al. JCO Maughan, et al. Lancet 2011; 4. Douillard, et al. NEJM 2013

41 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology Head-to-head comparisons of 1L bevacizumab versus EGFR inhibitors in KRAS WT mcrc PEAK 1 (phase II) Did not test any formal hypothesis Untreated, unresectable KRAS WT mcrc (n=285) R Bevacizumab + mfolfox6 Panitumumab + mfolfox6 PD PD FIRE-3 2 (phase III) Primary endpoint: ORR Untreated KRAS WT mcrc (n=592) R Bevacizumab + FOLFIRI Cetuximab + FOLFIRI PD PD CALGB (phase III) Primary endpoint: OS Untreated KRAS WT mcrc (n~1,200) R Bevacizumab + FOLFOX or FOLFIRI Cetuximab + FOLFOX or FOLFIRI PD PD Only CALGB has a primary endpoint of OS 1. Schwartzberg, et al. ASCO GI 2013; 2. Heinemann, et al. ASCO Venook, et al. WCGC 2013

42 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PEAK study mfolfox6 + panitumumab or bevacizumab in 1 st -line treatment of WT KRAS exon 2 mcrc Metastatic CRC WT KRAS exon 2 (n = 285) R 1:1 mfolfox6 (Q2W) + panitumumab 6 mg/kg (Q2W) mfolfox6 (Q2W) + bevacizumab 5 mg/kg (Q2W) Tumour Assessment Q8W (±7 days); Treatment administered until disease progression, death, or withdrawal from study Study endpoints: PFS (1 ); OS, ORR, safety, exploratory biomarker analysis No formal hypothesis testing was planned E n d o f t r e a t m e n t 30 days (+ 3 days) S a f e t y f o l l o w u p P o s t t r e a t m e n t f o l l o w u p Every 3 months (±28 days) until end of study E n d o f s t u d y Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 ORR, objective response rate; mfolfox6, modified FOLFOX6

43 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PEAK study RAS analysis KRAS, NRAS and BRAF mutation hotspots EXON 1 EXON 2 EXON 3 EXON 4 KRAS N/A # % 7% EXON 1 NRAS EXON 2 EXON 3 EXON % 6% 0% EXON 1 BRAF EXON 15 EXON % Overall RAS ascertainment rate: 82% 1. Schwartzberg L, et al. J Clin Oncol 2013; 31 (suppl):abstract Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 Percentages have been rounded; # WT KRAS exon 2 tumour status was defined in the trial eligibility criteria; N/A, not applicable

44 Proportion alive (%) PEAK study RAS analysis PFS (longer follow-up analysis) Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology WT RAS Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 Events n (%) Median (95% CI) months Panitumumab + mfolfox6 (n = 88) 57 (65) 13.0 ( ) Bevacizumab + mfolfox6 (n = 82) 66 (80) 10.1 ( ) HR* = 0.66 (95% CI, ) P = Months *Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4

45 Proportion event-free (%) PEAK study RAS analysis PFS (longer follow-up analysis) Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology WT KRAS exon 2 / MT other RAS Events n (%) Months Median (95% CI) months Panitumumab + mfolfox6 (n = 24) 22 (92) 8.4 ( ) Bevacizumab + mfolfox6 (n = 27) 23 (85) 8.8 ( ) HR* = 1.13 (95% CI, ) P = Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 *Stratified Cox proportional hazards model

46 Proportion alive (%) PEAK study RAS analysis OS (longer follow-up analysis) Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology WT RAS Months Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 Events n (%) Median (95% CI) months Panitumumab + FOLFOX6 (n = 88) 30 (34) 41.3 ( ) Bevacizumab FOLFOX6 (n = 82) 40 (49) 28.9 ( ) HR* = 0.63 (95% CI, ) P = 0.06 *Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4

47 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology PEAK study RAS analysis Conclusions In this updated analysis of the 1 st -line estimation study of previously untreated patients with WT RAS* mcrc, data suggest PFS and OS HR favoured panitumumab + mfolfox6 relative to bevacizumab + mfolfox6 PFS HR = 0.66 (95% CI, ; P = 0.03) for OS in favour of pmab OS HR = 0.63 (95% CI, ; P = 0.06) in favour of pmab The magnitude of improvement in PFS and OS in patients with WT RAS tumours treated with panitumumab is clinically relevant in the mcrc population A trend toward decreased PFS was observed in WT KRAS exon 2 / MT other RAS patients in the panitumumab arm relative to the bevacizumab arm The additional RAS mutations beyond KRAS exon 2 appear to be predictive for panitumumab treatment effect Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 *WT RAS, WT KRAS & NRAS exons 2/3/4; No formal hypothesis testing was planned; AE, adverse event; pmab, panitumumab

52 Median OS/PFS (months) 7.3 vs vs vs vs vs vs vs vs vs vs 12.1 Best Options Across the Continuum of Care for mcrc Improved OS and PFS in phase III studies of 2L mcrc clinicaloptions.com/oncology E (KRAS WT + MT) (n=286) ML18147 (TML) 2 (KRAS WT + MT) (n=409) EPIC 3 (KRAS WT) (n=97) Study (KRAS WT) (n=303) VELOUR 5 (KRAS WT + MT) (n=612) OS PFS OS PFS OS PFS OS PFS OS PFS Bevacizumab + FOLFOX4 + = significant compared to chemotherapy alone = not significant compared to chemotherapy alone *Oxaliplatin or irinotecan-based chemotherapy Bevacizumab + chemotherapy* Cetuximab + irinotecan Panitumumab + FOLFIRI Aflibercept + FOLFIRI 1. Giantonio, et al. JCO Bennouna, et al. Lancet Oncol Langer, et al. ESMO 2008; 4. Sobrero, et al. ASCO GI Van Cutsem, et al. JCO 2012

53 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology EGFR inhibitors are active in the 3L setting in patients with KRAS WT mcrc 0,7 0,6 0,5 0,4 Study CO ,3 0,2 0,1 0 COIN 1 PRIME 2 1- HR Favours EGFR inhibitor Favours control CRYSTAL 3 PICCOLO 4 EPIC 5 Study L 2L 3L and later lines 1. Maughan, et al. Lancet 2011; 2. Douillard, et al. NEJM Van Cutsem, et al. JCO 2011; 4. Seymour, et al. Lancet Oncol 2013; 5. Langer, et al. ESMO Peeters, et al. JCO 2010; 7. Amado, et al. JCO 2008; 8. Karapetis, et al. NEJM 2008

54 ASPECCT study Panitumumab vs cetuximab in 3 rd -line treatment of WT KRAS exon 2 mcrc WT KRAS exon 2 mcrc (n = 999) R 1:1 Primary endpoint: OS Panitumumab 6 mg/kg IV (Q2W) Cetuximab 400 mg/m 2 loading dose 250 mg/m 2 IV (QW) WT KRAS 1 Panitumumab (n = 499) Cetuximab (n = 500) Median PFS, mo HR (95% CI) P-value 1.00 ( ) NR Median OS, m HR (95% CI) P-value 22.0 ORR, % ( ) (95% CI) (n = 486) 0.97 ( ) ( ) (n = 485) Odds ratio (95% CI) 1.15 ( ) 1. Price TJ, et al. Lancet Oncol 2014;15:569 79; protocol ID: ; ClinicalTrials.gov identifier: NCT IV, intravenously; NR, not reported. WT KRAS = WT KRAS exon 2 (codons 12, 13).

55 ASPECCT study Summary of AEs of interest WT KRAS AEs, n (%) All AEs Grade 3 Grade 4 Grade 5 Price TJ, et al. Lancet Oncol 2014;15: Panitumumab (n = 496) 485 (98) 180 (36) 37 (7) 29 (6) Cetuximab (n = 503) 494 (98) 159 (32) 27 (5) 50 (10) Treatment-related fatal AEs 0 (0) 1 (0.2) Hypomagnesaemia (any grade) Grade 3 Grade 4 Infusion reactions (any grade) Grade 3 Grade 4 Diarrhoea (any grade) Grade 3 Grade 4 Skin and subcutaneous tissue toxicity (any grade) Grade 3 Grade (27) 26 (5) 9 (2) 15 (3) 1 (0.2) 0 (0) 91 (18) 7 (1) 3 (0.6) 430 (87) 60 (12) 2 (0.4) 89 (18) 10 (2) 3 (0.6) 72 (14) 5 (1) 4 (0.8) 89 (18) 9 (2) 0 (0) 440 (87) 48 (10) 0 (0) Includes AEs in the skin and subcutaneous tissue disorders system organ class of the Medical Dictionary for Regulatory Authorities (MedDRA, version 15.1).

56 ΕΠΙΠΣΩΕΙ ΣΟ ΔΕΡΜΑ ΑΠΟ ΑΝΑΣΟΛΗ ΣΟΤ ΑΞΟΝΑ HER1/EGFR Έκθραζη HER1/EGFR ζηα βαζικά κύηηαρα ηης επιδερμίδας, ζμηγμαηογόνοσς αδένες, κύηηαρα ηριτικού θσλάκοσ Ο σποδοτέας HER1/EGFR έτει ζημανηικό ρόλο: ηνλ πνιιαπιαζηαζκό θαη ηελ δηαθνξνπνίεζε ηωλ επηδεξκηδηθώλ θπηηάξωλ ηελ πξνζηαζία ηωλ επηδεξκηδηθώλ θπηηάξωλ θαηά ηωλ βιαβώλ ηεο UVR ηελ αλαζηνιή ηεο θιεγκνλήο ηελ επηηάρπλζε ηεο επνύιωζεο

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59 ΑΝΕΠΙΘΤΜΗΣΕ ΕΝΕΡΓΕΙΕ ΑΠΟ ΣΟ ΔΕΡΜΑ

60 Αληηκεηωπηοε βιαηηδνθιπθηαηλωδνπο εμαλζεκαηνο Ελεκέξωζε αζζελνύο Σαθηηθή παξαθνινύζεζε (θάζε 2 κε 4 εβδνκάδεο) Γεληθά κέηξα: Δεξκαηνινγηθή εμέηαζε πξηλ ηελ έλαξμε ηνπ εμαλζήκαηνο. Δέξκα μεξό, ή πεξηνρέο κε έληνλε μεξόηεηα: ελπδάηωζε 2 θνξέο ηελ εκέξα κε ζθεπάζκαηα ειεύζεξα αιθνόιεο (πρ 10% νπξία) Απνθπγή ηεο ειηαθήο έθζεζεο Υξήζε αληηειηαθώλ ζθεπαζκάηωλ SPF > 15 Πξνηηκόηεξε ε ρξήζε αληηειηαθώλ κε θπζηθά θίιηξα πκβνπιέο γηα ζωζηή ρξήζε αληηειηαθνύ Doxycycline 100 mg BID

61 Rash Grade Correlation: Rash & Survival/Response in CRC Grades 0-2 Grade 3 Cetuximab Vincenzi 2006 [1] P =.06 Grade 0 Grade 3 Cetuximab Saltz 2004 [2] P =.02 Grade 0-1 Grade 2-4 Panitumumab Hecht 2007 [3] HR: 0.72; 95% CI: Median OS (Mos)

62 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology ΚΟΣΟ Ενήλικα 75kg με BSA 1.7, panitumumab 75kg Υ6 Υ2=900 mg /μηνα Νοζοκομειακή ηιμή 320 eu/100mg ςνολό 2900eu/μήνα Cetuximab εβδομαδιαία σοπήγηζη 250 Υ1.7(CRYSTAL) για μηνιαία σοπήγηζη euro/μήνα

63 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology πλνπηηθά ΚΠΕ δεςηεπόρ ζε θνηηόηηηα. Οι αναζηολείρ EGFR πόλο μόνο ζηο μεηαζηαηικό ΚΠΕ. Οι δύο κύπιερ οδοί μεηαγωγήρ ζήμαηορ πος ενεπγοποιούνηαι από ηον EGFR είναι ηα RAS RAF ΜΑΡΚ και PI3K-PTEN/PTEN/AKT.Οδηγοςν ζε αύξηζη ηηρ ππωηεϊνοζύνθεζηρ, ηηρ κςηηαπικήρ ανάπηςξηρ, ηηρ κινηηικόηηηαρ ηηρ επιβίωζηρ, ζηην ππόοδο ηος κςηηαπικού κύκλος και ζηον πολλαπλαζιαζμό. KRAS, ΝRAS, BRAF μεηαλλάξειρ ανισνεύονηαι ζε 40%- 50% ηων αζθενών οι οποιοί δεν ανηαποκπίνονηαι ζηην ανηι EGFR θεπαπεία.

64 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology πλνπηηθά Ανάπηςξη αναζηολέων EGFR οπωρ Panitumumab, cetuximab με κςπιοηεπέρ μελέηερ ηιρ CRYSTAL,PRIME, PEAK,ASPECTT,CALGB 80405,FIRE. Αναγνώπιζη και ανηιμεηώπιζη ηων παπενεπγειών. Κόζηορ ζηοσεςμένων θεπαπειών /μήνα να δίνονηαι επι ενδείξεων και με ζύνεζη από ηην ογκολογική κοινόηηηα.

65 Best Options Across the Continuum of Care for mcrc clinicaloptions.com/oncology Treating CRC: NCCN Guidelines for Unresectable mcrc Oxaliplatin-Based First-Line Irinotecan- Based First-Line 5-FU or Capecitabine ± Bevacizumab or FOLFOXIRI Initial therapy FOLFOX ± Cet or pan a or FOLFOX/ CapeOX ± bev FOLFIRI + bev or FOLFIRI ± cet or pan a 5-FU/LV or cape + bev or FOLFOXIRI Therapy after first progression FOLFIRI or IRI ± aflib or bev or FOLFIRI or IRI ± cet or pan a FOLFOX or CapeOX ± bev or IRI + cet or pan a FOLFOX or CapeOX ± bev or IRI or FOLFIRI ± bev or aflib or IRI + Cet or OX pana + IRI ± bev Reg IRI Therapy after second progression Reg or Cet or pan a + IRI or Cet or pan a Reg, clinical trial, or BSC Reg or Cet or pan a + IRI or Cet or pan a FOLFOX or CapeOX Reg or Cet or pan a or IRI or Cet or pan a Reg, clinical trial, or BSC Therapy after third progression Reg, clinical trial, or BSC Reg, clinical trial, or BSC Reg, clinical trial, or BSC Reg, clinical trial, or BSC a RAS WT only. reg, regorafenib. NCCN Colon cancer

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