Combination Cetuximab-Chemotherapy Regimen Shows Survival Benefit in Patients with Advanced NSCLC

Roxanne Nelson

June 02, 2008

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Lead investigator of the study speaks with Medscape Oncology

June 2, 2008 (Chicago, Illinois) — Cetuximab (Erbitux) combined with cisplatin/vinorelbine increased overall survival in patients with advanced epidermal growth-factor receptor (EGFR)-detectable non-small-cell lung cancer (NSCLC), compared with chemotherapy alone, researchers here at the American Society of Clinical Oncology 44th Annual Meeting report.

Overall survival was 11.3 months in the cetuximab group and 10.1 months in the control group. One-year survival was 47% in the cetuximab group and 42% in the control group.

"Cetuximab added to the protocol demonstrated superior survival, compared with chemotherapy alone, in patients with NSCLC," said lead investigator Robert Pirker, MD, professor of internal medicine at the Medical University of Vienna, in Austria. "This sets a new standard for the first-line treatment of patients with NSCLC."

NSCLC is the most common type of lung cancer, comprising approximately 87% of all cases. In addition, more than 80% of NSCLC patients have tumors that express EGFR, and it is associated with a poorer prognosis.

The First-Line in Lung Cancer with Erbitux (FLEX) trial is a phase 3 study designed to compare the efficacy and safety of the EGFR-targeted monoclonal antibody cetuximab in combination with cisplatin/vinorelbine with the efficacy and safety of chemotherapy alone in a cohort of patients with advanced NSCLC.

"Cetuximab binds to EGFR, and is the established standard of care in colorectal cancer," said Dr. Pirker. "The rationale for the FLEX study was based on data from other trials. Our aim was to demonstrate superior survival in patients given cetuximab with chemotherapy, compared with patients given chemotherapy alone."

The cohort was comprised of 1125 patients with stage 3B or stage 4 EGFR-detectable NSCLC, who were randomized on a 1:1 basis to 1 of 2 groups. The cetuximab group received cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus cisplatin (80 mg/m2 on day 1) and vinorelbine (25 mg/m2 on day 1 and day 8) every 3 weeks; the control group received cisplatin/vinorelbine alone.

"We included patients with all histologies. Most of the patients had metastatic disease, so the trial represents a real-life population," explained Dr. Pirker.

The study population was 70% male, with a median age of 59 years. The majority (94%) had stage 4 disease, 47% of the patients had adenocarcinoma, 34% had squamous cell carcinoma, and 17% had an Eastern Cooperative Oncology Group performance status of 2, indicating an extensive tumor burden and overall poor prognosis.

The researchers performed a survival analysis after 868 events had occurred. "There was a 5% absolute gain in survival with cetuximab, so that is a clinical benefit," said Dr. Pirker. "There was a benefit in all of the subgroups that we looked at."

The preliminary results of prespecified subgroup analyses suggest that there was a greater benefit in whitepatients independent of histology, and there was generally a better prognosis in Asians. The median overall survival for Asians who received cetuximab was 20.4 months and for whites was 9.1 months.

Although overall survival was better among Asian patients, Dr. Pirker cautioned that the sample size is too small to come to any conclusions.

Median Survival by Subgroup

Population Cetuximab Group Control Group P Value
All (n = 1125) 11.3 months 10.1 months .0441
All whites (n = 945) 10.5 months 9.1 months .0025
Whites with adenocarcinoma (n = 412) 12.0 months 10.2 months .0673
Whites with squamous cell carcinoma
(n = 347)
10.2 months 8.9 months .0567
Asians (n = 121) 17.6 months 20.4 months .4992

The majority of patients in the trial were white (84%), and they experienced the largest benefit from the addition of cetuximab to the chemotherapy regimen, averaging a 1.4-month increase in survival.

When looking at secondary end points, the researchers observed that progression-free survival was the same in both treatment groups. The response rate was 36% in the cetuximab group and 29% in the control group.

The main adverse effect from cetuximab was an acne-like skin rash, which was manageable with medication.

Thomas J. Lynch, MD, professor of medicine at Harvard University, in Boston, Massachusetts, was a little more cautious about the study results. "The response rate was significantly improved but progression-free survival was unchanged," he said. "And overall survival is only marginally improved."

He also pointed out that cost has to be considered. It would cost $62,000 at Harvard University to prolong survival by adding cetuximab to the regimen. "Is a median of 1.4 months 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.

Lung cancer is notoriously difficult to treat, and even though intensive research is ongoing to develop new therapies and regimens, the results have been disappointing. Of 15 phase 3 trials that randomized 12,073 patients, only 2 have shown any benefit.

Dr. Lynch outlined the circumstances under which he felt that cetuximab should be used in patients with NSCLC. It should not be used alone, or as a second- or third-line therapy. Patients with squamous cell NSCLC can benefit from it, so it should be used in that population. It should also be used in maintenance therapy.

"In my opinion," he said, "cetuximab can prolong survival in a clinically meaningful way."

Dr. Lynch added that its use should be restricted to the NSCLC patients who are most likely to benefit from its use, and there is an urgent need to explore and target other biomarkers.

The FLEX trial was funded by Merck Serono. Dr. Pirker disclosed research funding from Merck.

American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstract 3. Presented June 1, 2008.

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