Although the results of the Iressa Pan-Asia study (IPASS) suggested that the oral agent gefitinib (Iressa) improved outcomes in patients with advanced non-small cell lung cancer (NSCLC)-particularly those with EGFR mutations-those benefits have not been proven in other recent trials of patients with either early stage or locally advanced NSCLC. In fact, the results of the BR.19 trial presented at the 2010 ASCO Annual Meeting suggest that patients with local resected NSCLC disease do worse on gefitinib than placebo, even if these patients have an EGFR mutation.1

Trial Halted Early

"Although BR.19 was an underpowered study, gefitinib in unselected as well as EGFR mutant patients was not beneficial," said Heather A. Wakelee, MD, Assistant Professor of Oncology at Stanford University Medical Center, who presented the study's results at the Best of ASCO Meeting in San Francisco. "It has yet to be really demonstrated that a targeted agent improves survival in resected non-small cell lung cancer. I strongly recommend against giving EGFR tyrosine kinase inhibitors (TKIs) in this setting even to patients with known EGFR mutations outside of a clinical trial," she said.

Researchers conducting the BR.19 study, begun in 2002, planned to randomly assign at least 1,160 patients with completely resected stage IB-IIIA NSCLC and a performance status of 0 to 2 to either gefitinib (250 mg daily) or placebo for 2 years. The primary endpoint was overall survival, and secondary outcomes included disease-free survival, toxicity, and evaluation of gefitinib's efficacy in patients with KRAS mutations, EGFR gene expression by FISH, and EGFR mutation status. Yet in 2004, the results of the ISEL (Iressa Survival Evaluation in Lung Cancer) trial showed a nonsignificant improvement in survival-with a hazard ratio of 0.89-in advanced NSCLC patients treated with gefitinib.

The BR.19 trial was finally halted with 503 patients enrolled when the Southwest Oncology Group (SWOG) interim analysis of their 0023 trial indicated that maintenance gefitinib was worse than placebo in patients with locally advanced disease. In the BR.19 trial, the median duration of treatment with gefitinib and placebo was less than 5 months, according to Glenn Goss, MD, of the Ottawa Hospital Regional Cancer Centre, who presented the study's results at the ASCO Annual Meeting. Although the trial did not show that gefitinib had efficacy in local NSCLC, the treatment was well tolerated, Dr. Wakelee said.

Biomarker Analysis

Despite the negative conclusions of the ISEL and SWOG 0023 studies, the results of the biomarker analysis in the BR.19 trial were eagerly anticipated, according to Dr. Wakelee. However, the BR.19 researchers found that neither the KRAS mutation, EGFR gene expression by FISH, nor EGFR mutation were prognostic of overall survival. Only 21% out of the 357 patients tested had the EGFR mutation, but these patients fared worse on gefitinib (with a hazard ratio of 1.58) than those who were EGFR wild-type. "Although the results are not statistically significant because of small patient numbers, they're very striking-especially when you consider the IPASS data we all heard so much about last year," Dr. Wakelee said.

Dr. Wakelee noted that chemotherapy is still the treatment of choice for NSCLC patients in the adjuvant setting, although the upcoming results of several studies-such as the RADIANT trial with erlotinib (Tarceva)-may provide further information about the use of EGFR TKIs and the targeted use of chemotherapy, she said. "There's only a 5% to 10% benefit with chemotherapy in NSCLC patients, so we have a long way to go toward improving treatments," she said. "We need to look forward to information from new adjuvant trials, including some exciting ongoing biomarker studies involving markers of chemotherapy resistance and E1505 with adjuvant bevacizumab," she said. ■

Reference

1. Goss GD, Lorimer I, Tsao MS, et al: A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19. Best of ASCO San Francisco. Abstract LBA7005. Presented July 17, 2010, by Heather A. Wakelee.