title: A randomized, placebo-controlled, multicenter, biomarker-selected, phase 2 study of apricoxib in combination with erlotinib in patients with advanced non-small-cell lung cancer.
abstract: Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in non-small-cell lung cancer (NSCLC) and may promote resistance to epidermal growth factor receptor inhibitors. This randomized phase 2 trial evaluated apricoxib, a novel COX-2 inhibitor, in combination with erlotinib in biomarker-selected patients. Patients with stage IIIB/IV NSCLC previously treated with platinum-based chemotherapy were randomized (2:1) to 400 mg/day apricoxib plus 150 mg/day erlotinib (AP/E) or placebo plus erlotinib (P/E) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was time to progression (TTP). A decrease of 50% or more from baseline urinary prostaglandin E2 metabolite after a 5-day, open-label, run-in period was used to select eligible patients. One hundred twenty patients (median age 64 years) were randomized (78 to AP/E and 42 to P/E). Overall median TTP was 1.8 months in the AP/E group and 2.1 months in the P/E group, with a 12% objective response rate in both groups (intent-to-treat analysis). A subgroup analysis in patients aged 65 years or younger demonstrated a statistically significant TTP benefit for AP/E (hazard ratio 0.5 [95% confidence interval: not applicable-0.9]; p=0.018) and overall survival advantage at minimum 1-year follow-up (median 12.2 versus 4.0 months; hazard ratio=0.5; p=0.021). The most common adverse events were rash, diarrhea, fatigue, and nausea. Toxicity contributed to early discontinuations in patients aged more than 65 years treated with AP/E. This is the first randomized placebo-controlled study of a COX-2 inhibitor in NSCLC to use a prospective patient-selection strategy. Although AP/E seemed to improve TTP and overall survival in a subset of patients aged 65 years or younger, the primary endpoint of the trial was not met.
authors.affiliation: *University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California; †Providence Cancer Center, Portland, Oregon; ‡University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida; §Ohio State University, Columbus, Ohio; ‖Vanderbilt University, Nashville, Tennessee; and ¶Tragara Pharmaceuticals, San Diego, California.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Gitlitz
authors.forename: Eric
authors.initials: E
authors.lastname: Bernstein
authors.forename: Edgardo S
authors.initials: ES
authors.lastname: Santos
authors.forename: Greg A
authors.initials: GA
authors.lastname: Otterson
authors.forename: Ginger
authors.initials: G
authors.lastname: Milne
authors.forename: Mary
authors.initials: M
authors.lastname: Syto
authors.forename: Francis
authors.initials: F
authors.lastname: Burrows
authors.forename: Sara
authors.initials: S
authors.lastname: Zaknoen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000652:urine; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000652:urine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000652:urine; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000652:urine; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000652:urine; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000652:urine; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000652:urine; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D011453:Prostaglandins / Q000652:urine*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D013449:Sulfonamides; C514354:apricoxib; C060526:7-hydroxy-5,11-dioxotetranorprostane-1,16-dioic acid; D000069347:Erlotinib Hydrochloride
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