Improved Outcomes in NSCLC After Screening for EGFR Mutations

Zosia Chustecka

August 20, 2009

August 20, 2009 — Patients with nonsmall-cell lung cancer (NSCLC) should be screened for epidermal growth-factor receptor (EGFR) mutations, and those who are found to have such mutations should receive treatment with the targeted agent erlotinib (Tarceva, Genentech) instead of chemotherapy, which will improve outcomes. This is the message from a large Spanish study showing that such screening is feasible.

The study, headed by Rafael Rosell, MD, from the Catalan Institute of Oncology in Badalona, Spain, was published online August 19 in the New England Journal of Medicine.

Erlotinib is already indicated for use in NSCLC in patients who have failed at least 1 chemotherapy regimen, but as a second-line treatment. This new study suggests using it as first-line therapy in patients with EGRF mutations (who made up 16% of the Spanish study population).

However, an accompanying editorial points out that the study was not randomized, and the outcomes for patients with EGRF mutations who were treated with erlotinib were compared with outcomes for historic controls.

Another study, also published online August 19 in the New England Journal of Medicine, was randomized; it showed that patients with EGRF mutations responded better to a targeted agent, gefitinib (Iressa, AstraZeneca), than to chemotherapy. Headed by Tony Mok, MD, from the Chinese University of Hong Kong, this study concluded that in the largely female nonsmoking Asian population that was studied, gefitinib was superior to chemotherapy as a first-line treatment, and that the benefit was greatest in patients with EGRF mutations (who made up 59.7% of the study population).

Erlotinib and gefitinib are both tyrosine kinase inhibitors, targeted agents that have milder adverse effects than chemotherapy and have the advantage of oral administration.

Both of the studies showed that NSCLC patients with EGRF mutations had an increase in the response rate and improved progression-free survival when treated with the targeted agent instead of chemotherapy. The nonrandomized Spanish trial showed an improvement in overall survival, but the randomized Asian trial did not.

These results leave several questions unanswered, according to Adi Gazdar, MD, from the University of Texas Southwestern Medical Center in Dallas, who wrote an accompanying editorial. It is unclear whether the results from Asian and Western populations can be extrapolated to one another, and whether erlotinib and gefitinib can be substituted for one another.

In addition, the relation between EGRF mutations and responsiveness to tyrosine kinase inhibitors (which include erlotinib and gefitinib) is complex, he writes. There are several different EGFR mutations, and 1 is involved in secondary resistance to these agents. "Almost all NSCLCs that respond initially to tyrosine inhibitors eventually relapse and resist further treatment," he notes.

Carefully selected subgroups of patients with NSCLC should be considered for first-line treatment with tyrosine inhibitors.

Nevertheless, these 2 studies and others suggest that carefully selected subgroups of patients with NSCLC should be considered for first-line treatment with tyrosine inhibitors instead of chemotherapy, Dr. Gazdar notes.

Preliminary results from both of these studies were presented last year at the European Society for Medical Oncology meeting, and were reported at that time by Medscape Oncology. Experts at the meeting welcomed the results for erlotinib and gefitinib, but emphasized the need for further study.

Large-Scale Screening Feasible

In the Spanish study, Dr. Rosell and colleagues screened lung cancer tissue from 2105 NSCLC patients in 129 institutions over the course of 3 years, and found 350 patients (16.6%) with EGFR mutations. These patients had stage IIIB disease with pleural effusions or stage IV disease.

EGFR mutations were significantly more frequent in women (representing 69% of the subgroup with mutations), in patients who had never smoked (66.5%), and in those with adenocarcinomas (80.9%) (P < .001 for all comparisons).

Patients with EGFR mutations were eligible for erlotinib (150 mg daily) but, for various reasons, not all of them received it, the researchers explain. In total, 217 patients received erlotinib and 197 could be evaluated for a response.

These 197 patients had a median progression-free survival of 14 months and a median overall survival of 27 months. In addition, 70% showed a complete or partial response to the drug.

Both of these are an improvement on what is usually seen with lung cancer, the researchers state, and they cite historic control data that suggest that this improvement is more than double. In NSCLC patients without the EGFR mutation, chemotherapy normally yields progression-free survival of 5 months, overall survival of 12 months, and a response rate of about 30%, they note.

These results highlight the idea that EGRF-mutant lung cancer is a distinct class of nonsmall-cell lung cancer.

"These results highlight the idea that EGRF-mutant lung cancer is a distinct class of nonsmall-cell lung cancer," Dr. Rosell and colleagues write.

They conclude that screening for EGFR mutations is warranted in women with lung cancer, in those who have never smoked, and in those with nonsquamous tumors. Large-scale screening is "feasible and improves outcomes," they add.

Results Cannot Be Taken Out of Context

The Asian study by Dr. Mok and colleagues, known as IPASS (Iressa Pan-Asian Study), involved 1217 previously untreated patients with advanced pulmonary adenocarcinoma who had never smoked or who had been only light smokers (≤10 pack-years of smoking and no smoking for at least 15 years). They were randomized to receive gefitinib (250 mg daily) or a standard first-line chemotherapy doublet (carboplatin and paclitaxel).

Gefitinib was superior to chemotherapy as an initial treatment in this patient population, the researchers report. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with chemotherapy.

About half of the trial participants provided tissue samples, and EGFR mutation data could be evaluated in 437 patients (35.9%). Of these, 261 (59.7%) were positive for EGFR mutations.

This subgroup of 261 patients who were positive for EGFR mutations showed a "remarkably high" response rate (71.2%) and prolonged progression-free survival with gefitinib, the researchers note. In contrast, patients without the EGRF mutation showed a poor response rate to gefitinib (1.1%), and progression-free survival favored chemotherapy.

"Our trial confirms the predictive value of EGFR mutations for the responsiveness of pulmonary adenocarcinoma to gefitinib as compared with carboplatin–paclitaxel," Dr. Mok and colleagues explain. "Patients in whom an EGFR mutation has been identified will benefit most from first-line therapy with gefitinib," they add.

Dr. Mok presented details of these EGRF mutation results recently at the 13th World Conference on Lung Cancer (WCLC), as reported by Medscape Oncology. At the time, David Gandara, MD, WCLC program chair and professor of medicine at the University of California-Davis, said: "This is an extraordinarily helpful trial because we can now learn more about lung cancer biology. But at the same time, it can't be taken out of context. The trial was done in Asia, entirely in those with adenocarcinoma, 94% of whom were never smokers and 80% of whom were female."

This is not a typical lung cancer population — especially in the United States.

"This is not a typical lung cancer population — especially in the United States," he added. Only 15% of American lung cancer patients have an EGFR mutation, "and gefitinib has a restricted indication for use only in patients who have previously benefited from the drug, he noted. Whether it should be used here in advanced lung cancer patients with EGFR mutations is controversial, Dr. Gandara noted.

The Asian IPASS study was supported by AstraZeneca. Dr. Mok reports receiving consulting fees from Roche, AstraZeneca, Pfizer, and Eli Lilly; lecture fees from Roche, AstraZeneca, and Eli Lilly; and a research grant from AstraZeneca Hong Kong. Some of his coauthors declare relevant financial relationships and some are employees of AstraZeneca, as detailed in the paper. Dr. Rosell and coauthors have disclosed no relevant financial relationships. Editorialist Dr. Gazdar reports receiving consulting fees from AstraZeneca.

N Engl J Med. Published online before print August 19, 2009.