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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 TumorsGenesTargetsDrugs
Epidermal Growth Factor Receptor Mutations
Study design Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 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 progression PS, 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 = EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p = Overall response rate (%) (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.
Response to treatment in the intention-to-treat population, according to treatment group* Maemondo M et al. N Engl J Med 2010;362:
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: 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."
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Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD