0. Panitumumab + FOLFIRI as 1st-line treatment for mCRC

1. Therapeutic indication (EU)
Panitumumab is indicated for the treatment of adult patients with wild-type RAS metastatic colorectal cancer (mCRC):
In first-line in combination with FOLFOX or FOLFIRI
In second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan)
As monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens
The combination of panitumumab with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown
The recommended dose of panitumumab is 6 mg/kg of bodyweight given once every two weeks
Vectibix® Summary of Product Characteristics.

2. Panitumumab + FOLFIRI as 1st-line treatment for mCRC Table of contents
Description
Slide
Introduction: panitumumab and RAS as a predictive biomarker in mCRC 4
study 13
PLANET study 19
Supporting evidence
Biological plausibility:
ASPECCT study
CRYSTAL study
Additional efficacy/safety data:
study 26 27 29 30
Summary 32

3. Introduction: panitumumab and RAS as a predictive biomarker in mCRC

4. EGFR activation may involve downstream signalling pathways that include RAS proteins
TGF-α
EGFR homodimer
EGF
EGFR
RAS GTP
RAS GDP
RAF
Nck
MEK
Rac
PI3K
Proliferation
Anti-apoptosis
Survival
Angiogenesis
Metastasis
PAK
PLCγ
PTEN
AKT
In normal cells, ligand-specific activation of the epidermal growth factor receptor (EGFR) activates a complex series of regulated signal transduction pathways.1,2
In cancerous cells, activation of these pathways is associated with various processes that contribute to the development of malignancy including cell growth, proliferation and survival, migration/motility, angiogenesis, inhibition of apoptosis, gene transcription and metastasis.1−3
The EGFR pathway plays an important role in controlling cell cycle events that affect survival:
EGFR activation induces cyclin D-1, a protein that activates cyclin-dependent kinases, allowing cell-cycle progression through G1.3,4
References:
Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov Med 2012;14:207−14.
Di Fiore F, et al. Molecular determinants of anti-EGFR sensitivity and resistance in metastatic colorectal cancer. Br J Cancer 2010;103:1765−72.
Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumours: a new paradigm for cancer therapy. Cancer 2002;94:1593−611.
Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett 2012;318:124−34.
JNKK
ERK
JNK
PKC
mTOR
S6K
Myc
Elk
Jun
Fos
Berg M, Soreide K. Discov Med 2012;14:207−14; Di Fiore F, et al. Br J Cancer 2010;103:1765−72;
Han W, Lo HW. Cancer Lett 2012;318:124−34; Herbst RS, Shin DM. Cancer 2002;94:1593−611.
EGFR, epidermal growth factor receptor. ©2007 Amgen Inc. All rights reserved

5. Panitumumab – a fully human, anti-EGFR mAb – inhibits ligand binding and EGFR dimerisation
Fully human, IgG2 mAb1
Binds with high affinity and specificity to the extracellular domain of the human EGFR
Dissociation constant: KD=0.05 nM1,2
Inhibits receptor activation of all known EGFR ligands3
Inhibits EGFR-dependent activity including cell activation and cell proliferation in various preclinical models1,2
Panitumumab
EGFR
Panitumumab inhibits ligand-induced EGFR tyrosine kinase phosphorylation by competitively binding to the extracellular domain and preventing the binding of natural activating ligands such as epidermal growth factor (EGF) or transforming growth factor-α (TGFα).1,2
Inhibition of EGF-dependent activity by panitumumab, including cell activation and proliferation, has been reported in various preclinical models.1,2
Panitumumab binds to the extracellular domain of EGFR with a dissociation constant (KD) of KD = 0.05 nM.2,3
KD is a type of equilibrium constant that measures the propensity of a bound complex (e.g. ligand + receptor) to separate reversibly into the component molecules. A lower dissociation constant therefore means a higher (stronger) binding affinity.
Point mutation analysis has shown that amino acids 349, 355, 412 and 438 on the surface of domain L2 of the EGFR molecule are critical for panitumumab binding.3
In vitro studies in A549 non-small cell lung cancer (NSCLC) tumour cells indicated that panitumumab can inhibit receptor activation of all known EGFR ligands.3
References:
Yang XD, et al. Eradication of established tumours by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999;59:1236−43.
Foon KA, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004;58:984−90.
Freeman D, et al. Panitumumab and cetuximab epitope mapping and in vitro activity. J Clin Oncol 2008;26(Suppl 15):14536 (and poster).
1. Foon KA, et al. Int J Radiat Oncol Biol Phys 2004;58:984−90;
2. Yang XD et al. Cancer Res 1999;59:1236−43; 3. Freeman D, et al. J Clin Oncol 2008;26(Suppl 15):abstract (and poster).
mAb, monoclonal antibody.

6. Panitumumab inhibits EGFR dimerisation and subsequent downstream signalling
TGF-α
Panitumumab
EGFR homodimer
EGFR
RAS GTP
RAS GDP
RAF
Nck
MEK
Rac
PI3K
Proliferation
Anti-apoptosis
Survival
Angiogenesis
Metastasis
PAK
PLCγ
PTEN
AKT
Panitumumab prevents EGF and other ligands from binding to EGFR.1,2
Inhibition of EGFR dimerisation and downstream signalling subsequently inhibits EGF-dependent cell activation, growth and proliferation.2
References:
Freeman D, et al. Panitumumab and cetuximab epitope mapping and in vitro activity. J Clin Oncol 2008;26(Suppl 15):abstract (and poster).
Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov Med 2012;14:207−14.
JNKK
ERK
JNK
PKC
mTOR
S6K
Myc
Elk
Jun
Fos
Berg M, Soreide K. Discov Med 2012;14:207−14; Freeman D, et al. J Clin Oncol 2008;26(Suppl 15):abstract (and poster).
©2007 Amgen Inc. All rights reserved

7. EGFR signalling via RAS Panitumumab inhibition of EGFR signalling
RAS proteins are predictive biomarkers for anti-EGFR monoclonal antibodies
RAS
GDP
GTP
EGFR dimer
EGF P
EGFR signalling via RAS
RAS effector pathways
e.g. Tumour proliferation
Attenuation of signalling
RAS WT
RAS
GDP
GTP
Panitumumab
Panitumumab inhibition of EGFR signalling
Inhibition of tumour proliferation
RAS MT
Panitumumab
RAS
GTP
Constitutive signalling
Tumour proliferation
Left figure:
RAS proteins couple receptor activation to downstream effector pathways that control diverse cellular responses including proliferation, differentiation and survival.1
RAS proteins are small GTPases that cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound conformations.1
Growth factor binding to cell-surface receptors creates intracellular docking sites for adaptor molecules and signal-relay proteins that recruit and activate guanine nucleotide-exchange factors (GEFs); GEFs displace guanine nucleotides from RAS and permit passive binding to GTP.1
GTP bound RAS can interact with more than 20 effectors to regulate various cellular responses.1
Elevated expression of EGFR is found in many malignancies and may play a role in tumourigenesis.2
Centre figure:
Binding of panitumumab to EGFR inhibits EGFR autophosphorylation and subsequent downstream signalling, and consequently cell growth and proliferation terminates.2,3
Right figure:
Activating RAS mutations result in a constitutively active GTP-bound protein, which consequently renders the downstream pathway permanently “switched on” irrespective of the activation status of upstream receptors including EGFR.4,5
This constitutive pathway activation leads to unregulated proliferation, impaired differentiation, and resistance to anti-EGFR therapies.4,5
References:
Schubbert S, et al. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295–308.
Foon KA, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004;58:984–90.
Yang XD, et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999;59:1236–43.
Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov Med 2012;14:207–14.
Custodio A, Feliu J. Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: beyond KRAS mutations. Crit Rev Oncol Hematol 2013;85:45–81.
1. Schubbert S, et al. Nat Rev Cancer 2007;7:295–308; 2. Foon KA, et al. Int J Radiat Oncol Biol Phys 2004;58:984–90; 3. Berg M, Soreide K. Discov Med 2012;14:207–14; 4. Custodio A, Feliu J. Crit Rev Oncol Hematol 2013;85:45–81.
EGF, epidermal growth factor; MT, mutant; WT, wild type. Example signalling pathways, simplified for illustrative purposes.

8. Panitumumab in mCRC Clinical development highlights and European approvals
(PEAK)
1st-line Phase 2 mFOLFOX6 + pmab vs
mFOLFOX6 + bev
(PRIME)
1st-line Phase 3
FOLFOX ± pmab
(ASPECCT)
Chemorefractory 3rd-line Phase 3 (non-inferiority)
pmab vs cmab
2nd-line Phase 3
FOLFIRI ± pmab
1st-line Phase 2 (single arm) FOLFIRI + pmab
Chemorefractory Phase 3
pmab vs BSC
Extension of indication:1
FOLFIRI (1st-line) in WT RAS mCRC
2003
2004
Panitumumab clinical development highlights and product labelling are summarised on this slide.1−7
References:
European Commission, Pharmaceuticals – Community Register. Vectibix Product Information. Available at: Accessed
ClinicalTrials.gov Identifier: NCT Evaluating panitumumab (ABX-EGF) plus best supportive care versus best supportive care in patients with metastatic colorectal cancer. Available at: ClinicalTrials.gov. Accessed
ClinicalTrials.gov Identifier: NCT PRIME: panitumumab randomized trial in combination with chemotherapy for metastatic colorectal cancer to determine efficacy. Available at: ClinicalTrials.gov. Accessed
ClinicalTrials.gov Identifier: NCT Comparison of treatment effect of chemotherapy with panitumumab to chemotherapy alone. Available at: ClinicalTrials.gov. Accessed
ClinicalTrials.gov Identifier: NCT Panitumumab plus FOLFIRI in first-line treatment of metastatic colorectal cancer. Available at: ClinicalTrials.gov. Accessed
ClinicalTrials.gov Identifier: NCT PEAK: panitumumab plus mFOLFOX6 vs. bevacizumab plus mFOLFOX6 for first line treatment of metastatic colorectal cancer (mCRC) patients with wild-type kirsten rat sarcoma-2 virus (KRAS) tumors. Available at: ClinicalTrials.gov. Accessed
ClinicalTrials.gov Identifier: NCT ASPECCT: A study of panitumumab efficacy and safety compared to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Available at: ClinicalTrials.gov. Accessed
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
Monotherapy WT KRAS exon 2 mCRC
Monotherapy (chemorefractory)
Combination WT KRAS exon 2 mCRC
FOLFOX (1st-line); FOLFIRI (2nd-line);
monotherapy (chemorefractory)
RAS label variation
WT RAS mCRC
FOLFOX (1st-line); FOLFIRI (2nd-line);
monotherapy (chemorefractory)
1. European Commission, Pharmaceuticals – Community Register. Available at: Accessed
Bev, bevacizumab; BSC, best supportive care; cmab, cetuximab; pmab, panitumumab.

9. PRIME study FOLFOX4 ± panitumumab in 1st-line treatment of mCRC
Primary endpoint: PFS
Prospective-retrospective extended RAS analysis
WT RAS2,3
Panitumumab + FOLFOX4 (n = 259)
FOLFOX4 (n = 253)
Median PFS, mo*
10.1
7.9 HR
(95% CI) P-value
0.72
(0.58–0.90) P = 0.004
Median OS, mo*
26.0
20.2
(95% CI)
P-value
0.78 (0.62–0.99) P = 0.04
ORR, %*‡ 59
(52–65) 46
(40–53)
Odds ratio
1.63§
P = 0.009
mCRC†1
(n = 1183) R
1:1
FOLFOX4 (Q2W) + panitumumab 6 mg/kg (Q2W)
FOLFOX4 (Q2W)
PRIME was an open-label, randomised, multicentre Phase 3 trial to evaluate the combination of panitumumab and FOLFOX4 vs FOLFOX4 alone in patients with previously untreated mCRC.1
Originally designed to compare the treatment effect in all randomised patients, the design was amended to focus on prospective hypothesis testing in the WT KRAS (codons 12 and 13) stratum.
Patients were stratified by:1
Performance status (Eastern Cooperative Oncology Group [ECOG] 0−1 vs 2)
Geographical region (Western Europe, Canada, and Australia vs rest of the world).
Patients were evaluated every 8 weeks (Q8W) until progression. Responses were confirmed at least 4 weeks after the criteria for response were first met.
Patients were followed for safety 30 days after the last study drug administration and for survival every 3 months (Q3M).
Please refer to Douillard JY, et al. J Clin Oncol 2010;28:4697−705 and Douillard J-Y, et al. N Engl J Med 2013;369:1023−34 for further information.1,2
References:
Douillard JY, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697−705.
Douillard J-Y, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023−34.
1. Douillard JY, et al. J Clin Oncol 2010;28:4697−705; 2. Douillard J-Y, et al. N Engl J Med 2013;369:1023−34; 3. Vectibix® EPAR Assessment Report. 2013; EMA/CHMP/367675/2013.
†Design amended to focus on prospective hypothesis testing in the WT KRAS (codons 12 and 13) stratum; ‡By central radiological assessment. ORR in 149 and 114 patients, respectively;§Adjusted odds ratio; *Primary analysis. ORR, objective response rate; Q2W, every 2 weeks. RAS ascertainment rate: 90%. WT RAS = WT KRAS and NRAS exons 2, 3, 4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations).

10. RAS mutation status does not appear to be prognostic for survival in mCRC
The prognostic effect of RAS mutation status was evaluated in PRIME by comparing the HR for death from any cause in WT vs MT RAS subgroups within and across treatment groups1
Most HRs were neutral in the FOLFOX4 alone treatment arm
OS by RAS genotype subgroup in PRIME (primary analysis)1
Favours WT
Favours MT n
HR (95% CI)
FOLFOX4
Panitumumab + FOLFOX4
310
0.92 (0.63–1.35)
0.58 (0.39–0.84)
0.10
10.00
1.00
HR (WT/MT)
RAS mutation status, while predictive of response to anti-EGFR therapy,1 does not appear to be prognostic for survival in mCRC.1,2
In line with observations in PRIME (see slide), comparing the HR for PFS in WT vs MT RAS subgroups in Study (panitumumab vs BSC in chemorefractory mCRC) revealed a neutral HR in the BSC arm.2
References:
Douillard JY, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023−34, and supplements available at:
Patterson SD, et al. Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase 3 metastatic colorectal cancer (mCRC) study ( ). J Clin Oncol 2013;31(Suppl):abstract 3617 (and poster).
1. Douillard JY, et al. N Engl J Med 2013;369:1023−34 and supplements available at:

11. mFOLFOX6 (Q2W) + panitumumab 6 mg/kg (Q2W)
Phase 2 PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line treatment of WT KRAS exon 2 mCRC
Primary endpoint: PFS
No planned formal hypothesis testing
Prespecified extended RAS analysis
WT RAS1
Panitumumab + mFOLFOX6
(n = 88)
Bevacizumab + mFOLFOX6
(n = 82)
Median PFS, mo*
13.0
9.5 HR
(95% CI) P-value
0.65 (0.44–0.96)
P = 0.029
Median OS, mo†
41.3
28.9
(95% CI)
P-value
0.63 (0.39–1.02) P = 0.058
ORR, %*
63.6
(52.7–73.6)
60.5
(49.0–71.2)
mCRC
WT KRAS exon 2
(n = 285) R
1:1
mFOLFOX6 (Q2W) + panitumumab 6 mg/kg (Q2W)
mFOLFOX6 (Q2W) +
bevacizumab 5 mg/kg
(Q2W)
PEAK was a multicentre, randomised, Phase 2 study to evaluate the combination of panitumumab + (modified) mFOLFOX6 and bevacizumab + mFOLFOX6 in patients with previously untreated WT KRAS exon mCRC.1
Patients were stratified by prior adjuvant oxaliplatin therapy using permuted blocks.1
The extended RAS analysis was prespecified and included all intent-to-treat patients with available RAS biomarker information.1
Please refer to Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7 for further information.1
Reference:
Schwartzberg LS, et al. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014;32:2240−7.
1. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7;
Protocol ID: ; ClinicalTrials.gov identifier: NCT
*Primary analysis; †longer follow-up analysis. RAS ascertainment rate: 82%. WT RAS = WT KRAS/NRAS exons, 2, 3, 4.

12. Panitumumab + FOLFIRI in 1st-line treatment of mCRC
study (Phase 2)

13. 20060314 study Panitumumab + FOLFIRI in 1st-line treatment of mCRC
Study endpoints: ORR (1º), DCR, DoR, PFS, DoSD, TTP, safety
Retrospective, descriptive RAS analysis2
Panitumumab 6 mg/kg (Q2W) + FOLFIRI (Q2W)
mCRC1
(n = 154)
Follow-up
Treatment until PD, unacceptable toxicity or consent withdrawal
Response evaluation Q8W until Week 48 then Q3M until PD
Please refer to Köhne CH, et al. J Cancer Res Clin Oncol 2012;138:65−72 and Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P) for further information.1,2
References:
Köhne CH, et al. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol 2012;138:65−72.
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
1. Köhne CH, et al. J Cancer Res Clin Oncol 2012;138:65−72; 2. Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P); protocol ID: ; ClinicalTrials.gov identifier: NCT
DCR, disease control rate; DoR, duration of response; DoSD, duration of stable disease; PD, progressive disease; TTP, time to progression. RAS ascertainment rate: 93%. WT RAS = WT KRAS/NRAS exons 2, 3, 4.

14. 20060314 study RAS mutation hotspots
EXON 1
EXON 2
EXON 3
EXON 4 12 13 13 59 59 61
117
146
146
KRAS
38.3%
3.4%
2.7%
EXON 1
EXON 2
EXON 3
EXON 4 12 12 13 13 59 59 61 61
117
117
146
146
NRAS
2.0%
2.0% 0%
Please refer to Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P) for further information.1
Reference:
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
RAS ascertainment rate: 93%.

15. 20060314 study RAS analysis ORR by RAS status
Panitumumab + FOLFIRI
WT RAS
(n = 68)
MT RAS
(n = 73)
ORR, n (%)
40 (59)
30 (41)
(95% CI)
(46.2−70.6)
(29.7−53.2)
Unadjusted odds ratio
2.0
(1.0−4.2)
Please refer to Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P) for further information.1
Reference:
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).

16. 20060314 study RAS analysis PFS by RAS status
100 80 60 40 20 4 8 12 24 28 16
Months
Proportion event-free (%) 44 32 36 48 90 70 50 30 10
Median, months (95% CI)
WT RAS (n = 69)
11.2 (7.6–14.8)
MT RAS (n = 74)
7.3 (5.8–7.5)
Panitumumab + FOLFIRI:
HR = 0.37 (95% CI, 0.24–0.58)
Please refer to Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P) for further information.1
Reference:
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Censor indicated by vertical bar.

17. 20060314 study RAS analysis Summary of adverse events
Panitumumab + FOLFIRI
WT RAS (n = 69)
MT RAS (n = 74)
Any AE, n (%)
69 (100)
74 (100)
Worst grade ≥ 3
59 (86)
57 (77)
Serious AE
40 (58)
38 (51)
AE leading to discontinuation†
21 (30)
18 (24)
Any treatment-related AE, n (%)
50 (72)
50 (68)
20 (29)
16 (23)
13 (18)
Please refer to Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P) for further information.1
Reference:
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Karthaus M, et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
†Permanent discontinuation of any study drug. AE, adverse event.

18. Panitumumab + FOLFOX4 or FOLFIRI in patients with WT KRAS exon mCRC and liver-limited disease (LLD)
PLANET study (Phase 2)

19. Panitumumab 6 mg/kg (Q2W) +
PLANET study Panitumumab + FOLFOX4 or FOLFIRI in patients with WT KRAS exon mCRC and LLD
Study endpoints: ORR for entire panitumumab + CT treatment period (1), PFS, OS, liver metastases resection rate, time to resection, safety, peri-operative safety
Exploratory endpoint: protocol predefined RAS analysis
mCRC, LLD
(n = 77)
Treatment until progression or resectability achieved Response evaluation Q8W
Panitumumab 6 mg/kg (Q2W) +
FOLFOX4 (Q2W)
FOLFIRI (Q2W) R
1:1 PD
Or additional surgery
Follow-up
Q3 ±1M after safety evaluation (up to 36M)
Safety: 30 ±3 days after last study drug administration
PLANET was a Phase II, open-label, randomised, multicentre, two-parallel-group study.
Preoperative panitumumab + FOLFOX4 or FOLFIRI was administered Q2W for 4−8 cycles, and surgery was performed 4−6 weeks after the last chemotherapy dose.
Patients who did not achieve stable disease (SD) or resectability received additional cycles until PD or unacceptable toxicity. Adjuvant treatment was also administered after surgery.
Patients were stratified by prior adjuvant FOLFOX therapy and resectability of liver metastases.
After 4 cycles of neoadjuvant/adjuvant therapy, if partial response was ≥ 75% or there was a nearly complete response and resection was feasible, surgery was performed immediately.
Tumour assessments (RECIST version 1.1) were performed by investigators Q8W during the treatment phase.
Please refer to Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P) for further information.1
Reference:
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P); ClinicalTrials.gov identifier: NCT
1M, 1 month; 36M, 36 months; CT, chemotherapy. RAS ascertainment rate: 83.1%. WT RAS = WT KRAS/NRAS exons 2, 3, 4.

20. PLANET study RAS analysis (interim results) ORR
WT RAS
Panitumumab + FOLFOX4
(n = 27)
Panitumumab + FOLFIRI
(n = 26)
ORR†, n (%)
21 (77.8)
19 (73.1)
(95% CI)
(62.1−93.5)
(56.0−90.1)
Please refer to Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P) for further information.1
Reference:
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
†Not confirmed, patients resected before response confirmation.

21. PLANET study RAS analysis (interim results) PFS and OS
WT RAS
PFS OS
Months
Proportion event-free (%) 40 30 20 10
100 80 60 90 70 50
Months
Proportion alive (%) 40 30 20 10
100 80 60 50 90 70
Wilcoxon P-value = 0.675
Wilcoxon P-value = 0.634
Median, months
(95% CI)
Panitumumab + FOLFOX4
39.0 (26.4–NA)
Panitumumab + FOLFIRI
45.8 (32.8–51.5)
Median, months
(95% CI)
Panitumumab + FOLFOX4
12.8 (6.2–22.0)
Panitumumab + FOLFIRI
14.8 (7.1–18.7)
Please refer to Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P) for further information.1
Reference:
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
NA, not achieved.

22. PLANET study RAS analysis (interim results) Summary of AEs
WT RAS
AEs, n (%)
Panitumumab + FOLFOX4
(n = 27)
Panitumumab + FOLFIRI
(n = 26)
Grade 3/4 AEs
22 (81.5)
20 (76.9)
Treatment-related grade 3−4 AEs
18 (66.7)
16 (61.5)
Fatal AEs
1 (3.7)
3 (11.5)
Treatment-related fatal AEs
Serious AEs
6 (22.2)
7 (26.9)
Panitumumab and/or CT-related serious AEs
Perioperative AEs†
1 (10.0)
5 (27.8)
Please refer to Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P) for further information.1
Reference:
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
†In patients who underwent surgery.

23. PLANET study RAS analysis (interim results) Summary of AEs (continued)
WT RAS
AEs, n (%)
Panitumumab + FOLFOX4
(n = 27)
Panitumumab + FOLFIRI
(n = 26)
P-value
Grade 3−4† treatment-related AEs
Neutropenia
7 (25.9)
2 (7.7)
0.077
Conjunctivitis
1 (3.7)
1 (3.8)
0.978
Diarrhoea
3 (11.1)
1 (3.9)
0.317
Asthenia
4 (14.8)
0.172
Neuropathy
5 (18.5)
0.051
Decreased appetite
2 (7.4)
0.157
Please refer to Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P) for further information.1
Reference:
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
†There were no grade 5 AEs related to panitumumab and/or CT.

24. Panitumumab + FOLFIRI as 1st-line treatment for mCRC Summary
Efficacy and safety of 1st-line panitumumab + FOLFOX has been established in patients with WT RAS mCRC1,2
1st-line panitumumab + FOLFIRI was associated with longer PFS and a higher ORR in patients with WT RAS vs MT RAS mCRC3†
Panitumumab was equally effective and had a similar safety profile in combination with either 1st-line FOLFOX4 or FOLFIRI in patients with WT RAS mCRC4†‡
Patients with MT RAS tumours do not benefit from the addition of panitumumab to FOLFOX4 and may experience worse outcomes1
On 30 March 2015, the European Commission approved a variation to the terms of the marketing authorisation for panitumumab5
Extension of indication to include 1st-line panitumumab in combination with FOLFIRI in patients with WT RAS mCRC
References:
Douillard J-Y, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023−34.
Schwartzberg LS, et al. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014;32:2240−7.
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
European Commission, Pharmaceuticals – Community Register. Vectibix Product Information. Available at: Accessed
1. Douillard J-Y, et al. N Engl J Med 2013;369:1023−34; 2. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7; 3. Karthaus M et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P); 4. Abad A, et al. Ann Oncol 2014;25 (Suppl 4):iv189 (poster 551P); 5. European Commission, Pharmaceuticals – Community Register. Available at: Accessed
†Phase 2 study; ‡LLD.

25. Supporting evidence Biological plausibility:
ASPECCT study
CRYSTAL study
Additional efficacy/safety data:
study

26. ASPECCT study Panitumumab vs cetuximab in 3rd-line treatment of WT KRAS exon 2 mCRC
Primary endpoint: OS
WT KRAS1
Panitumumab (n = 499)
Cetuximab (n = 500)
Median PFS, mo
4.1
4.4 HR
(95% CI) P-value
1.00 (0.88–1.14) NR
Median OS, m
10.4
10.0
(95% CI)
P-value
0.97 (0.84–1.11)
ORR, %
22.0 (18.4−26.0)
(n = 486)
19.8 (16.3−23.6)
(n = 485)
Odds ratio
1.15
(0.83−1.58)
WT KRAS exon 2 mCRC (n = 999) R
1:1
Panitumumab
6 mg/kg IV (Q2W)
Cetuximab
400 mg/m2 loading dose
250 mg/m2 IV (QW)
Patients were followed for survival for 24 months after the last randomisation and, for safety, 30 days after last study drug administration.
Response assessment was at Week 6 (±1) and Q8W (±1) thereafter. Laboratory assessments were Q4W.
Please refer to Price TJ, et al. Lancet Oncol 2014;15:569−79 for further information.1
Reference:
Price TJ, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014;15:569−79.
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).

27. ASPECCT study Summary of AEs of interest
WT KRAS
AEs, n (%)
Panitumumab (n = 496)
Cetuximab (n = 503)
All AEs
Grade 3
Grade 4
Grade 5
485 (98)
180 (36)
37 (7)
29 (6)
494 (98)
159 (32)
27 (5)
50 (10)
Treatment-related fatal AEs
0 (0)
1 (0.2)
Hypomagnesaemia (any grade)
Grade 3 Grade 4
136 (27) 26 (5) 9 (2)
89 (18) 10 (2) 3 (0.6)
Infusion reactions (any grade) Grade 3 Grade 4
15 (3) 1 (0.2) 0 (0)
72 (14) 5 (1) 4 (0.8)
Diarrhoea (any grade)
91 (18)
7 (1)
3 (0.6)
89 (18)
9 (2)
Skin and subcutaneous tissue toxicity† (any grade)
430 (87) 60 (12) 2 (0.4)
440 (87)
48 (10) 0 (0)
Please refer to Price TJ, et al. Lancet Oncol 2014;15:569−79 for full adverse event data.1
Reference:
Price TJ, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014;15:569−79.
Price TJ, et al. Lancet Oncol 2014;15:569−79.
†Includes AEs in the skin and subcutaneous tissue disorders system organ class of the Medical Dictionary for Regulatory Authorities (MedDRA, version 15.1).

28. FOLFIRI + cetuximab (n = 178)
CRYSTAL study RAS analysis FOLFIRI ± cetuximab in 1st-line treatment of EGFR-expressing mCRC
Primary endpoint: PFS
Extended post-hoc RAS analysis in 430/666 (64.6%) patients with WT KRAS exon 2 tumours
WT RAS3
FOLFIRI + cetuximab (n = 178)
FOLFIRI (n = 189)
Median PFS, mo
11.4
8.4 HR
(95% CI) Log-rank P-value
0.56 (0.41–0.76)
< 0.001
Median OS, mo
28.4
20.2
(95% CI)
Log-rank P-value
0.69 (0.54–0.88)
ORR, %
66.3
38.6
Odds ratio
P-value†
3.11
(2.03−4.78) < 0.001
EGFR- expressing, mCRC1−3 (n = 1198) R
1:1
FOLFIRI (Q2W) + cetuximab 400 mg/m² loading dose,
250 mg/m² IV (QW)
FOLFIRI (Q2W)
Response assessment was Q8W until disease progression or withdrawal. Follow-up evaluations were performed Q3M.1,2
Polymerase chain reaction (PCR) clamping and the melting curve method was used for KRAS testing.1
BEAMing analysis, with a 5% cut-off, was used for RAS analysis.1
Please refer to Van Cutsem E, et al. N Engl J Med 2009;360:1408−17, Van Cutsem E, et al. J Clin Oncol 2011;29:2011−9 and Van Cutsem E, et al. J Clin Oncol 2015;33:692−700 for further information.1−3
References:
Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408−17.
Van Cutsem E, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29:2011−9.
Van Cutsem E, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33:692−700.
1. Van Cutsem E, et al. N Engl J Med 2009;360:1408−17; 2. Van Cutsem E, et al. J Clin Oncol 2011;29:2011−9; 3. Van Cutsem E, et al. J Clin Oncol 2015;33:692−700. ClinicalTrials.gov identifier: NCT
†Cochran-Mante-Haenszel test. RAS ascertainment rate: 64.6%. WT RAS = WT KRAS/NRAS exons 2,3, 4.

29. Panitumumab + FOLFIRI (n = 208)
study RAS analysis FOLFIRI ± panitumumab in 2nd-line treatment of mCRC
Primary endpoint: PFS and OS
Prospective-retrospective RAS analysis
WT RAS1
Panitumumab + FOLFIRI (n = 208)
FOLFIRI (n = 213)
Median PFS, mo*
6.4
4.6 HR
(95% CI) Log-rank P-value
0.70
(0.54–0.91)
0.007
Median OS, mo*
16.2
13.9
(95% CI)
Log-rank P-value
0.81 (0.63–1.03) 0.08
ORR, %*
41 (34−48)
(n = 204)
10 (6−15)
(n = 207)
mCRC1
(n = 1186) R
1:1
FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W)
FOLFIRI (Q2W)
Patients were followed for survival Q3M and for safety 30 days after the last study drug administration. Disease assessment was Q8W.1
Please refer to Peeters M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster) for further information.1
Reference:
Peeters M, et al. Updated analysis of KRAS/NRAS and BRAF mutations in study of panitumumab + FOLFIRI for 2nd-line treatment of metastatic colorectal cancer (mCRC). J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster).
1. Peeters M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster); protocol ID: ; ClinicalTrials.gov identifier: NCT
*Primary analysis. RAS ascertainment rate: 85%; WT RAS = WT KRAS and NRAS exons 2, 3, 4.

30. 20050181 study RAS analysis Summary of AEs
WT RAS (primary analysis)
AE, n (%)
Panitumumab + FOLFIRI
(n = 207)
FOLFIRI
(n = 213)
Any AE
207 (100)
211 (99)
Worst grade 3
114 (55)
78 (37)
Worst grade 4
41 (20)
35 (16)
Worst grade 5
8 (4)
13 (6)
Any serious
94 (45)
67 (31)
Leading to permanent discontinuation of any study drug
50 (24)
25 (12)
Not serious
30 (14)
19 (9)
Serious
24 (12)
Please refer to Peeters M, et al. J Clin Oncol 2014; 32(Suppl 5):abstract 3568 (and poster) for further information.1
Reference:
Peeters M, et al. Updated analysis of KRAS/NRAS and BRAF mutations in study of panitumumab + FOLFIRI for 2nd-line treatment of metastatic colorectal cancer (mCRC). J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster).
Peeters M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster).

31. Summary

32. 1st-line panitumumab + FOLFIRI in mCRC
Studies of interest in relation to potential utility of 1st-line panitumumab + FOLFIRI in mCRC
1st-line panitumumab + FOLFIRI in mCRC
Safety/efficacy of 1st-line FOLFIRI combination
Study 314
1st-line: FOLFIRI + pmab (Phase 2, single arm)
n = 154
Safety/efficacy of 2nd-line FOLFIRI combination
Safety/efficacy with FOLFOX & FOLFIRI
Study 181 2nd-line: FOLFIRI + pmab vs FOLFIRI (Phase 3)
n = 1186
PLANET 1st-line:
FOLFIRI + pmab vs FOLFOX + pmab
(Phase 2 LLD)
n = 77
ASPECCT
3rd-line: cmab vs pmab
(Phase 3)
n = 999
PRIME
1st-line: FOLFOX + pmab vs FOLFOX
(Phase 3)
n = 1183
Biological plausibility
Safety/efficacy of FOLFOX combination
CRYSTAL
1st-line:
FOLFIRI + cmab vs FOLFIRI
(Phase 3)
n = 1198
References:
Schwartzberg LS, et al. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014;32:2240−7.
Douillard J-Y, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023−34.
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Peeters M, et al. Updated analysis of KRAS/NRAS and BRAF mutations in study of panitumumab + FOLFIRI for 2nd-line treatment of metastatic colorectal cancer (mCRC). J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster).
Price TJ, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014;15:569−79.
Van Cutsem E, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33:692−700.
PEAK
1st-line: FOLFOX + pmab or bev
(Phase 2)
n = 285
Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7; Douillard J-Y, et al. N Engl J Med 2013;369:1023−34; Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P); Karthaus M et al. Ann Oncol 2014;25(Suppl 4); iv188 (poster 549P); Peeters M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster); Price TJ, et al. Lancet Oncol 2014;15:569−79; Van Cutsem E, et al. J Clin Oncol 2015;33:692−700.
This summarises some of the key data sets that supported European Commission approval for the label variation to include panitumumab + FOLFIRI in 1st-line WT RAS mCRC.

33. Panitumumab + FOLFIRI as 1st-line treatment for mCRC Summary
Efficacy and safety of 1st-line panitumumab + FOLFOX has been established in patients with WT RAS mCRC1,2
1st-line panitumumab + FOLFIRI was associated with longer PFS and a higher ORR in patients with WT RAS vs MT RAS mCRC3†
Panitumumab was equally effective and had a similar safety profile in combination with either 1st-line FOLFOX4 or FOLFIRI in patients with WT RAS mCRC4†‡
Comparable efficacy of anti-EGFR mAb agents (panitumumab and cetuximab) was demonstrated in patients with chemorefractory mCRC (WT KRAS exon 2 tumours)5
Addition of cetuximab to FOLFIRI improved outcomes in 1st-line WT RAS mCRC6
Addition of panitumumab to FOLFIRI improved outcomes in 2nd-line WT RAS mCRC7
The safety profiles of anti-EGFR mAbs, as monotherapy and in combination with chemotherapy, are consistent and well established1−7
References:
Douillard J-Y, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023−34.
Schwartzberg LS, et al. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014;32:2240−7.
Karthaus M, et al. Impact of tumour RAS/BRAF status on efficacy of first-line panitumumab + FOLFIRI in patients with metastatic colorectal cancer. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P).
Abad A, et al. RAS analysis of the PLANET study: Phase II trial of panitumumab (Pmab) plus FOLFOX4 or FOLFIRI in subjects with wild-type (WT) KRAS colorectal cancer (CRC) and liver-limited disease (LLD). Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).
Price TJ, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014;15:569−79.
Van Cutsem E, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33:692−700.
Peeters M, et al. Updated analysis of KRAS/NRAS and BRAF mutations in study of panitumumab + FOLFIRI for 2nd-line treatment of metastatic colorectal cancer (mCRC). J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster).
1. Douillard J-Y, et al. N Engl J Med 2013;369:1023−34; 2. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7; 3. Karthaus M et al. Ann Oncol 2014;25(Suppl 4);iv188 (poster 549P); 4. Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P); 5. Price TJ, et al. Lancet Oncol 2014;15:569− Van Cutsem E, et al. J Clin Oncol 2015;33:692−700; 7. Peeters M, et al. J Clin Oncol 2014;32(Suppl 5):abstract 3568 (and poster).
†Phase 2 study; ‡LLD. This summarises some of the key data sets that supported European Commission approval for the label variation to include panitumumab + FOLFIRI in 1st-line WT RAS mCRC.

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