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PANITUMUMAB (VECTIBIX)
DR VIBHAY PAREEK
Introduction:
Classification: Monoclonal antibody; anti – EGFR antibody Category: biological response modifier agent Drug manufacturer: Amgen Trade name: Vectibix
EGFR Activation Enhances Pathways Important for Tumor Cell
Growth
AngiogenesisCell
Survival
MetastaticSpread
EGFR Activation
Tumor
BloodVessel
BloodVessel
Proliferation
EGF TGF
Ligand Binding
Phosphorylation and ActivationDimerization
HeterodimerHomodimer
ATPATP ATP
Highaffinitybinding
Ligand Binding and Dimerization Results in TK Activation
P13K
FKHR
Akt
mTOR
PTEN
MEK 1/2
MAPK
BADGSK-3
SOS
Grb-2
Shc
Grb-2
SOS Ras
Raf
JunFOS Myc
p27Cyclin D-1
LigandLigand
SignalAdaptersand Enzymes
SignalCascade
EGFr dimer
MAPK = mitogen-activatedprotein kinase
P13k = phosphatidylinositol3-kinase
TranscriptionFactors
EGFR Activation and Signaling Pathways
EGFR can be overexpressed in colorectal cancerTumor cell proliferation and growth can result from EGFR-mediated signalsIn 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 deathMonoclonal antibodies can inhibit the binding of ligands such as EGF, TGF-, and other ligands to EGFR
Epidermal Growth Factor Receptor (EGFR) in Colorectal Cancer
•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.
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
NORMAL
SMALL ADENOMA
APC bcatenin
aCANCER
PIK3CA PTEN P53
BAXSmad4 TGFbIIR
K-ras B-raf
LARGE ADENOMA
EGFR
METASTASES
PRL-3
Metalloproteinases activation
ANGIOGENESIS
Colorectal Tumorigenesis
RAS: a predictive biomarker for anti-EGFR-
targeted treatment in patients with mCRC
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
RASInactive
GDP
ActiveRAS
GTP
Specific mutations result in a constitutively active RAS protein
Mutant NRAS
RASInactive
GDP
ActiveRAS
GTP
Hyperproliferation
Mutant KRAS
Suppression ofapoptosis
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):175-184www.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, NSCLCPhase I-2 Trials: Colorectal cancer
Panitumumab (ABX-EGF) Fully human IgG2
Phase 2-3 Trials: Colorectal cancer, NSCLC, Others
Tyrosine kinase inhibitors
(gefitinib, erlotinib)
MonoclonalAntibodies
(trastuzumab,cetuximab, panitutumab)
Signal Transduction
R R
K K
Ligands
EGFR- targeting therapies
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.
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
PANITUMUMAB
Mouse antibody genes inactivated
Human antibody genes introduced
XenoMouseâ
mouseXenoMouse generates fully human antibodiesPanitumumab is a fully human IgG2 directed against EGFrHigh Affinity, Kd = 5 x 10-11 M
100% Mouse Protein
Mouse
~10% Mouse Protein
Humanized
~34% Mouse Protein
Chimeric Fully Human
100% Human Protein
cetuximabrituximab
bevacizumab panitumumab
The Development of Human Monoclonal Ab
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
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.
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.
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.
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
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.
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.
Limitation of Use:
Not indicated for treatment in RAS mutant mCRC RAS mutation status unknown
Summary of Key Clinical Studies in metastatic Colorectal Carcinoma (mCRC)
Trial Name
Phase
Line of treatmen
t
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 vsFOLFIRI + Bev PFS
STEPP5 II SecondIn 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 vsBSC PFS
ASPECCT7 III Third Pmab (Q2W) vs
Cmab (QW) OS
1.)
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
PRIME study RAS analysisConclusions 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
PRIME study RAS analysisConclusions 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
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)
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
ASPECCT studyConclusions
.
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
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
Thank You