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Erlotinib fails to reduce risk for oral cancer among high-risk individuals
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Loss of heterozygosity predicted increased risk for oral cancer among patients with oral premalignant lesions, according to the results of a randomized clinical trial.
Although loss of heterozygosity (LOH) also appeared associated with increased EGFR copy number — the target of erlotinib (Tarceva; Genentech, Astellas Oncology) — this intervention failed to improve cancer-free survival (CFS) among patients with LOH-positive or high-EGFR gene copy number lesions, according to the researchers.
“One of the greatest challenges in developing chemopreventive agents is to identify the population at highest cancer risk,” William N. William, Jr., MD, assistant professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “Not all patients with an oral premalignant lesion will develop oral cancer. By using a molecular test that can identify those at highest risk, we can focus on preventive efforts on these specific individuals.”
Thus, William and colleagues conducted the randomized, controlled Erlotinib Prevention of Oral Cancer (EPOC) trial to determine whether the EGFR inhibitor erlotinib reduced oral cancer development in patients with high-risk oral premalignant lesions by specific LOH profiles.
EPOC included data from 395 patients enrolled at five U.S. academic referral institutions between November 2006 and July 2012. Patients with oral premalignant lesions underwent LOH profiling, after which the researchers classified them as high-risk (LOH-positive; n = 254) or low-risk (LOH-negative; n = 141).
CFS served as the primary endpoint. Prospective validation of LOH as a prognostic marker in oral premalignant lesions served as a secondary endpoint.
The researchers randomly assigned 150 of the patients (median age, 57 years) with LOH-positive disease to 150 mg daily oral erlotinib (n = 75) or placebo (n = 75).
Median follow-up was 35 months.
A comparable proportion of patients in the erlotinib and placebo arms achieved 3-year CFS (70% vs. 74%; HR = 1.27; 95% CI, 0.68-2.38).
However, patients with LOH-positive oral premalignant lesions had a significantly lower 3-year CFS rate than LOH-negative groups (74% vs. 87%; HR = 2.19; 95% CI, 1.25-3.83), which suggested validation of LOH as a predictive marker for increased oral cancer risk. The difference in CFS between LOH-positive and LOH-negative groups remained significant in multivariate analyses adjusted for number of prior oral cancers, histologic findings and treatment (HR = 2.2; 95% CI, 1.16-4.19).
Increased EGFR gene copy number appeared associated with LOH-positive status (P < .001) and lower CFS (P = .01); however, copy number status was not predictive of erlotinib efficacy.
The researchers observed an association between erlotinib-induced skin rash and improved CFS (P = .01).
“It is vital to know what doesn’t work as well as what does, and this research furthered progress in other ways,” Scott M. Lippman, MD, study researcher and director of Moores Cancer Center at UC San Diego Health, said in the release. “For example, we demonstrated that erlotinib-treated patients who develop a skin rash, a common side effect of the drug, had the lowest incidence or oral cancer. Further investigations of this association could point to novel biomarkers, mechanisms and trial designs related to the effects of EGFR-targeted agents in patients with oral premalignant lesions or head and neck cancers.”
Scott M. Lippman
In an accompanying editorial, Julie E. Bauman, MD, MPH, associate professor of medicine and director of the head and neck and thyroid cancer sections at University of Pittsburgh Cancer Institute, and Jennifer Grandis, MD, professor of head and neck surgery and assistant vice chancellor of clinical and translational research at University of California, San Francisco, noted that the EPOC trial benefits future chemoprevention research despite the lack of success with erlotinib.
“Despite the promise of precision chemoprevention, erlotinib now joins the list of agents that have been tested and failed to prevent oral carcinogenesis,” Bauman and Grandis wrote. “The identification of an effective, well-tolerated chemopreventive agent remains an unmet global need. However, by prospectively validating a molecularly selected, high-risk population and demonstrating the feasibility of a CFS endpoint, the EPOC study has initiated a new epoch in head and neck squamous cell carcinoma chemoprevention trials.” – by Cameron Kelsall
Disclosure: OSI Pharmaceuticals provided funding for this study. William reports no relevant financial disclosures. Other study researchers report advisory board memberships with AstraZeneca, Bristol-Myers Squibb, Celgene, Clovis, Eli Lilly, Genentech/Roche, GlaxoSmithKline and Synta, as well as participation in educational activities on behalf of Boehringer Ingelheim, Medscape and Pfizer. Bauman and Grandis report no relevant financial disclosures.
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