CETUXIMAB IN ADVANCED NSCLC NOT COST EFFECTIVE WITHOUT SELECTION

April 30, 2009 — In patients with advanced non-small-cell lung cancer (NSCLC), the addition of the targeted agent cetuximab (Erbitux) to platinum-based chemotherapy offers a small survival advantage. Patients given chemotherapy plus cetuximab had a median overall survival of 11.3 months, compared with 10.1 months for control subjects.

However, adding cetuximab to the regimen had no effect on progression-free survival, which was the same for patients receiving cetuximab and those receiving standard treatment (median, 4.8 months).

These results from the FLEX (First-Line Erbitux in Lung Cancer) trial have been published in the May 2 issue of the Lancet. They were first presented at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO), as reported by Medscape Oncology at that time.

At the ASCO presentation, Thomas J. Lynch, MD, professor of medicine at Harvard University in Boston, Massachusetts, pointed out that although the response rate was significantly improved, progression-free survival was unchanged and overall survival was only marginally improved.

Dr. Lynch, who was not involved in the FLEX trial, also said that cost has to be considered. At Harvard University, it would cost $62,000 to prolong survival by adding cetuximab to the regimen. He questioned whether a "median of 1.4 months is worth it, especially if we don't know if the quality of life has been improved."

"If we can bring survival up to 2.5 months, then it would be in line with other therapies," he said.

Cetuximab Added to Chemotherapy

Cetuximab, a monoclonal antibody directed against epidermal growth factor receptor (EGFR), is currently approved for use in metastatic colorectal cancer and head and neck cancer. It is not approved for use in lung cancer; FLEX was a phase 3 study designed to explore its use in this potential indication.

Led by Robert Pirker, MD, professor of internal medicine at the Medical University of Vienna in Austria, the FLEX trial involved 1125 chemotherapy-naive adult patients with advanced EGFR-expressing stage wet IIIB or stage IV NSCLC. The cohort was randomly assigned to chemotherapy plus cetuximab (n = 557) or chemotherapy alone (n = 568).

The chemotherapy regimen consisted of an intravenous infusion of cisplatin 80 mg/m² on day 1 and intravenous infusions of vinorelbine 25 mg/m² on days 1 and 8 of every 3-week cycle, for up to 6 cycles. An intravenous infusion of cetuximab was given over 2 hours at a starting dose of 400 mg/m² on day 1, and from day 8 onward was given over 1 hour at 250 mg/m² per week. It was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred.

The median follow-up for both groups was 23.8 months, and the addition of cetuximab was associated with a survival benefit for most patient subgroups and all histologic subgroups of NSCLC. In addition to an improvement in overall survival, response rates were better for the combination of chemotherapy plus cetuximab than for chemotherapy alone (36% vs 29%).

Potentially Fills an Unmet Medical Need

In an accompanying editorial, Roy S. Herbst, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, and Fred R. Hirsch, MD, PhD, from the University of Colorado in Denver, point out that cetuximab potentially fills an unmet medical need for patients with advanced NSCLC, especially since the FLEX trial enrolled patients with all NSCLC subtypes. This included patients with squamous cell carcinoma, who have been excluded from treatment with bevacizumab (Avastin), which acts on a different target, because of concerns about toxicity.

The editorialists say that the survival results in FLEX are noteworthy because they contrast with negative studies that used oral tyrosine kinase inhibitors of EGFR, such as erlotinib (Tarceva) and gefitinib (Iressa).

In agreement with Dr. Lynch, they note that the survival benefit is small and did not affect progression-free survival. They also question whether a more rigorous selection of patients for the molecular target might have altered the outcome in FLEX. As an example, KRAS status has become important in selecting colorectal cancer patients who are most likely to benefit from cetuximab.

Another issue that needs to be addressed is the EGFR mutation status and gene-copy number because EGFR mutations are important for response to small-molecule tyrosine kinase inhibitors of this receptor, they write.

There appears to be a role for cetuximab in the treatment of NSCLC, but it is not yet well defined, the editorialists comment. However, "a positive survival trial in lung cancer is a major advance and the treatment is worthy of consideration," they write. "Additionally, these regimens have the potential to be moved up into the earlier, more curative NSCLC setting with radiation or surgical therapy."

They also emphasize the need for new biomarkers to predict sensitivity to cetuximab, because these will be important in understanding exactly which patients will benefit most from any given therapy.