Best Practices in Nursing Management of EGFR Inhibitor Rash

Best Practices in Nursing Management of EGFR Inhibitor RashBeth Eaby-Sandy, MSN, CRNP, OCNNurse PractitionerAbramson Cancer CenterUniversity of Pennsylvania Health System

Disclosures of Conflicts of InterestMs. Eaby-Sandy, MSN, CRNP, OCN, discloses the following commercial relationships: Amgen (speakers bureau)Celgene (speakers bureau)Eisai (speakers bureau)Merck (speakers bureau)Clovis (consultant)Astra Zeneca (consultant)

Learning ObjectivesDistinguish current clinical applications for EGFR inhibitor therapyDescribe appropriate grading of EGFR inhibitor rashApply evidence-based treatment strategies for EGFR inhibitor rash

EGFR Inhibitor OverviewNot a chemotherapy, but rather a targeted therapy for cancerCan be a tyrosine kinase inhibitor (TKI) or monoclonal antibody (MAB)Administered as a single agent or in combination with chemotherapyApproved for multiple tumor types

HER1erbB-1EGFR HER2/neu erbB-2HER3 erbB-3HER4erbB-4Tyrosine kinase domain (TKD)Ligand-bindingdomainTransmembrane

HER = human epidermal growth factor receptor.Franklin et al, 2002; Roskoski, 2004; Rowinsky, 2004.HER Family of ReceptorsNo intrinsic kinase activity

EGFR is also known as HER1 or erbB-1, and is a member of a family of membrane receptor tyrosine kinases known as the HER family, which also includes HER2, HER3, and HER4, as shown in this slide.

These receptors have different ligand-binding affinities:

EGF and transforming growth factor alpha (TGF-) are the two most important ligands of HER1The neuregulins (NRGs) are important ligands for HER3 and HER4In normal cells, HER2 is intrinsically devoid of any ligand-binding activity. It is an important signaling partner of HER1 and HER3, and functions as a co-receptor

Ligand binding leads to receptor interaction, and the resulting stearic change activates the intrinsic kinase activity of these HER family receptor tyrosine kinases.

The activated kinase phosphorylates itself and its partner on conserved tyrosine residues and initiates a signal transduction cascade that eventually activates key regulators like mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K).

All HER family proteins, with the exception of HER3, have intrinsic kinase activity.

Since 1984, it has been recognized that HER1 can be overexpressed in lung cancer. HER2 appears to be less frequently expressed in non-squamous cell lung cancer (NSCLC), proving that expression levels of HER1 and HER2 are independent. Considerably less information is available on the expression of HER3 and HER4 in lung cancer. Patterns of coexpression of HER3 and HER4 are not well defined.Franklin et al., 2002; Roskoski, 2004; Rowinsky, 2004KEY POINT: EGFR/HER1 is a member of the HER family of receptors.

EGFR Ligand BindingMAPK = mitogen-activated protein kinase.Roskoski, 2004; Rowinsky, 2004.

Signaling cascadesEGFR (receptor)

PI3KMAPK

NucleusGene activationCell cycle progressionMG1SG2MycFosJun

PP

Survival

ProliferationAngiogenesis

Invasion

ApoptosisMetastasis

Ligand

Cell surface receptors bind ligands that activate the receptor and regulate cell functions. EGFR can bind EGF as well as several other ligands (eg, TGF-). The binding of ligand results in two receptors joining together in a process known as dimerization.

Upon dimerization, the intracellular TKDs of the receptor may transphosphorylate the dimer partner, initiating a signaling cascade. Subsequent transduction of the signal to the nucleus leads to regulation of genetic functions, such as gene activation/suppression and cell cycle regulation.

In malignancies such as NSCLC, overexpression or dysregulation of EGFR may increase the signaling response and result in:Cell cycle progression leading to cellular proliferationDecreased apoptotic response leading to increased cellular survival even in the presence of abnormal cell functions resulting from toxic stimuli such as radiation or chemical damageProduction of cell factors that promote angiogenesis and further cellular proliferationIncreased invasiveness and metastasis

Franklin et al., 2002; Roskoski, 2004; Rowinsky, 2004KEY POINT: Dysregulation of the EGFR-driven cellular pathways can result in outcomes that impact tumorigenesis, including increased invasiveness and metastasis, proliferation, angiogenesis, and decreased cell death.

EGFR InhibitionRoskoski, 2004; Rowinsky, 2004.

Signaling cascadesEGFR inhibitor (TKI) blocks downstream signal

PI3KMAPK

NucleusGene activationCell cycle progressionMG1SG2MycFosJun

PP

Survival

ProliferationAngiogenesis

Invasion

ApoptosisMetastasis

EGFR inhibitor (MAB) blocks ligand bindingXXXXXXXX

KEY POINT: Dysregulation of the EGFR-driven cellular pathways can result in outcomes that impact tumorigenesis, including increased invasiveness and metastasis, proliferation, angiogenesis, and decreased cell death.

Approved EGFR InhibitorsAgentMethod of AdministrationTumor Type(s)DoseCetuximabIVColon cancer,Squamous cell cancer of the head and neck400 mg/m2 loading, then 250 mg/m2 weeklyErlotinibPOLung cancer150 mg dailyPancreatic cancer100 mg dailyPanitumumabIVColon cancer6 mg/kg every 14 daysGefitinibPOLung cancer 250 mg dailyAfatinibPOLung cancer EGFR mutation(+)40 mg daily

Erbitux prescribing information, 2015; Tarceva prescribing information, 2015; Iressa prescribing information, 2015; Vectibix prescribing information, 2015; Yang, Shih et al, 2012.

EGFR Inhibitor RashMost common toxicity associated with EGFR inhibitorsTends to appear on the face and chest but can be seen on any part of the bodyCan range from mild to severeOften described as a papulopustular eruption

Why Does EGFR Inhibitor Rash Occur?The epidermis relies on EGFThe keratinocytes located in the basal layers of the epidermis express elevated level of EGFInhibition of EGF will result in negative effects on cell growth in this layer of the epidermisThis results in thinning, which decreases ability of skin to hold in moistureThe damage also causes recruitment of the immune system response and thus, a pustular eruption

Adapted from Lacouture, 2006.

Incidence and Severity of RashAgentAll Rash IncidenceGrade 3/4 IncidenceCetuximab89%(70% in FLEX trial)12%(10% in FLEX trial)Erlotinib75% 9%Panitumumab89%12%GefitinibRash 43%Acne 25%0% (only reported 5%) 0%Afatinib89%16%

Pirker et al, 2009; Gatzemeier et al, 2008.

Is there a correlation between skin rash and clinical benefit from EGFR inhibitors?

Skin Toxicity and Benefit in NSCLCErlotinib phase II trial: 57 patients

0510152025300.250.500.751.00No RashGr 1 Rash(P