ALK fusion and MET amplification as
molecular markers and therapeutic targets
in advanced lung adenocarcinomas
Marileila Varella Garcia, PhD
On behalf of the Lung Cancer Mutation Consortium Investigators
Grand Opportunity Grant- NCI 1 RC2 CA148394; PI Paul Bunn
Lung Cancer Mutation Consortium
• Define molecular status of 10 relevant genes in 1000
advanced lung adenocarcinomas
– Activation of KRAS, EGFR, BRAF, HER2, PIK3CA, AKT1, NRAS, MEK
tested by mutation analyses (Johnson, O16.01)
– Activation in ALK (gene fusion) and MET (amplification) tested by
FISH analyses
• Assist in the implementation of qualified molecular
diagnostic laboratories
• Identify personalized therapy with approved/trial agent
targeting specific mutations
Lung Cancer Mutation Consortium
14 US Institutions
Study Preliminary Conclusions


Protocols and reagents for 10 markers were
optimized
High quality molecular diagnosis for multiple
markers was achieved in a period of time
reasonable to select patients for target therapy
 Turn Around Time for 2 FISH tests was <1 week
 Turn Around Time for all 10 tests was ~2 weeks

Current panel of mutations may be easily
optimized for increased number of driver
mutations
Actionable driver mutations were detected in 4.1%
of adenocarcinomas in MET (amplification) and in
9.6% in ALK (rearrangements)
90.4%
ALK-
N=643
9.6%
ALK+
94.9%
MET-
N=295
4.1%
MET+
0
20
40
60
80
~55% adenocarcinomas carry mutations for one of 10
markers tested (Johnson, O16-01)
100
ALK positive patients are sensitive to crizotinib
Significant fraction of ALK+ patients were enrolled in
crizotinib trials with excellent response
Some progressed in crizotinib and are now
considered for other clinical trials
MET amplified patients are resistant to EGFR TKI
inhibitors and sensitive to MET inhibitors
Some MET+ patients were enrolled in the Pfizer
A8081001 with good response
Efforts are ongoing to enroll MET+ patients in other
trials with specific MET inhibitors
Conclusions

ALK fusions and MET amplification are present in significant
fraction of lung adenocarcinomas

Identification of tumors with actionable driver significantly
improves clinical outcome when patients are treated with specific
inhibitors

FISH technology is a robust platform for testing biomarkers in lung
tumors within a short turn around time and low failure rate

Collaborative efforts are essential to qualify laboratories for
molecular testing in a cost-effective and efficient manner

The Lung Cancer Mutation Consortium study sponsored by NCI
represents a successful model for translational science in lung
cancer