6. EGFR can be overexpressed in colorectal cancer
Tumor cell proliferation and growth can result from EGFR-mediated signals
In vitro and in vivo data suggest that preventing the binding of natural ligands
to EGFR may result in inhibition of tumor cell growth and lead to cancer cell
death
Monoclonal antibodies can inhibit the binding of ligands such as EGF, TGF-,
and other ligands to EGFR
Epidermal Growth Factor Receptor (EGFR)
in Colorectal Cancer
7. •NSCLC •40-80
•SCCHN •95
•Colorectal •25-77
•Glioblastoma •40-60
•Breast •14-91
•Prostate •41-100
•Ovarian •35-70
•Esophageal •35-88
•Pancreatic •30-50
EGFR Expression (%)Tumor Type
EGFR Expression Correlates With Poor
Prognosis in Selected Solid Tumors
*Responses observed in various solid tumors for gefitinib, erlotinib, and cetuximab.
8. Colorectal cancer 75-82%
Head and neck
cancer
90-100%
NSCLC 40-80%
Breast Cancer 14-91%
Ovarian Cancer 35-70%
Renal cell Cancer 50-90%
Lung
(NSCLC)
Colorectal
Head & Neck
(SCC)
EGFR expression in solid tumor
10. RAS: a predictive biomarker for
anti-EGFR-
targeted treatment in patients with
mCRC
11. What is RAS?
• RAS is a group of genes (including KRAS, NRAS and HRAS) that encode small, GTP-binding
proteins called RAS (KRAS, NRAS and HRAS), that are involved in signal transduction1
• A variety of stimuli activate RAS which in turn stimulate other intracellular proteins1
• RAS proteins are a part of the epidermal growth factor receptor (EGFR) signaling pathway
also2
• In tumours, activation of RAS by EGFR contributes to EGFR-mediated increased proliferation,
survival and the production of pro-angiogenic factors2
11
13. Anti-EGFr Monoclonal Antibodies
Mendelsohn J. J Clin Oncol. 2002;20(suppl 18):1s-13s. Tewes M, et al. Proc Am Soc Clin Oncol. 2002. Abstract 378.
Sridhar SS, et al. Lancet Oncol. 2003;4:397-406. Vanhoefer U, et al. J Clin Onc 2004;22(1):175-184
www.clinicaltrials.gov
Monoclonal Antibody Description Status
Cetuximab
(C-225)
Chimeric IgG1
Approved: Colorectal cancer
Submitted: Head and Neck (H&N)
cancer
Phase 2: NSCLC, Others
Matuzumab
(EMD 72000)
Humanized IgG1
Phase 2 Trials: Recurrent ovarian
cancer, NSCLC
Phase I-2 Trials: Colorectal cancer
Panitumumab
(ABX-EGF)
Fully human IgG2
Phase 2-3 Trials: Colorectal
cancer, NSCLC, Others
14. Tyrosine kinase inhibitors
(gefitinib, erlotinib)
Monoclonal
Antibodies
(trastuzumab,cetuximab,
panitutumab)
Signal Transduction
R R
K K
Ligands
EGFR- targeting therapies
15. Mechanism of action:
• Fully human IgG2 monoclonal antibody directed against the EGFR.
• Precise mechanism(s) of action remains unknown.
• Binds with nearly 40-fold higher affinity to EGFR than normal ligands EGF and TGF-a, which results in
inhibition of EGFR.
`Prevents both homodimerization and heterodimerization of the EGFR, which leads to inhibition of
autophosphorylation and inhibition of EGFR signaling.
• Inhibition of the EGFR signaling pathway results in inhibition of critical mitogenic and antiapoptotic signals
involved in proliferation, growth, invasion/metastasis, and angiogenesis.
• Inhibition of the EGFR pathway enhances the response to chemotherapy and/or radiation therapy.
16. Panitumumab Inhibits Ligand Binding
to EGFR and Dimerization
Panitumumab
Inhibition of EGF
binding to EGFR
This may lead to:
Cell proliferation
Cell survival
Angiogenesis
Metastatic spread
EGF, TGFα or other
ligands binding to EGFR
• A fully human* lgG2 monoclonal
antibody to EGFR
• High affinity, KD = 5 x 10-11 M
• Inhibits ligand-induced EGFR
tyrosine phosphorylation
17. PANITUMUMAB
Mouse antibody
genes inactivated
Human antibody
genes introduced
XenoMouse
mouse
XenoMouse generates fully human antibodies
Panitumumab is a fully human IgG2 directed against EGFr
High Affinity, Kd = 5 x 10-11 M
19. Panitumumab administered as a single agent or in combination with
chemotherapy exhibits nonlinear pharmacokinetics
Steady-state is obtained after 3 doses at 6 mg/kg given once every 2 weeks
without the need of a loading dose
The mean half-life value during the dosing interval is 7.5 days (range: 3.6 -
10.9 days) for the 6 mg/kg dose
.
Panitumumab pharmacokinetics
20. Distribution: Not well characterized
Metabolism: not extensively characterized; clearance of antibody was saturated at a weekly dose of 2
mg/kg; half life is on the order of 6-7 days.
21. Indications:
FDA-approved as monotherapy for the treatment of advanced colorectal cancer following
fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens. Use of panitumumab is not
recommended in mutant KRAS mCRC.
Approved in Europe as monotherapy for advanced, refractory disease in wild-type KRAS CRC.
FDA-approved for the first-line treatment of wild-type KRAS (exon 2 in codons 12 or 13) mCRC in
combination with FOLFOX chemotherapy.
22. Dosage range:
Recommended dose for the treatment of mCRC is 6 mg/kg IV on an every 2-week schedule.
An alternative schedule is 2.5 mg/kg IV every week.
23. Toxicities:
Dermatological Toxicities – Dermatitis, pruritis, erythema, rash, skin exfoliation, paronychia, dry
skin, skin fissures
Severe complication: Necrotizing Fascitis, abscesses and sepsis, SJS and TEN
Infusion related symptoms – fever, chills, urticarial, flushing, headache (with first infusion)
Pulmonary Toxicity – ILD (<1%)
Hypomagnesemia
Diarrhea, Asthenia, Generalised Malaise, Paronychial inflammation
24. Special consideration:
1. The incidence of infusion reactions is lower when compared with cetuximab, as panitumumab
is a fully human antibody. Reduce infusion rate by 50% in patients who experience grade 1/2
infusion reaction for the duration of that infusion. The infusion should be terminated in patients
who experience a severe infusion reaction.
2. The level of EGFR expression does not correlate with clinical activity, and as such, EGFR testing
should not be required for clinical use.
3. Extended RAS testing should be performed in all patients to determine KRAS and NRAS status.
Only patients whose tumors express wild-type KRAS and NRAS should receive panitumumab
therapy.
4. Development of skin toxicity appears to be a surrogate marker for panitumumab clinical
activity.
25. 5. Use with caution in patients with underlying ILD as these patients are at increased risk for developing
worsening of their ILD.
6. In patients who develop a skin rash, topical antibiotics such as clindamycin gel or erythromycin
cream/gel either oral clindamycin, oral doxycycline, or oral minocycline may help. Patients should be
warned to avoid sunlight exposure.
7. Electrolyte status (magnesium and calcium) should be closely monitored during therapy and for up to 8
weeks after completion of therapy.
8. Pregnancy category C. Breastfeeding should be avoided.
26. Limitation of Use:
Not indicated for treatment in RAS mutant mCRC
RAS mutation status unknown
27. Summary of Key Clinical Studies in metastatic Colorectal Carcinoma
(mCRC)
Trial Name Phase Line of
treatment
Treatment Primary Endpoint
PRIME1
III First
FOLFOX4 + Pmab vs
FOLFOX4
PFS
PEAK2
II First
mFOLFOX6 + Pmab vs
mFOLFOX6 + Bev
PFS
181 Trial3 III Second
FOLFIRI + Pmab vs
FOLFIRI
PFS & OS (co-primary end points)
SPIRITT4 II Second
FOLFIRI + Pmab vs
FOLFIRI + Bev
PFS
STEPP5 II Second
In patients receiving Pmab+FOLFIRI or Ir,
Preemptive vs Reactive skin treatment
Grade 2 skin toxicities during the
6-wk skin treatment period
408 trial6 III Third
Pmab + BSC vs
BSC
PFS
ASPECCT7 III
Third Pmab (Q2W) vs
Cmab (QW)
OS
1.)
28. PRIME study: Panitumumab + FOLFOX4 vs FOLFOX4
Randomised phase 3 study of panitumumab with FOLFOX4 vs. FOLFOX4 alone as
1st-line treatment in mCRC patients
(Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic
Colorectal Cancer to Determine Efficacy)
Douillard JY, et al. J Clin Oncol 2010; 28:4697-705
29. PRIME study RAS analysis
Conclusions I
RAS ascertainment rate was 90%
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, 0.62–0.99; P = 0.043)
PFS HR = 0.72 (95% CI, 0.58–0.90; 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, 1.02–1.55; P = 0.03)
PFS HR = 1.31 (95% CI, 1.07–1.60; P = 0.008)
The benefit-risk profile of panitumumab + FOLFOX4 was improved by excluding patients
with MT RAS mCRC tumours
30. PRIME study RAS analysis
Conclusions II
Douillard JY, et al. Ann Oncol 2013; 24 (suppl 4):abstract PD-0024 (and poster).
In patients with WT RAS mCRC, a higher rate of tumour shrinkage at week 8 was observed for
panitumumab + FOLFOX4 vs. FOLFOX4
Improved PFS and OS outcomes in patients achieving ≥30% tumour shrinkage by week 8 of treatment
For patients with liver limited disease, significantly higher rate of ≥30% tumour shrinkage at W8 for
panitumumab + FOLFOX4 vs. FOLFOX4 (79% vs. 51%; P = 0.015) and numerically higher rates of OR,
metastasectomy, complete resection and 3-year OS with panitumumab + FOLFOX4 vs. FOLFOX4
Panitumumab + FOLFOX4 provides a useful 1st-line treatment as it offers the possibility of rapid tumour
shrinkage
31. PEAK study: mFOLFOX6 + panitumumab vs
mFOLFOX6 + bevacizumab
Randomised open-label phase 2 study with mFOLFOX6 + panitumumab or
bevacizumab in 1st-line treatment of WT KRAS exon 2 mCRC
(Panitumumab Efficacy in Combination With mFOLFOX6 Against Bevacizumab
Plus mFOLOFOX6 in mCRCSubjects With Wild-Type KRAS Tumors)
32. PEAK study RAS analysis
Conclusions
In this updated analysis of the 1st-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, 0.46–0.95; P = 0.03) for OS in favour of pmab
OS HR = 0.63 (95% CI, 0.39–1.02; 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
33.
34. ASPECCT study
Conclusions
.
First phase 3 study evaluating the efficacy and safety of panitumumab vs. cetuximab in 3rd-line WT KRAS
exon 2 mCRC
ASPECCT met its primary endpoint of non-inferiority for OS
Panitumumab retained 106% (95% CI, 82–129) of the OS benefit of cetuximab over BSC in patients with
WT KRAS exon 2 mCRC
Observed safety profiles between the two treatment arms were consistent with previously reported
studies for both agents
No new toxicities or safety signals were identified for panitumumab
35. Summary:
Panitumumab is the first and only fully human antibody with established efficacy, safety and
tolerability across all treatment lines in mCRC
Panitumumab is the only anti-EGFR antibody with positive phase 3 trials results based on
prospective KRAS data