Targeted treatment of Lung Cancer

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Targeted treatment of Lung Cancer

• Dr Nick Pavlakis
• Department of Medical Oncology
• Royal North Shore Hospital

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What is targeted therapy?

• Tailored treatment based on efficacy defined by a
  target group or tumour feature.
• Defining the target group
• Clinical Phenotype/target
• Asian, Adeno CA, nonsmokers, female anti-EGFR
• Molecular phenotype/target
• Exon 19/20 mutation predictive for anti-EGFR TKI
  therapy
• Kras mutation predictive for no benefit from
  anti-EGFR
• Histologic target
• Adeno CA greater response to pemetrexed
  (Alimta)
• Non-adenoCA other chemo
• Pharmacogenomic targeted selection - based on
  presence of genes predicting for specific chemo
  benefit or lack of benefit or greater toxicity
• Pathologic process as a target
• Angiogenesis or angiogenic growth factors eg VEGF

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NSCLC Treatment Guidelines are currently EMPIRIC

• SI/II Surgery /- ? Adjuvant chemotherapy
• Operable SIIIA Neo-adjuvant chemotherapy
  surgery OR surgery adjuvant chemo
• Inoperable SIIIA IIIB without effusion
  Combined chemo (platinum based) radiotherapy
• SIIIB (effusion)/IV (gt60)
• First-line 2 drug chemotherapy (PSlt2) /-
  palliative radiotherapy
• Second-line docetaxel or pemetrexed (Alimta)
• 3rd Line erlotinib (Tarceva )
• Other gefitinib (IRESSA) (only if EGFR gene
  mutation )

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Can we use molecular methods to select patients
most likely to benefit from chemotherapy or other
treatments?
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Pharmacogenomics

• Human Genetics
• SNPs
• Haplotypes
• Sequencing
• Expression Profiling
• Specific transcript levels
• Total RNA profiling
• Proteomics
• Specific biochemical markers
• Protein profiling

• Phenotype
• Drug response
• Disease

Prediction
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Reported Predictive Molecular Markers in Tumor
for Response to Chemotherapy in NSCLC
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Advances in first line chemotherapy in
advanced/metastatic NSCLC?Targeted chemotherapy
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Pemetrexed (Alimta) multi-targeted anti-folate
Increased in Lung cancer and SCC
Pemetrexed
TS
5-FU, Raltitrexed
dUMP
dTMP
DNA
5,10-CH2-THF
10-CHO-THF
DHF
NADPH
GARFT
DHFR
PRPP
Methotrexate
THF
NADP
GAR
fGAR
AMP, GMP
DNA, RNA
TS thymidylate synthase DHFR dihydrofolate
reductase GARFT glycinamide ribonucleotide
formyltransferase
Hanauske et al. The Oncologist 6363-373, 2001
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JMDB 1st Line PIII Trial Cis/pemetrexed
Cis/gem v Overall BUT increased survival in
Patients with Adenocarcinoma or Large Cell Ca.
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Subgroup Analyses Forest Plot
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Implications for practice

• Pemetrexed/platinum may be best empiric
  chemotherapy for adenocarcinoma
• For SCC ? Other platinum (P) or non-platinum
  combo eg P/vin or P/taxane
• Currently pemetrexed on PBS as 2nd line therapy
  in NSCLC

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Incorporating advances in understanding of
tumour biology Where targeted therapy refers to
drugs specifically targeting important biologic
pathways
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Angiogenesis is involved throughout tumour
formation, growth and metastasis
Premalignant stage
Malignant tumour
Tumourgrowth
Vascularinvasion
Dormantmicrometastasis
Overtmetastasis
(Avascular tumour)
(Angiogenicswitch)
(Vascularisedtumour)
(Tumour cellintravasation)
(Seeding indistant organs)
(Secondary angiogenesis)
Stages at which angiogenesis plays a role in
tumour progression
Adapted from Poon RT-P, et al. J Clin Oncol
200119120725
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VEGF is a key mediator of angiogenesis but its
over - expression is affected by multiple
factors, themselves potential Targets
Hypoxia
PDGF
IGF-1
EGF
IL-8
Binding and activation of VEGF receptor
VEGF release
bFGF
COX-2 Nitric oxide Oncogenes
P
P
Increased expression (MMP, tPA, uPA, uPAr, eNOS,
etc.)
P
P
Proliferation
Survival
Migration
Permeability
ANGIOGENESIS
IGF insulin-like growth factor PDGF
platelet-derived growth factor
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Agents Targeting the VEGF Pathway
Anti-VEGF antibodies (bevacizumab - Avastin )
Soluble decoy VEGF receptors (VEGF-TRAP)
VEGF
VEGFR-1
VEGFR-2
Small-molecule receptor tyrosine kinase(VEGFR)
inhibitors- TKIs (PTK787, SU11248,
ZD6474) AMG706, BAY 43-9006.....
Endothelial cell
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Anti-VEGF therapy in NSCLC

• 2 large RCTS
• Standard chemo /- Avastin (Bevazicumab)
• Exclusions
• SCC, central and/or cavitating lesions, CNS
  metastases
• Recent arterio-venous thrombotic events eg CVA,
  AMI

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Bevacizumab in Advanced NSCLC
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E4599 haematological toxicity
NS not significant
Sandler A, et al. N Engl J Med 2006
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E4599 non-haematological toxicity
Sandler A, et al. N Engl J Med 2006
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E4599 bleeding events
GI gastrointestinal
Sandler A, et al. N Engl J Med 2006
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Conclusions re anti-VEGF therapy with bevacizumab

• Two positive RCTs for RR, PFS, OS (data pending
  for Avail study)
• Benefit at expense of some increased toxicity
  bleeding events.
• Patient selection VERY important and benefit
  restricted to non-SCC
• Implications for nursing practice
• Monitor BP, U/A, patient history of bleeding
  events

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Small molecule inhibitors of EGFR tyrosine kinase
(EGFR-TKIs)

• Intracellular inhibition of tyrosine
  autophosphorylation and downstream intracellular
  signaling
• Compete with ATP for binding with the
  intracellular catalytic domain of TK
• Modeling used to design potent and selective
  EGFR-TKIs
• Examples
• ZD1839 (Gefitinib Iressa)
• OSI-774 (Erlotinib Tarceva )

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Overview of oral TKI EGFRI

• Four 1st line randomized trials
• Chemotherapy /- gefitinib (IRESSA) v placebo
• Chemotherapy /- erlotinib (TARCEVA) v placebo
• The addition of an oral TKI to standard
  chemotherapy DOES NOT improve survival.
• Three 2nd/3rd line randomized trials
• Gefitinib v placebo (ISEL) erlotinib v placebo
  (BR21) Gefitinib v docetaxel
• Key studies
• Erlotinib v placebo, N 731, NEJM 05
• Improved OS (HR 0.71) and symptoms/quality of
  life. Presence of rash MAY predict for efficacy
• Gefitinib v docetaxel Equivalent and less toxic

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Key observations with anti-EGFR TKIs

• Greatest benefit in
• Never smokers
• AdenoCA
• Asians
• Women
• BUT efficacy observed with erlotinib in male,
  smokers with SCC
• EGFR gene mutation (exons19,21) predicts for high
  response rate (gefitinib, erlotinib) high gene
  copy number for survival
• K-ras mutation () a negative predictor (ie no
  benefit erlotinib PIII)
• Survival correlates with rash
• Cigarette smoking may reduce efficacy ?through
  liver enzyme induction

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EGFR IHC 85 One cell sufficient
Primary endpoint OS
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Oral EGFRI toxicity skin rash (NOT Acne),
diarrhoea erlotinib (tarceva)gt gefitinib
(Iressa)
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Managing anti-EGFR toxicity

• No formal guidelines but numerous practice based
  guidelines eg.http//www.communityoncology.n
  et/journal/articles/0504202.pdf
• Lynch et al Oncologist, May 1, 2007
  12(5) 610 - 621.
• If severe Dose-interruption ie stop, restart
  when better, ? Reduce dose
• Eg. Practical Tips
• DIARRHOEA loperamide or lomotil, adequate
  hydration
• RASH
• Makeup to cover rash without making it worse.
• Avoid sun exposure.
• Use sunscreen lotions, wear loose-fitting cotton
  clothing and hats to protect the scalp.
• Take baths instead of showers. Aveeno oatmeal
  bath products are sometimes soothing to the skin.
• Within 5 minutes of bathing, apply mild emollient
  moisturizer. Eg Neutrogena Norwegian Formula Hand
  Cream, Vaseline Intensive Care Advanced Healing
  Lotion, and Aquaphor Healing Ointment made by
  Eucerin are helpful.
• Use mild soap such as Cetaphil
• Avoid over-the-counter acne treatments.
• Tetracycline/doxycycline in severe cases

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Other targeted drugs in development

• Small molecule multi-targeted tyrosine kinase
  inhibitors
• Eg anti-VEGF, PDGF, EGFR, raf..
• Sunitinib
• Sorafenib
• Zactima
• AMG706
• New pathway targets
• Insulin like growth factor (IL-GF) Mabs in
  trial
• Src pathway inhibitors

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Targeted therapy of Lung Cancer in Australia
2008

• TRIALS numerous new agents
• TGA listed (available on private script)
• Avastin (RCC, CRC).
• Cetuximab (HNC, CRC)
• PBS available in NSCLC
• Iressa (2nd Line AND EGFR Gene mutation )
• Tarceva (2nd/3rd line, unselected)

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Nursing role in era of targeted therapy

• Important role in patient education and follow up
• Opportunity to develop LOCAL practical guidelines
  for Side effect awareness and management
• Anti-EGFR rash, diarrhoea
• Anti-Angiogenesis (VEGF) hypertension,
  proteinurua, bleeding (epistaxis, haemoptysis)
• Mab infusion reactions
• Multi-targeted TKIs Rare but significant
  toxicities eg thyroid dysfunction, QT
  prolongation