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Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw,
unedited content. Select slides from the original presentation are omitted where Research To
Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for
your use in place of any omitted slides.
Biology of EGFR Mutations and Acquired Resistance to EGFR
TKIs
Thomas J. Lynch, Jr., M.D.
Director, Yale Cancer Center
Physician-in-Chief, Smilow Cancer Hospital
Cancer Paradigm 2011
Epidermal Growth Factor Receptor Mutations
Study design
Gefitinib(250 mg / day)
Carboplatin (AUC 5 or 6) /
paclitaxel (200 mg / m2)
q 3 weeks#
1:1 randomisation
*Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; #limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progressionPS, performance status; EGFR, epidermal growth factor receptor
Patients• Chemonaïve• Age ≥18 years • Adenocarcinoma histology
• Never or light ex-smokers*
• Life expectancy≥12 weeks
• PS 0-2• Measurable stage IIIB / IV disease
Primary• Progression-free survival (non-inferiority)
Secondary• 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
Endpoints
Mok TS et al. N Engl J Med 2009;361(10):947-57; Mok T et al. ESMO 2008;LBA2.
Objective response rate in EGFR mutation positive and negative patients
Gefitinib Carboplatin / paclitaxel
EGFR M+ odds ratio (95% CI) = 2.75(1.65, 4.60), p = 0.0001
EGFR M- odds ratio (95% CI) = 0.04(0.01, 0.27), p = 0.0013
Overallresponserate (%)
(n = 132) (n = 129) (n = 91) (n = 85)
Odds ratio >1 implies greater chance of response on gefitinib
71.2%
47.3%
1.1%
23.5%
Mok TS et al. ESMO 2008;LBA2.
Progression-free survival in EGFR mutation positive and negative patients
Mok TS et al. ESMO 2008;LBA2.
Progression-free survival events Gefitinib
Carboplatin +paclitaxel
Hazard ratio (95% CI) p-value
EGFR mutation-positive(n = 132; 129)
73.5% 86.0% 0.48 (0.36-
0.64)<0.0001
EGFR mutation-negative(n = 91; 85)
96.7% 82.4%2.85 (2.05-
3.98)<0.0001
Response to treatment in the intention-to-treat population, according to treatment group*
Maemondo M et al. N Engl J Med 2010;362:2380-2388.
Maemondo M et al. N Engl J Med 2010;362:2380-2388.
Progression-free survival among the study patients
Median PFS Gefitinib (n = 114), 10.8 months Carboplatin/paclitaxel (n = 110), 5.4 months
Hazard ratio 0.30
p-value < 0.001
Maemondo M et al. N Engl J Med 2010;362:2380-2388.
Overall survival among the study patients
Median survival Gefitinib (n = 114), 30.5 months Carboplatin/paclitaxel (n = 114), 23.6 months
Hazard ratio not reported
p-value = 0.31
Resistance mechanisms in EGFR mutant NSCLC
EGFR T790M
MET
Amplification
HGF
Production
Small Cell Transformation
Regales et al. JCI 2009
Combination of BIBW2992 and cetuximab is effective against EGFR T790M
"The combination of both agents together
induced dramatic shrinkage of erlotinib-resistant tumors
harboring the T790M mutation, because together they
efficiently depleted both
phosphorylated and total EGFR."
Research To Practice could not obtain permission to reproduce this slide at the time of publication. To access the
following abstract, please visit our Select Publications page:
Horn L et al. Proc IASLC 2011;Abstract O19.07.
Saturday, February 11, 2012Hollywood, Florida
Faculty
Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD
Co-Chair and ModeratorNeil Love, MD
Chandra P Belani, MDJohn Heymach, MD, PhDPasi A Jänne, MD, PhD
Thomas J Lynch Jr, MDHeather Wakelee, MD