Biology of EGFR Mutations and Acquired Resistance to EGFR TKIs

1. 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.

2. 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

8. Cancer Paradigm 2011

9. Epidermal Growth Factor Receptor Mutations

10. Gefitinib(250 mg / day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m2) q 3 weeks# Study design Endpoints • 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 • Patients • Chemonaïve • Age ≥18 years • Adenocarcinoma histology • Never or light ex-smokers* • Life expectancy≥12 weeks • PS 0-2 • Measurable stage IIIB / IV disease *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 Mok TS et al. N Engl J Med 2009;361(10):947-57; Mok T et al. ESMO 2008;LBA2.

11. Objective response rate in EGFR mutation positive and negative patients Overallresponserate (%) 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 71.2% 47.3% 23.5% 1.1% (n = 132) (n = 129) (n = 91) (n = 85) Odds ratio >1 implies greater chance of response on gefitinib Mok TS et al. ESMO 2008;LBA2.

12. Progression-free survivalin EGFR mutation positive and negative patients Mok TS et al. ESMO 2008;LBA2.

13. 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.

14. 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.

15. 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 Maemondo M et al. N Engl J Med 2010;362:2380-2388.

16. EGFR T790M HGF Production MET Amplification Small Cell Transformation Resistance mechanisms in EGFR mutant NSCLC

17. 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." Regales et al. JCI 2009

18. 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.

19. Saturday, February 11, 2012Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD