Erlotinib and the Risk of Oral Cancer: The Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial.

Abstract

IMPORTANCE:

Standard molecularly based strategies to predict and/or prevent oral cancer development in patients with oral premalignant lesions (OPLs) are lacking.

OBJECTIVE:

To test if the epidermal growth factor receptor inhibitor erlotinib would reduce oral cancer development in patients with high-risk OPLs defined by specific loss of heterozygosity (LOH) profiles. Secondary objectives included prospective determination of LOH as a prognostic marker in OPLs.

DESIGN:

The Erlotinib Prevention of Oral Cancer (EPOC) study was a randomized, placebo-controlled, double-bind trial. Accrual occurred from November 2006 through July 2012, with a median follow-up time of 35 months in an ambulatory care setting in 5 US academic referral institutions. Patients with OPLs were enrolled in the protocol, and each underwent LOH profiling (N = 379); they were classified as high-risk (LOH-positive) or low-risk (LOH-negative) patients based on their LOH profiles and oral cancer history. The randomized sample consisted of 150 LOH-positive patients.

INTERVENTIONS:

Oral erlotinib treatment (150 mg/d) or placebo for 12 months.

MAIN OUTCOMES AND MEASURES:

Oral cancer-free survival (CFS).

RESULTS:

A total of 395 participants were classified with LOH profiles, and 254 were classified LOH positive. Of these, 150 (59%) were randomized, 75 each to the placebo and erlotinib groups. The 3-year CFS rates in placebo- and erlotinib-treated patients were 74% and 70%, respectively (hazard ratio [HR], 1.27; 95% CI, 0.68-2.38; P = .45). The 3-year CFS was significantly lower for LOH-positive compared with LOH-negative groups (74% vs 87%, HR, 2.19; 95% CI, 1.25-3.83; P = .01). Increased EGFR gene copy number correlated with LOH-positive status (P < .001) and lower CFS (P = .01). The EGFR gene copy number was not predictive of erlotinib efficacy. Erlotinib-induced skin rash was associated with improved CFS (P = .01).

CONCLUSIONS AND RELEVANCE:

In this trial, LOH was validated as a marker of oral cancer risk and found to be associated with increased EGFR copy number (the target of the intervention). Erlotinib did not, however, improve CFS in high-risk patients with LOH-positive or high-EGFR-gene-copy-number OPLs. These results support incorporation of LOH testing as a prognostic tool in routine clinical practice but do not support erlotinib use in this setting.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00402779.

• Authors: William N William Jr, Vassiliki Papadimitrakopoulou, J Jack Lee, Li Mao, Ezra E W Cohen, Heather Y Lin, Ann M Gillenwater, Jack W Martin, Mark W Lingen, Jay O Boyle, Dong M Shin, Nadarajah Vigneswaran, Nancy Shinn, John V Heymach, Ignacio I Wistuba, Ximing Tang, Edward S Kim, Pierre Saintigny, Elizabeth A Blair, Timothy Meiller, J Silvio Gutkind, Jeffrey Myers, Adel El-Naggar, Scott M Lippman
• Journal: JAMA oncology (JAMA Oncol) Vol. 2 Issue 2 Pg. 209-16 (Feb 2016) ISSN: 2374-2445 [Electronic] United States
• PMID: 26540028 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Protein Kinase Inhibitors
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors

Topics

• Administration, Oral
• Anticarcinogenic Agents (administration & dosage, adverse effects, therapeutic use)
• Disease-Free Survival
• Double-Blind Method
• Drug Administration Schedule
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride (adverse effects, therapeutic use)
• Female
• Humans
• Loss of Heterozygosity
• Male
• Middle Aged
• Mouth Neoplasms (diagnosis, enzymology, genetics, prevention & control)
• Precancerous Conditions (diagnosis, drug therapy, enzymology, genetics)
• Prospective Studies
• Protein Kinase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Risk Assessment
• Risk Factors
• Time Factors
• Treatment Outcome
• United States