Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
BACKGROUND
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.


METHODS
After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.


RESULTS
Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.


CONCLUSIONS
The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Kwak
Eunice L
EL
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. ekwak@partners.org
Bang
Yung-Jue
YJ
Camidge
D Ross
DR
Shaw
Alice T
AT
Solomon
Benjamin
B
Maki
Robert G
RG
Ou
Sai-Hong I
SH
Dezube
Bruce J
BJ
Jänne
Pasi A
PA
Costa
Daniel B
DB
Varella-Garcia
Marileila
M
Kim
Woo-Ho
WH
Lynch
Thomas J
TJ
Fidias
Panos
P
Stubbs
Hannah
H
Engelman
Jeffrey A
JA
Sequist
Lecia V
LV
Tan
WeiWei
W
Gandhi
Leena
L
Mino-Kenudson
Mari
M
Wei
Greg C
GC
Shreeve
S Martin
SM
Ratain
Mark J
MJ
Settleman
Jeffrey
J
Christensen
James G
JG
Haber
Daniel A
DA
Wilner
Keith
K
Salgia
Ravi
R
Shapiro
Geoffrey I
GI
Clark
Jeffrey W
JW
Iafrate
A John
AJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D000077547:Crizotinib; D018450:Disease Progression; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases / Q000235:genetics
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D017978:Receptors, Growth Factor; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases