Download EGFR TKI

personalized medicine in lung cancer
R4 김승민
Personalized Medicine in Lung Cancer
• patients with specific types and stages of cancer should be
treated according to standardized predetermined protocols
• the molecular characterization of tumors
genome wide RNA expression, DNA copy-number and sequence
analyses, and microRNA and proteomic profiling
• individualized selection of treatment as determined by the
characteristics of the patient and the tumor.
• Lung cancer
 EGFR TKI (gefitinib, erlotinib)
 ALK kinase inhibitor crizotinib
EGFR TKI (gefitinib, erlotinib)
Incidence of EGFR gene mutations
(global data from literature; n=2880)
EGFR mutation (%)
70
Ethnicity
Gender
Smoking Hx
Histology
60
50
40
30
20
10
0
Non asian
asian
Male
Female
Non smoker AdenoNon-adeno
EGFR mutations in NSCLC
EGFR: First line VS second line ?
EGFR: First line VS second line ?
• EGFR TKI is recognized as a standard first-line therapy for patients
with activating EGFR mutations.
• All six randomized studies
 higher tumor response rates and longer progression-free survival
• none of these studies has been able to demonstrate improvement
in overall survival (OS).
• the use of first- or second-line EGFR TKI and explore the potential
differences between the two orders of administration
IPASS
Endpoints
Patients
Primary
• Chemonaïve
• Age
≥18 years
• Adenocarcinoma
histol
Gefitinib
(250 mg / day)
Secondary
ogy
• Never
or light ex-smok
ers*
• Life
expectancy
≥12 weeks
• PS
0-2
• Measurable
IV disease
stage IIIB /
• Progression-free survival (no
n-inferiority)
1:1 randomisation
Carboplatin
(AUC 5 or 6) /
paclitaxel
(200 mg / m2)
3 weekly#
• Objective response rate
• Overall survival
• Quality of life
• Disease-related symptoms
• Safety and tolerability
Exploratory
• Biomarkers
• EGFR mutation
• EGFR-gene-copy number
• EGFR protein expression
•
Mok et al NEJM 2009
IPASS
second line EGFR-TKI
• Use of second-line and/or third-line EGFR TKI in patients with
EGFR mutation
• multiple prospective single-arm studies, retrospective biomarker
analyses of phase II studies, and limited subgroup analysis from
phase III studies
• Current data on treatment outcomes of second- and/or third-line
EGFR therapy are inconsistent, and there is a possible explanation
for the lower tumor response rates
First-line Therapy
• difference in exposure to EGFR TKI
• difference in quality of life
• better tolerance by patients with poor performance status
• deferral of whole-brain radiation therapy for patients with brain
metastasis
First-line Therapy
• difference in exposure to EGFR TKI
• difference in quality of life
• better tolerance by patients with poor performance status
• deferral of whole-brain radiation therapy for patients with brain
metastasis
First-line Therapy
• difference in exposure to EGFR TKI
• difference in quality of life
• better tolerance by patients with poor performance status
• deferral of whole-brain radiation therapy for patients with brain
metastasis
EGFR: First line VS second line ?
ALK in lung cancer
Introduction
• ALK rearrangement several distinctive clinicopathologic features.
• Absence of smoking history..
among patients with ALK-positive lung cancer, more than 90% are
never- or light smokers (as 10 pack-years).
• younger age at diagnosis
• adenocarcinoma histology
• absence of other oncogenic drivers.
• study of crizotinib was in progress when EML4-ALK was reported in
lung cancer.
Introduction
• NCCN Current guidelines
 all patients with advanced, non squamous NSCLC for both EGFR
mutation and ALK rearrangement.
• newly diagnosed, ALK-positive patients can be prescribed crizotinib in
the first-line setting.
• the NCCN does recommend crizotinib as first-line therapy in
advanced, ALK-positive NSCLC.
• This recommendation to use crizotinib as first-line therapy is largely
based on our experience with EGFR-mutant NSCLC
Bone metastases and skeletal-related events
• Mechanisms
Personalized Medicine in Lung Cancer
• histologic subtype is clearly an important factor in selecting
among standard cytotoxic chemotherapies
• the presence of key oncogenic alterations predicts responsiveness
to selective targeted therapies
activating mutations and chromosomal rearrangements
• Lung cancer
 EGFR TKI (gefitinib, erlotinib)
 ALK kinase inhibitor crizotinib
EGFR TKI Ex: gefitinib, erlotinib
•
First line VS second line
• Six randomized studies
 improvement in tumor response rate and PFS over platinum-based
combination chemotherapy
 difference in exposure to EGFR TKI
 difference in quality of life
 better tolerance by patients with poor performance status
 deferral of whole-brain radiation therapy for patients with brain
metastasis
ALK inhibitor
• ALK is now a validated kinase target in lung and other cancers.
ALK-positive cancers are oncogene
• ALK-positive lung cancer demonstrated impressive activity and
clinical benefit
• patients with ALK-positive lung cancer invariably relapse with
crizotinib as a result of the development of resistance