Biology of EGFR Mutations and Acquired Resistance to EGFR TKIs

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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

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."

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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