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.

Trial registration: ClinicalTrials.gov NCT00652340.

Conflict of interest statement

Disclosure: MS and FB are employees of Tragara. SZ was employed at Tragara during this study and is currently an employee of Polynoma, LLC, San Diego, CA. The other authors declare no conflict of interest.

Figures

FIGURE 1

Consolidated Standards of Reporting Trials (CONSORT) diagram. P/E, placebo plus erlotinib; AP/E, apricoxib plus 150 mg/day erlotinib; ITT, intent-to-treat; PS, performance status.

FIGURE 2

Kaplan–Meier estimate of time to progression by treatment group in the intent-to-treat population (A) and among patients ≤65 years of age (B). Kaplan–Meier estimate of overall survival by treatment group in the intent-to-treat population (C) and among patients ≤65 years of age (D). P/E, placebo plus erlotinib; AP/E, apricoxib plus 150 mg/day erlotinib; HR, hazard ratio; CI, confidence interval, NA, not applicable.