Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma.
BACKGROUND
A prospective, randomized phase II study, with mandatory tumor sampling at current disease stage, aimed to identify biomarkers predictive of improved progression-free survival (PFS) in patients with pancreatic cancer treated with erlotinib.


METHODS
Patients with histologically/cytologically confirmed, unresectable, locally advanced/metastatic pancreatic cancer, who had failed on or were unsuitable for first-line chemotherapy, underwent a tumor biopsy and were then randomized to receive once-daily erlotinib 150 mg or placebo. The primary end point was identification of biomarkers predicting improved PFS with erlotinib. Secondary end points included PFS, overall survival, response and toxicity.


RESULTS
At data cut-off, 207 patients were enrolled and analyzed. Prespecified biomarker analyses of EGFR protein expression, EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib. In the primary analysis, the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms, respectively [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.63-1.10; P = 0.1909]. However, observed baseline imbalances indicated worse prognosis in the erlotinib arm. After adjustment for baseline characteristics, a significant PFS benefit for erlotinib was observed (HR 0.68; 95% CI 0.50-0.91; P = 0.0102). Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib.


CONCLUSIONS
This study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib. Exploratory analyses suggested high amphiregulin might predict PFS benefit from erlotinib.
NCT00674973.
Barts Cancer Institute, Queen Mary University of London, London, UK. Electronic address: d.j.propper@qmul.ac.uk.
D
D
Propper
State Medical Institution Clinical Oncology Dispensary, Krasnodar, Russia.
I
I
Davidenko
University College London Cancer Institute, London, UK.
J
J
Bridgewater
Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
L
L
Kupcinskas
Roche Products Ltd, Welwyn Garden City, UK.
A
A
Fittipaldo
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
C
C
Hillenbach
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
B
B
Klughammer
Institut Gustave Roussy, Villejuif, France.
M
M
Ducreux
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010919:Placebos; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D011799:Quinazolines / Q000378:metabolism / Q000627:therapeutic use*
D014408:Biomarkers, Tumor; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride
biomarkers; erlotinib; pancreatic cancer; personalized therapy; predictive markers