EGFR Targets in Head and Neck Cancer

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EGFR Targets in Head and Neck Cancer
Francisco G. Pernas, M.D. Vicente A. Resto, M.D.,
Ph.D. The University of Texas Medical
Branch Department of Otolaryngology Grand Rounds
Presentation March 31, 2011
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EGFR Targets in Head and Neck Cancer

• Outline
• Introduction SCCA HN
• Molecular Therapeutics
• EGF Receptor
• EGFR vIII Mutant
• Updates in mAb Literature
• Updates in Tki Literature
• Conclusions

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Introduction SCCA HN
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SCC of the Head and Neck

• 5th most common cancer worldwide.
• In US alone 40,000 new cases annually.1
• 11,000 Deaths annually.1
• 200,000 Deaths worldwide annually.
• Majority of cases present in advanced stages.

Site New Diagnoses Deaths
oral cavity pharynx 30,990 7,430
larynx 9,510 3,740
nasal cavity, nasopharynx, paranasal sinuses, cervical esophagus, skin nasal cavity, nasopharynx, paranasal sinuses, cervical esophagus, skin nasal cavity, nasopharynx, paranasal sinuses, cervical esophagus, skin
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SCC of the Head and Neck

• 60 of patients develop local disease recurrence
  within two years. 4
• Current standard of care
• Surgery and radiation
• Platinum, 5-flourouracil or taxane based
  chemoradiation regimens.
• Improvements in surgery and chemoradiation offer
  better organ preservation but they have resulted
  in only modest improvement in the 5-year survival
  of HNSCC in the past three decades.

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SCC of the Head and Neck

• 5-year survival rates of patients with locally
  advanced or metastatic disease are 48 and 26,
  respectively.
• We need a better understanding of HNSCC at the
  cellular and molecular levels to guide
  development and use of new therapeutic
  interventions.

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Risk factors for HNSCC

• Lifestyle insults believed to cause 80 of HNSCC
• Other causes include
• HPV types 16 and 18 E6/E7 oncogenes
• EBV LMP1 oncogene (nasopharyngeal carcinomas)

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Molecular Therapeutics
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Molecular Therapeutics

• Only cetuximab (Erbitux) has been approved for tx
  of unresectable HNSCC.
• Several drugs are in Phase III investigation.
  (All are EGFR targets)
• Drugs in development
• EGFR mAb
• EGFR TKi EGFR/HER-2 dual TKi
• VEGF mAb
• COX-2 inhibitor
• Farnesyl transferase inhibitor
• Hypoxic cell sensitizer
• Proteasome inhibitor
• VEGF-2 TKi

Erolotinib, gefitinib, GW572016
SCH 66336
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Biologics - Nomenclature

• mab are monoclonal antibodies. i.e.
  Ceti(Humira)
• ximab are chimeric monoclonal antibodies. i.e.
  Cetuximab (Erbitux)
• mumab are humanized monoclonal antibodies.
  i.e. panitumumab, (Vectibix)
• tinib are tyrosine kinase inhibitors. i.e..
  Gefitinib (Iressa), Erlotinib (Tarceva)
• zomib are proteasome inhibitors. i.e.
  Bortezomib

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Biologics - Nomenclature

• Chimeric and humanized monoclonal antibodies
  are thought to be less likely to elicit
  neutralizing antibodies that can possibly reduce
  effectiveness.
• cept indicate fusion of a receptor to the Fc
  portion of human IgG1 (alefacept Amevive for
  psoriasis, and etanercept Enbrel for rheumatoid
  arthritis). 

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EGF Receptor
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EGFR

• A 170180 kD transmembrane glycoprotein tyrosine
  kinase receptor.
• Binds epidermal growth factor (EGF), transforming
  growth factor (TGF)-alpha, and other regulating
  proteins.
• Activation results in a complex cascade of
  signaling pathways that influence normal cellular
  proliferation and differentiation and lead to
  strong mitogenic activity.

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EGFR

• Ligand binding results in
• receptor dimerisation
• activation of the intrinsic kinase domain
• phosphorylation of tyrosine residues within the
  cytoplasmic tail.
• Proteins dock on phosphorylated residues, leading
  to the activation of signaling pathways that
  promote cell growth, proliferation,
  differentiation, and migration.

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ErbB subfamily of Tyrosine Kinase

• Enzyme that can transfer phosphate from ATP to a
  tyrosine residue at the C-terminus.
• An important mechanism in signal transduction.
• Tyrosine kinase inhibitors act by competing with
  ATP for binding to the kinase.
• Block transfer of phosphate.

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erbB Family Ligands

• Epidermal Growth Factor (EGF)
• Transforming Growth Factor-a (TGF-a)

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erbB Family of Receptors

• erbB receptor family consists of 4 closely
  related members
• erb B1 (EGFR, Her1)
• erb B2 (Her2/neu)
• erb B3 (Her3)
• erb B4 (Her4)

Gefitinib, Cetuximab, Erlotinib
Herceptin
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EGFR in HNSCC

• Over-expression of EGFR is observed in 42 to 80
  of studied HNSCCs.
• 7/8 trials showed a poorer outcome for patients
  with EGFR over-expression (756 patients).
• EGFR expression seems to be strongly correlated
  with worse prognosis in HNSCC in patients treated
  with either chemotherapy /or XRT.
• Suggesting over-expression may be associated with
  chemo/XRT resistance in these patients.

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EGFR Structure
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Simplified signaling cascade downstream of EGFR
EGFR
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Reasons to block EGFR

• Activation of receptor plays a critical role in
  the activation of cascades that been implicated
  in
• Cell proliferation
• Metastasis
• Resistance to radiotherapy
• Angiogenesis
• Inhibition of apoptosis.
• Over-expressed or constitutively activated in
  80-100 of SCCHN tumors.
• Over-expression is correlated to resistance to tx
  and poorer outcomes.

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Ways to Block EGFR
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Anti-EGFR Therapeutic Agents
Tyrosine Kinase Inibitors (TKIs) Monoclonal Antibodies (mAb)
Agents gefitinib (Iressa) erlotinib (Tarceva) lapatinib cetuximab (Erbitux) panitumumab
Mechanism bind selectively to intracellular tyrosine kinase domain of EGFR bind specifically to extracellular ligand-binding domain of EGFR
Administration oral daily intravenous every 1-3 weeks
Adverse Effects rash diarrhea nausea rash hypersensitivity reactions
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Updates in Cetuximab Literature
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• International Phase III trial
• Stage III or IV SCCA, nonmetastatic Ca of
  oropharynx, hypopharynx, or larynx
• 424 Pts. (73 centers in US, 14 Intl)
• 213 ? XRT only
• 211 ? XRT cetuximab

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• Conclusions
• Cetuximab XRT is better than XRT alone in
  increasing locoregional disease control and
  survival
• Downfalls
• Does not compare to standard chemotherapy (5-FU
  and Cisplatin).

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• Retrospective chart review
• Comparing cetuximab XRT with double modality
  chemo (ie, cisplatin 5-FU) XRT
• SCCA of oral cavity, oropharynx, or larynx
• Stage III to IVB
• Unclear how selection of cetuximab vs chemo
  was done.

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• There did not appear to be differences in LRC,
  DMFS, DSS, or OS.

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• 2 yrs, 221 pts retrospective chart review
• SCCA oropharynx, larynx, or hypopharynx
• Compared concurrent cisplatin XRT to cetuximab
  XRT.
• Patients were selected to receive cetuximab
  rather than cisplatin secondary to
• auditory concerns, 30.6
• renal,4.1
• cardiac, 2.0
• performance status, 16.3

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Failure-free survival among patients with cancer
of (A) oropharynx, hypopharynx, or larynx (B)
oropharynx and (C) hypopharynx/ larynx treated
with cisplatin
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Over-all survival among patients with cancer of
(A) oropharynx, hypopharynx, or larynx (B)
oropharynx and (C) hypopharynx/ larynx treated
with cisplatin
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• Conclusions
• Concurrent cisplatin achieved better control
  rates, failure free survival and overall survival
  than cetuximab
• Downfalls
• Retrospective
• Non-blinded
• potential for pts selected to get cetuximab to
  be sicker.

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Cetuximab vs Doublet Chemo

• Holy Grail?
• Double blind studies comparing cetuximab versus
  Cisplatin/5FU or Cisplatin/Taxol.
• Most researchers instead focusing on adding
  cetuximab to existing protocols.

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• Prospective, blinded, 2 arms
• Pts w confirmed recurrent or metastatic
  squamous-cell carcinoma of HN

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• Treatment
• Arm 1
• Carboplatin or cisplatin 5-Fu
• Arm 2
• Carboplatin or cisplatin 5-Fu cetuximab

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• Conclusions
• Cetuximab does not seem to worsen XRT-related
  mucositis, but there is risk of acneiform rash
• Addition of cetuximab improved overall survival
  when given as first-line treatment in patients
  with recurrent or metastatic SCCA

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• Phase II
• Enrolled 36 patients, Stage III-IVb, previously
  untreated

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• Findings
• HPV expression resulted in better progression
  free survival and overall survival.
• EGFR expression was observed in 37 of 39
  available biopsies and did not impact response to
  therapy or clinical outcome.
• 3-year progression-free survival ? 87
• 3-year overall survival ? 91
• Complete response in 70 of patients.

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• Conclusions
• Demonstrated that addition of cetuximab to
  induction chemo followed by maintenance cetuximab
  produced acceptable rates of cumulative cisplatin
  toxicities.
• Three-year PFS and OS survival were very
  promising in a population with more than 90
  stage IV disease.

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• Panitumumab FDA approved for Colon Ca
• fully human IgG2 mAb targeting EGFR
• Less immunogenic than chimeric mAb
• Longer half-life and higher affinity for EGFR
  than other mAbs

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• Treatment algorithm
• Panitumumab was administered weekly
• Paclitaxel was given weekly i.v. over 60 min
  after panitumumab
• Carboplatin was given i.v. over 3045 min
  following paclitaxel
• Patients were treated using a dose-painting IMRT
  approach with a single plan to deliver 35
  fractions once daily over 7 weeks

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• Conclusions
• Generally well tolerated with comparable and
  acceptable rates of mucositis.
• At median follow-up of 21 months, 18 of 19
  patients (95) remained disease free

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Areas of Future Research
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• EGFRvIII
• Extensively studied in gliomas where it is
  related to increased tumorigenicity.
• Not observed in normal tissue, unique to cancer.
• Truncated version of wildtype EGFR, that is
  constitutively phosphorylated in a
  ligand-independent manner.
• Difficult to study in-vitro, must transfect cells.

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EGFRvIIIA.k.a. de2-7 EGFR or ?EGFR

• Variant III EGFR (100-140kDa) oncoprotein.
• Has an in-frame deletion of extracellular domain.
  

• Preferentially activates cascade by PI3K.

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• EGFRvIII
• Present in 42 of patients with HNSCC

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• EGFRvIII
• Less in vitro cellular death when treated with
  cetuximab
• Larger tumor volumes and decrease response in
  mouse model

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Conclusions EGFRvIII cells were less sensitive
to cisplatin and cetuximab. This leads to
enhanced growth and resistance to targeting.
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Interestingly EGFRvIII Cells were equally
susceptible to EGFR TKI treatment. This is
consistent with the fact that both EGFRvIII and
EGFRwt contain an intact tyrosine kinase domain.
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Is HPV a Factor?
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• Conclusions
• HPV positive OP cancer higher overall survival,
  disease-free progression and lower local-regional
  relapse
• Implications in EGFR directed therapy?

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HPV EGFR Over-expression

• In general, there is a greater benefit from
  cetuximab for patients with oropharyngeal cancer
  compared with other subsites.
• RTOG 0920 will help determine if HPV status has
  clinical implications in regards to response to
  cetuximab.

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Importance of Rash

• Acneiform rash induced by cetuximab was initially
  thought to be reason to stop therapy.

• Seems the more severe the rash the better
  response to cetuximab.
• Biomarker of response?

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Importance of Rash

• Rash may be due to EGFR-R521K genotype or other
  EGFR variation.
• Specifically EGFR-R521K demonstrates increased
  cetuximab binding.
• Pts with EGFR-R521K developed more severe rash.
• Patients with the G/G genotype of EGFR-R521K who
  significantly developed skin rash showed a trend
  to prolonged progression-free survival on
  cetuximab/docetaxel treatment.

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Updates in TKi Literature
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Tumor Microenvironment

• Response of tumors to radiation depends on
• Cell-extracellular matrix interactions
• Tumor oxygenation
• Manipulating this microenvironment has proven
  challenging.
• Anti-angiogenic therapy has been used to
  normalize tumor microenvironment (VEGF)

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Tumor Microenvironment

• Pharmacologic inhibition of EGFR can decrease
  VEGF expression and therefore modify
  angiogenesis.
• Theory
• Erlotinib would indirectly lead to vascular
  normalization and decrease tumor hypoxia.
• Thereby leading to greater effects of chemo and
  radiotherapy.

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• In mice, Erlotinib
• Increased blood flow
• Decreased hypoxia

• Oxygenation benefits
• Better drug delivery
• Free radical formation

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Chemo-sensitized Radio-sensitized
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• Conclusions
• Erlotinib
• Modulated tumor vascularity
• Modulated tumor oxygenation
• Resulted in improved response to cisplatin and
  radiation.
• Similar effects have been shown with cetuximab.

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• Tyrosine Kinase Inhibitors
• What makes Tki clinically interesting
• Orally administered
• Small molecule size
• Intra-cellular target
• Chemo-sensitizer
• Radio-sensitizer
• While gefitinib has had poor clinical responses,
  other TKis have shown promise.
• Only demonstrated in vitro.

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Cetuximab induced EGFR translocation to nucleus.
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Radiation induced EGFR translocation to nucleus.
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Dasatinib blocked XRT and cetuximab induced EGFR
translocation to nucleus and phosphorylation of
EGFR.
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• Conclusions
• Nuclear translocation of EGFR has been shown to
  correlate with resistance to both cetuximab and
  radiation.
• Cetuximab can result in paradoxical
  phosphorylation/activation of EGFR.
• Suggests that Dasatinib can limit EGFR
  translocation to the nucleus and may enhance
  radiotherapy plus cetuximab.

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• Phase I/II trial.
• 31 patients (Stage III IV).
• Received erlotinib daily throughout XRT and 8
  days prior to XRT with 70Gy.
• Cisplatin at days 8, 29, and 50.

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• Complete response seen in 74.2 of patients.
• Progression free survival ? 61 (3yrs)
• Overall survival ? 72 (3yrs)

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Patients who developed acneiform rash tended to
have better overall survival.
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Future

• Work started by Bonner et. al. by adding
  cetuximab to XRT needs to be supplemented in view
  of
• Doublet chemotherapy advancement in HN
• Further studies combining EGFR targeted therapies
  with cisplatin/5FU
• Demonstrate chemo and radio sensitizing
  properties of EGFR blockade in patients
• Take advantage of sensitizing properties of EGFR
  biologics

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Conclusions

• EGFR is highly over expressed in HN Scca
• Mutant forms exist, which are constitutively
  activated, resulting in decreased activity of
  EGFR blocking.
• Early Phase II trial data suggests addition of
  cetuximab or erlotinib improves disease free
  progression and survival.
• HPV status may help target therapy.
• Acneiform rash is a marker of positive response
  to both monoclonal antibodies and TKi.

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Conclusions

• Targeting EGFRvIII specifically with Tki.
• Further work is needed to determine which tumors
  are responders to EGFR targets.
• Further work is needed to develop new protocols
  that limit toxicities of combining chemo and EGFR
  biologics.