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COX-2 Inhibition Shown as Not Effective against Non-small Cell Lung Cancer

Carlson, Robert H.

doi: 10.1097/01.COT.0000451389.31977.19


SAN DIEGO—With substantial data from laboratory and preclinical studies suggesting that inhibition of the COX-2 pathway might be effective treatment for patients with non-small cell lung cancer (NSCLC), researchers in the CALGB/Alliance 30801 trial had reason to believe a clinical trial would bear this out. But that was not the case, according to a presentation here at the American Association for Cancer Research Annual Meeting.

The randomized, placebo-controlled Phase III trial showed that treatment with the COX-2 inhibitor celecoxib did not extend progression-free survival in patients with advanced NSCLC and elevated COX-2 by immunohistochemistry (IHC) (Abstract CT238).

The trial also failed to confirm the adverse prognostic/predictive value of COX-2 expression by IHC, which had been predicted by the earlier CALGB 30203 trial.

There was a positive aspect to the new CALGB 30801 results, however, in that preliminary data show that a metabolite of urinary prostaglandin E (PGE-M), a marker of activation of the COX-2 pathway, was both predictive and prognostic for outcomes.

The lead author of the trial, Martin J. Edelman, MD, Professor of Hematology/Oncology in the Department of Internal Medicine at the University of New Mexico and Associate Director for Clinical Research at the UNM Cancer Center, explained that COX-2 is overexpressed in non-small cell lung cancer (NSCLC) and is a known marker of poor prognosis in stage 1 disease. There is substantial preclinical and epidemiologic data suggesting that COX-2 inhibitors have antitumor and chemopreventive efficacy, he noted. And COX-2 inhibition has been shown to induce apoptosis and induce antiangiogenic effects in lung cancer.



Patients in the CALGB 30801 study had stage 3b or -4 NSCLC and were randomly assigned to receive chemotherapy with either celecoxib (400 mg bid) or placebo.

Chemotherapy selection was based on histology: Patients with non-squamous NSCLC received carboplatin and pemetrexed, while those with squamous histology received carboplatin and gemcitabine.

Edelman said that after 312 of the planned 322 patients had been assigned to a study arm, the study was halted for futility. “Based on the first 300 patients, there were no significant differences between the two study arms. Subset analyses evaluating histology, chemotherapy regimen, or incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition.”

He noted that several trials of COX-2 inhibitors have given tantalizing clues that this was a good strategy, including CALGB 30202, which showed that COX-2 over-expression was a negative prognostic factor but a positive predictive factor for COX-2 inhibition. “But the top-line results in CALGB 30801 were very negative,” Edelman reported, “with no advantage for celecoxib and if anything, somewhat worse outcomes.”

The trial also did not confirm the adverse prognostic/predictive value of COX-2 by IHC, which was surprising, he said.

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Directing Standard Therapy Histologically

While the outcomes data on celecoxib were negative—“and very discouraging”—the trial “demonstrated excellent survival in a population treated by ‘histologically’ directed therapy,” Edelman said.

With treatment selected based on squamous versus non-squamous histology, progression-free survival ranged from 4.4 to 6.1 months, and overall survival from 9.0 to 14.8 months.

And CALGB 30801 showed that PGE-M, a metabolite of prostaglandin E (PGE), could be a prognostic biomarker for COX-2-sensitive disease.

“Patients in this trial with elevated baseline PGE-M clearly did far worse when treated with celecoxib in terms of progression-free and overall survival than those with low baseline PGE-M,” Edelman said. “In fact, patients with low baseline PGE-M may be harmed.”

© 2014 by Lippincott Williams & Wilkins, Inc.
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