Metastatik Kolorektal Kanser Tedavisinde Yeni Biyobelirteçler Sonrası Panitumumab. Prof. Dr. N. Faruk Aykan Antalya 22 Mart 2014

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1 Metastatik Kolorektal Kanser Tedavisinde Yeni Biyobelirteçler Sonrası Panitumumab Prof. Dr. N. Faruk Aykan Antalya 22 Mart 2014

2 St. Louis, ABD

11 Kinase growth factor pathway Activated receptor Tyrosine kinase receptor Ligand binding Cell membrane Tyrosine kinase domain Signal transduction Proliferation Survival Migration Tumour growth and metastases

13 (Human Epidermal Growth Factor Receptors)

EGFR expression in CRC EGFR overexpression in CRC: 49 82 % EGFR testing has

14 EGFR expression in CRC EGFR overexpression in CRC: % EGFR testing has no predictive value for response to anti-egfr! a: Primary CRC, b: Metastasis

16 IgG1 IgG2

20 Specific mutations result in a constitutively active RAS protein Mutant KRAS Inactive RAS GDP Active RAS GTP Mutant NRAS Inactive RAS GDP Active RAS GTP Hyperproliferation Suppression of apoptosis Haigis KM, et al. Nat Genet 2008; 40:600-8; Wang Y, et al. Cancer Discov 2013; 3:

22 BRAF mutasyonu BRAF V600E MSS Tm. lerde % 10 MSI-H Tm. lerde %13-78 Prognostik Meta-analiz (26 çalışma) Mortalite artışı HR=2.25 PLoSOne (2012) 7:e47054 Sağ kolon

Panitumumab - a Fully Human Anti-EGFR mab Inhibits Ligand Binding and EGFR Dimerisation Panitumumab EGFR Fully human, monoclonal IgG2 antibody Binds with high affinity and

05 nm 1 Inhibits receptor activation of all known EGFR ligands 2 Inhibits EGFR-dependent activity including cell activation and cell proliferation in various tumours 2-5 1.

23 Panitumumab - a Fully Human Anti-EGFR mab Inhibits Ligand Binding and EGFR Dimerisation Panitumumab EGFR Fully human, monoclonal IgG2 antibody Binds with high affinity and specificity to the extracellular domain of the human EGFR Dissociation constant: KD=0.05 nm 1 Inhibits receptor activation of all known EGFR ligands 2 Inhibits EGFR-dependent activity including cell activation and cell proliferation in various tumours 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.

24 Panitumumab Inhibits EGFR Dimerisation and Subsequent Downstream Signalling 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 Yang XD, et al. Cancer Res 1999; 59: ; Foon KA, et al. Int J Radiat Oncol Biol Phys 2004; 58:984-90; Hecht JR, et al. Proc Am Soc Clin Oncol 2004; 22:A3511; Crawford J, et al. Proc Am Soc Clin Oncol 2004; 22:A Amgen Inc. All rights reserved

25 Panitumumab in 1 st -line mcrc Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab plus FOLFOX versus FOLFOX as 1 st -line treatment for metastatic colorectal cancer

27 PRIME Trial 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 Stratification by: Performance status (ECOG 0-1 vs. 2) Geographic region: Western Europe, Canada, and Australia vs. Rest of the World 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 Douillard JY, et al. J Clin Oncol 2010; 28: ; protocol ID: ; ClinicalTrials.gov identifier: NCT HRQoL, Health-related Quality of Life

28 PRIME Trial FOLFOX4 ± Panitumumab in 1 st -line Treatment of Metastatic CRC Patient number: 1183 K-ras exon 2 evaluated: % % K-ras mutant % K-ras wild type

29 Proportion Event-Free (%) Oliner K, et al. J Clin Oncol 31, 2013 (suppl; abstr 3511); 1. Douillard JY, et al. J Clin Oncol 2010;28: PRIME RAS/RAF Primary Analysis PFS in Patients with WT KRAS Exon 2 mcrc Original WT KRAS exon 2 testing Events n (%) HR=0.80 (95% CI: ) p=0.02 Median (95% CI) months Panitumumab + FOLFOX4 (n=325) 199 (61) 9.6 ( ) FOLFOX4 (n=331) 215 (65) 8.0 ( ) Months

30 Proportion alive (%) Oliner K, et al. J Clin Oncol 31, 2013 (suppl; abstr 3511); 1. Douillard JY, et al. J Clin Oncol 2010;28: PRIME RAS/RAF Primary Analysis OS in Patients with WT KRAS Exon 2 mcrc Original WT KRAS exon 2 testing Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n=325) 165 (51) 23.9 ( ) FOLFOX4 (n=331) 190 (57) 19.7 ( ) HR=0.83 (95% CI: ) p= Months

31 K-ras Mutant hastalarda

33 PRIME Trial FOLFOX4 ± Panitumumab in 1 st -line Treatment of Metastatic CRC Patient number: 1183 Pan Ras* evaluated: % % ras mutant % ras wild type Pan Ras*: K-ras exon 2, 3 ve 4 + N-ras exon 2, 3 ve 4

PRIME study RAS analysis RAS status prevalence of RAS mutations among 1,060 evaluable patients PRIME (KRAS exon 2) PRIME RAS analysis (refinement of patient population by RAS mutation status) MT KRAS

34 PRIME study RAS analysis RAS status prevalence of RAS mutations among 1,060 evaluable patients PRIME (KRAS exon 2) PRIME RAS analysis (refinement of patient population by RAS mutation status) MT KRAS (exon 3, 4) n = 60/641 (9.4%) n = 440/1,096 (40.1%) n = 656/1,096 (59.9%) n = 548/1,060 (51.7%) n = 512/1,060 (48.3%) MT WT MT NRAS (exon 2, 3, 4) n = 48/641 (7.5%) Douillard JY, et al. N Engl J Med 2013; 369: MT KRAS exon 3 (codon 61) & exon 4 (codons 117/146); MT NRAS exon 2 (codons12/13), exon 3 (codon 61) & exon 4 (codon117/146)

35 Oliner K, et al. J Clin Oncol 31, 2013 (suppl; abstr 3511). PRIME RAS/RAF Analysis RAS-RAF Mutation hot spots EXON 1 EXON 2 EXON 3 EXON 4 RAS KRAS 4% (24/641) 6% (36/641) NRAS Additional MT found in KRAS WT 3% (22/641) 4% (26/641) 0% (0/641) EXON 15 RAF* 600 BRAF 8% (53/641)

36 Proportion Event-Free (%) Oliner K, et al. J Clin Oncol 31, 2013 (suppl; abstr 3511). PRIME RAS/RAF Analysis Primary Analysis Set PFS in Patients with WT RAS mcrc WT RAS Events n (%) HR=0.72 (95% CI: ) p=0.004 Median (95% CI) months Panitumumab + FOLFOX4 (n=259) 156 (60) 10.1 ( ) FOLFOX4 (n=253) 170 (67) 7.9 ( ) Months

37 Proportion alive (%) Oliner K, et al. J Clin Oncol 31, 2013 (suppl; abstr 3511). PRIME RAS/RAF Analysis Primary Analysis Set OS in Patients with WT RAS mcrc WT RAS Events n (%) HR=0.78 (95% CI: ) p=0.043 Median (95% CI) months Panitumumab + FOLFOX4 (n=259) 128 (49) 26.0 ( ) FOLFOX4 (n=253) 148 (58) 20.2 ( ) Months

38 PRIME RAS/RAF Biomarker Analysis Analysis of Genotype Subgroups Prognostic impact of BRAF V600E mutations regardless of treatment arm Genotype n HR (95% CI) Favours WT Favours MT RAS: FOLFOX4 RAS: Pmab + FOLFOX ( ) 0.58 ( ) BRAF exon 15 (codon 600): FOLFOX4 BRAF exon 15 (codon 600): Pmab + FOLFOX4 KRAS exon 3 (codon 61): FOLFOX4 KRAS exon 3 (codon 61): Pmab + FOLFOX4 KRAS exon 4 (codon 117/146): FOLFOX4 KRAS exon 4 (codon 117/146): Pmab + FOLFOX4 KRAS exon 3/4 combined: FOLFOX4 KRAS exon 3/4 combined: Pmab + FOLFOX4 NRAS exon 2 (codon 12/13): FOLFOX4 NRAS exon 2 (codon 12/13): Pmab + FOLFOX4 NRAS exon 3 (codon 61): FOLFOX4 NRAS exon 3 (codon 61): Pmab + FOLFOX4 NRAS exon 2/3/4 combined: FOLFOX4 NRAS exon 2/3/4 combined: Pmab + FOLFOX ( ) 0.38 ( ) 1.15 ( ) 0.48 ( ) 1.07 ( ) 0.73 ( ) 1.10 ( ) 0.62 ( ) 1.12 ( ) 0.61 ( ) 0.57 ( ) 0.57 ( ) 0.77 ( ) 0.57 ( ) Hazard Ratio (WT/MT) BRAF V600 mutations appeared to be prognostic conferring a poor prognosis regardless of treatment arm Oliner K, et al. J Clin Oncol 31, 2013 (suppl; abstr 3511). Pmab, panitumumab

39 PEAK Trial mfolfox6 + Panitumumab or Bevacizumab in 1 st -line Treatment of WT KRAS exon 2 mcrc (Open Label, Phase 2) Metastatic CRC (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, resection rate, safety, exploratory biomarker analysis *PFS, progression-free survival; defined as time from date of randomisation to date of first radiographic disease (per modified RECIST v1.0), or death within 60 days after the last evaluable tumour assessment or randomisation (whichever is later). Patients not meeting the criteria by the cut-off date were censored at the last evaluable tumour assessment date; OS, overall survival; ORR, objective response rate; mfolfox6, modified FOLFOX6 Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631); Protocol ID: ; ClinicalTrials.gov identifier: NCT 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

40 Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631); ClinicalTrials.gov identifier: NCT PEAK Trial Key Eligibility Criteria Metastatic adenocarcinoma of the colon or rectum WT KRAS exon 2 tumour status No prior chemotherapy, anti-vegf therapy, or anti-egfr therapy for mcrc Measurable disease ECOG performance status 0 1 Adequate haematologic, renal and hepatic function Signed informed consent ECOG, Eastern Cooperative Oncology Group

41 PEAK Trial Expanded RAS Analysis Prevalence of Mutations in PEAK Tumour Samples within the WT KRAS Exon 2 Subset (80% Ascertainment*) KRAS EXON 1 EXON 2 EXON 3 EXON N/A % 7% NRAS EXON 1 EXON 2 EXON 3 EXON % 6% 0% BRAF EXON 1 EXON 15 EXON % *Ascertainment defined as percentage of patients with a known codon sequence result at all listed positions above; N/A, not applicable Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631).

42 Proportion event-free (%) Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631). Proportion event-free (%) PEAK Trial Biomarker Analysis PFS in Patients with WT KRAS exon 2 and WT RAS mcrc Treated with Panitumumab + mfolfox6 # Original WT KRAS exon 2 (ITT set) WT RAS (exons 2,3,4 of KRAS/NRAS) Months Months Events n (%) Median (95% CI) months Events n (%) Median (95% CI) months Panitumumab + mfolfox6 (n=142) 90 (63) 10.9 ( ) Panitumumab + mfolfox6 (n=88) 50 (57) 13.0 ( ) Bevacizumab + mfolfox6 (n=143) HR*=0.87 (95% CI: ) p= (66) 10.1 ( ) Bevacizumab + mfolfox6 (n=82) HR*=0.65 (95% CI: ) p=0.03 # Data cutoff 30 May 2012; *Stratified Cox proportional hazards model 60 (73) 9.5 ( )

43 Proportion alive (%) PEAK Trial Biomarker Analysis OS in Patients with WT KRAS exon 2 and WT RAS mcrc Treated with Panitumumab + mfolfox6 with Longer Follow-Up Time # Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631). Proportion alive (%) WT KRAS exon 2 (ITT set) WT RAS (exons 2,3,4 of KRAS/NRAS) Months Months Panitumumab + mfolfox6 (n=142) Events n (%) Median (95% CI) Months 52 (37) 34.2 (26.6 NR) Panitumumab + mfolfox6 (n=88) Events n (%) Median (95% CI) months 30 (34) 41.3 ( ) Bevacizumab + mfolfox6 (n=143) HR*=0.62 (95% CI: ) p= (55) 24.3 ( ) Bevacizumab + mfolfox6 (n=82) HR*=0.63 (95% CI: ) p=0.058 # Data cutoff 3 Jan 2013; *Stratified Cox proportional hazards model; NR, not reached 40 (49) 28.9 ( )

51 Panitumumab in 2 nd -line mcrc The study: Panitumumab + FOLFIRI treatment in WT RAS mcrc

53 study FOLFIRI ± panitumumab in 2 nd -line treatment of metastatic CRC Metastatic CRC (n = 1186) R 1:1 FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFIRI (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 and OS (1 ), ORR, safety Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). ORR, objective response rate

54 study Key eligibility criteria 18 years of age Adenocarcinoma of the colon / rectum Radiographically confirmed disease progression 6 months after prior 1 st -line fluoropyrimidine-based chemotherapy No prior EGFR inhibitor therapy or irinotecan Measurable disease Paraffin-embedded tumour tissue from primary tumour or metastasis available for central biomarker testing ECOG performance status of 0, 1, or 2 Peeters M, et al. J Clin Oncol 2010; 28:

55 study KRAS exon 2 analysis Demographics and disease characteristics WT KRAS (n = 597) MT KRAS (n = 486) Panitumumab + FOLFIRI (n = 303) FOLFIRI (n = 294) Panitumumab + FOLFIRI (n = 238) FOLFIRI (n = 248) Sex men, n (%) 188 (62) 191 (65) 133 (56) 148 (60) Age years, median (min, max) 60 (28, 84) 61 (29, 86) 61 (29, 83) 64 (29, 86) Race white, n (%) 294 (97) 278 (95) 226 (95) 238 (96) ECOG performance status, n (%) (95) 273 (93) 224 (94) 233 (94) 2 15 (5) 21* (7) 14 (6) 15 (6) Primary tumour type, n (%) Colon 187 (62) 189 (64) 156 (66) 164 (66) Rectal 116 (38) 105 (36) 82 (34) 84 (34) Sites of metastatic disease, n (%) Liver only 51 (17) 59 (20) 37 (16) 35 (14) Liver + other 205 (68) 189 (64) 166 (70) 172 (69) Other only 47 (16) 44 (15) 34 (14) 39 (16) Missing or unknown 0 (0) 2 (<1) 1 (<1) 2 (<1) Prior oxaliplatin therapy, n (%) 204 (67) 191 (65) 164 (69) 169 (68) Prior bevacizumab therapy, n (%) 55 (18) 60 (20) 45 (19) 43 (17) Peeters M, et al. J Clin Oncol 2010; 28: *Included 1 patient with ECOG 3

56 study KRAS exon 2 analysis Efficacy in patients with WT KRAS tumours Panitumumab + FOLFIRI (n = 303) FOLFIRI (n = 294) Median PFS, months Hazard ratio (P-value) 0.73 (P = 0.004) Median OS, months Hazard ratio (P-value) ORR, n (%) (95% CI) (35) (30 41) (n = 297) 0.85 (P = 0.12) (10) (7 14) (n = 285) Peeters M, et al. J Clin Oncol 2010; 28: By central review; *P < (descriptive); exact test of odds ratio stratified by randomisation factors

57 study RAS analysis Mutation hotspots EXON 1 KRAS EXON 2 # EXON 3 EXON % 4.4% 7.7% EXON 1 NRAS EXON 2 EXON 3 EXON % 5.6% 0% Overall RAS ascertainment rate: 85% 18% (107/597) of WT KRAS exon 2 tumours have RAS mutations Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). Prevalence is defined as mutations detected in a population of WT KRAS exon 2 patients whose tissues were deemed evaluable for RAS testing; # The KRAS exon 2 data is from the overall population; WT RAS, KRAS & NRAS exons 2/3/4

58 Proportion event-free (%) study RAS analysis PFS (primary analysis) WT RAS Events n (%) Median (95% CI) months Panitumumab + FOLFIRI (n = 204) 117 (57) 6.4 ( ) FOLFIRI (n = 211) 138 (65) 4.4 ( ) HR = (95% CI, ) Log-rank p-value = Months Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). RAS ascertainment rate: 85%; WT RAS, WT KRAS & NRAS exons 2/3/4

59 Proportion alive % study RAS analysis OS (primary analysis) WT RAS Panitumumab + FOLFIRI (n = 204) Events n (%) Median (95% CI) months 127 (62) 16.2 ( ) FOLFIRI (n = 211) 141 (67) 13.9 ( ) HR = (95% CI, ) Log-rank p-value = Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). Months RAS ascertainment rate: 85%; WT RAS, WT KRAS & NRAS exons 2/3/4

60 study RAS analysis Refinement of patient population by WT RAS status (primary analysis) Median PFS, months Hazard ratio (P-value) Panitumumab + FOLFIRI (n = 303) WT KRAS exon 2 1 WT RAS 2 FOLFIRI (n = 294) Panitumumab + FOLFIRI (n = 204) FOLFIRI (n = 211) (P = 0.004) (P = 0.006) Median OS, months Hazard ratio (P-value) 0.85 (P = 0.12) (P = 0.08) ORR, % (95% CI) 35 (30 41) (n = 297) 10 (7 14) (n = 285) 41 (32 48) (n = 200) 10 (6 15) (n = 205) 1. Peeters M, et al. J Clin Oncol 2010; 28: ; 2. Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). WT RAS, WT KRAS & NRAS exons 2/3/4

61 study RAS analysis Refinement of patient population by MT RAS status (primary analysis) Median PFS, months Hazard ratio (P-value) Panitumumab + FOLFIRI (n = 238) MT KRAS exon 2 1 MT RAS 2 FOLFIRI (n = 248) Panitumumab + FOLFIRI (n = 299) FOLFIRI (n = 294) (P = 0.14) (P = 0.14) Median OS, months Hazard ratio (P-value) 0.94 (P = *ND) (P = 0.34) ORR, % (95% CI) 13 (9 18) (n = 232) 14 (10 19) (n = 237) 15 (11 20) (n = 292) 13 (9 17) (n = 282) 1. Peeters M, et al. J Clin Oncol 2010; 28: ; 2. Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). *ND, not done; WT RAS, WT KRAS & NRAS exons 2/3/4

62 study RAS analysis Conclusions 18% WT KRAS exon 2 patients harboured additional RAS mutations Improvements were seen in the treatment effect by PFS and OS in WT RAS patients compared to WT KRAS exon 2 patients MT RAS patients are unlikely to benefit by the addition of panitumumab to FOLFIRI Adverse events similar to those reported in the panitumumab + FOLFIRI arm of WT KRAS exon 2 patients No new safety signals were identified These results support RAS testing to determine potentially appropriate mcrc patients for panitumumab treatment Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). RAS ascertainment rate was 85%

63 Panitumumab in 3 rd -line mcrc Randomised Phase 3 Study of Panitumumab with Best Supportive Care vs. Best Supportive Care Alone as 3 rd -line Treatment in Patients with Metastatic Colorectal Cancer: the Trial RAS Analysis

65 Trial Panitumumab in mcrc Patients who have Failed Chemotherapy Schema for Pivotal Phase 3 ( ) and Optional Crossover Study ( ) Adapted from: Van Cutsem E, et al. J Clin Oncol 2007; 25: ; Peeters M, et al. Clin Cancer Res 2013; 19: Metastatic CRC (n=463) R 1:1 Study endpoints: PFS (1 ) ORR (per mrecist version 1.0) OS Randomisation stratification: ECOG score: 0-1 vs. 2 Geographic region 231 patients 147 with multi-marker info 82 KRAS WT mcrc Panitumumab 6.0 mg/kg Q2W + BSC (n=231) Best Supportive Care (BSC) (n=232) 232 patients 141 with multi-marker info 71 KRAS WT mcrc PD PD 76% of BSC alone patients entered crossover study Optional Panitumumab Crossover Study ( ; n=176) 176 patients 110 with multi-marker info 56 KRAS WT mcrc compared efficacy and safety of pmab + BSC vs. BSC in previously treated KRAS exon 2 mcrc patients Local and central reviews were conducted for all assessments Archival CRC samples were analyzed for KRAS mutations (codons 12-13) using allele-specific PCR (DxS/Qiagen) F o l l o w u p

68 study KRAS exon 2 analysis Patient demographics Panitumumab + BSC (n = 124) WT KRAS exon 2 MT KRAS exon 2 BSC (n = 119) Panitumumab + BSC (n = 84) BSC (n = 100) Sex male, % 83 (67) 76 (64) 47 (56) 64 (64) Age years, median (min, max) 62.5 (29 82) 63.0 (32 81) 62.0 (27 79) 62.0 (27 83) Race white, % 122 (98) 118 (99) 84 (100) 97 (97) ECOG performance status, % 0-1 2* Primary tumour site 53 (43) 40 (34) 43 (51) 37 (37) 56 (45) 62 (52) 28 (33) 47 (47) 15 (12) 17 (14) 13 (15) 16 (16) Colon 86 (69) 82 (69) 53 (63) 65 (65) Rectum 38 (31) 37 (31) 31 (37) 35 (35) Prior adjuvant chemotherapy yes, n (%) 50 (40) 32 (27) 27 (32) 40 (40) Prior lines of chemotherapy (64) 63 (53) 54 (64) 74 (74) 41 (33) 49 (41) 23 (27) 24 (24) Amado RG, et al. J Clin Oncol 2008; 26: *Of patients treated with BSC, one patient with WT KRAS status and one patient with MT KRAS status had an ECOG PS of 3

69 study KRAS exon 2 analysis Summary of efficacy data WT KRAS exon 2 Panitumumab + BSC (n = 124) BSC (n = 119) OS events, n Median OS, weeks Hazard ratio (95% CI) Median PFS, weeks Hazard ratio (95% CI) ORR, % 12.3 ( ) 16.9 ( ) 0.99 ( ) 0.45 ( ) P < ( ) 0 ( ) Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster); Amado RG, et al. J Clin Oncol 2008; 26:

70 study KRAS exon 2 analysis Summary of efficacy data MT KRAS exon 2 Panitumumab + BSC (n = 84) BSC (n = 100) OS events, n Median OS, weeks Hazard ratio (95% CI) 1.02 ( ) Median PFS, weeks Hazard ratio (95% CI) 0.99 ( ) ORR, % 0 0 Amado RG, et al. J Clin Oncol 2008; 26:

71 study RAS analysis KRAS and NRAS mutation hotspots in the study EXON 1 EXON 2* EXON 3 EXON 4 KRAS % 5% 5% NRAS EXON 1 EXON 2 EXON 3 EXON % 3% 1% Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster). Percentages have been rounded; *KRAS exon 2 data from overall population; remaining data within WT KRAS exon 2 subset and based on samples that yielded a result

72 study RAS analysis PFS (quantitative interaction test for treatment and KRAS status) WT RAS, n 136 PFS events, n 131 Hazard ratio (95% CI) 0.36 ( ) WT KRAS exon 2 / MT other RAS, n 29 Number of PFS events 27 Hazard ratio (95% CI) 0.71 ( ) P-value for Quantitative Interaction Test Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster).

Proportion event-free (%) Proportion event-free (%) 20020408 study RAS analysis PFS 100 WT KRAS exon 2 100 WT RAS 90 80 HR = 0.45 (95% CI, 0.34 0.59) P < 0.001 90 80 HR = 0.36 (95% CI, 0.25 0.

73 Proportion event-free (%) Proportion event-free (%) study RAS analysis PFS 100 WT KRAS exon WT RAS HR = 0.45 (95% CI, ) P < HR = 0.36 (95% CI, ) P < Weeks Weeks Panitumumab + BSC (n = 124) Events n (%) Median, weeks (95% CI) 115 (93) 12.3 ( ) BSC (n = 119) 114 (96) 7.3 ( ) Panitumumab + BSC (n = 73) Events n (%) Median, weeks (95% CI) 70 (96) 14.1 ( ) BSC (n = 63) 61 (97) 7.0 ( ) Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster); Amado RG, et al. J Clin Oncol 2008; 26: WT RAS, WT KRAS & NRAS exons 2/3/4

74 Panitumumab in 3 rd -line mcrc The ASPECCT study: Panitumumab or cetuximab treatment in WT KRAS exon 2 mcrc (open-label, phase 3 study)

75 ASPECCT study Panitumumab vs. cetuximab in 3 rd -line treatment of WT KRAS exon 2 mcrc (open-label, phase 3) Metastatic mcrc WT KRAS exon 2 (n = 999) R 1:1 Panitumumab 6 mg/kg IV (Q2W) Cetuximab 1:1 400 mg/m 2 loading dose, 250 mg/m 2 IV (QW) PD PD S u r v i v a l Study endpoints: OS (1 ); PFS, ORR, safety Crossover between arms during study treatment was not allowed Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); Protocol ID: ; ClinicalTrials.gov identifier: NCT WT KRAS, WT KRAS in codons 12/13

76 ASPECCT study Key eligibility criteria 18 years Metastatic adenocarcinoma of the colon or rectum WT KRAS exon 2 tumour status No prior anti-egfr therapy Disease progression or intolerability on irinotecan-, oxaliplatin- and fluorouracil-based therapy for mcrc Measurable or non-measurable disease Adequate hematologic, renal, hepatic, metabolic function No symptomatic brain metastases Signed informed consent Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); Protocol ID: ; ClinicalTrials.gov identifier: NCT

77 ASPECCT study Statistical considerations I Non-inferiority design Compare the effect of panitumumab vs. cetuximab on OS Treatment effect of cetuximab compared to BSC was derived from the CO.17 trial vs. 4.8 months, HR = 0.55 Retention rate What fraction of the treatment effect of cetuximab over BSC is preserved by panitumumab (point estimate and CI)? Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); 1. Karapetis CS, et al. N Engl J Med 2008; 359: CI, confidence interval

78 Proportion alive (%) ASPECCT study OS (primary analysis) Events n (%) Median, months (95% CI) Panitumumab (n = 499) 383 (76.8) 10.4 ( ) Cetuximab (n = 500) 392 (78.4) 10.0 ( ) HR = 0.97 (95% CI, ) P = Z-score = Retention score = 1.06 (95% CI, ) Months Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation).

79 ASPECCT study Objective response rates (primary analysis) Best tumour response over the study, n (%) Panitumumab (n = 486) Cetuximab (n = 485) Complete response 2 (0.4) 0 (0) Partial response 105 (21.6) 96 (19.8) Stable disease or non-cr / non-pd 226 (46.5) 236 (48.7) Patients with objective response*, n (%) 107 (22.0) 96 (19.8) Rate (95% CI), % Odds ratio (95% CI) ( ) 1.15 ( ) ( ) Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation). CR, complete response; PD, progressive disease

80 ASPECCT study Incidence of grade 3 AEs of interest (primary analysis) Adverse events, n (%) Fatal AEs Colon cancer Others Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation). Panitumumab (n = 496) 29 (5.8) 20 (4.0) 9 (1.8) Cetuximab (n = 503) 50 (9.9) 34 (6.8) 16 (3.2) Treatment-related fatal AEs 0 (0) 1 (0.2) Skin and subcutaneous tissue AEs Any grade Grade 3 Grade 4 Serious Hypomagnesaemia Any grade Grade 3 Grade 4 Infusion reactions Any grade Grade 3 Grade 4 Diarrhoea Any grade Grade 3 Grade (86.7) 60 (12.1) 2 (0.4) 1 (0.2) 143 (28.8) 27 (5.4) 9 (1.8) 14 (2.8) 1 (0.2) 0 (0) 91 (18.3) 7 (1.4) 3 (0.6) 440 (87.5) 48 (9.5) 0 (0) 0 (0) 95 (18.9) 10 (2.0) 3 (0.6) 63 (12.5) 5 (1.0) 4 (0.8) 89 (17.7) 9 (1.8) 0 (0.0)

83 Terapötik endikasyon (Türkiye) VECTİBİX, daha önce panitumumab veya diğer anti-egfr tedavileri kullanmamış, ECOG performans skoru: 0-1 olan, KRAS wild tip metastatik kolorektal kanserde birinci veya ikinci seri tedavide, FOLFOX veya FOLFİRİ kombinasyon kemoterapi rejimlerinin sadece birisi ile progresyona kadar kullanımda endikedir. Progresyon durumunda veya beraberindeki kemoterapi rejiminin değiştirilmesi durumunda panitumumab veya başka bir anti-egfr tedavisi kullanılamaz. Önerilen panitumumab dozu iki haftada bir verilmek üzere 6 mg/kg vücut ağırlığı şeklindedir. Vectibix Kısa Ürün Bilgisi.

ADVANCED COLORECTAL CANCER: UNRESECTABLE OR BORDERLINE RESECTABLE (GROUP 1) CHEMOTHERAPY +/- TARGETED AGENTS. Andrés Cervantes. Professor of Medicine

ADVANCED COLORECTAL CANCER: UNRESECTABLE OR BORDERLINE RESECTABLE (GROUP 1) CHEMOTHERAPY +/- TARGETED AGENTS Andrés Cervantes Professor of Medicine 1995 One option Advances in the treatment of mcrc 2000