Combination Therapy for Previously Untreated Stage IV NSCLC

Key Points

  • In patients with previously untreated stage IV NSCLC, no overall benefit was observed with the addition of cetuximab to chemotherapy with or without bevacizumab.
  • A survival advantage was observed among cetuximab patients with EGFR FISH-positive squamous cell carcinoma.

As reported in The Lancet Oncology by Herbst et al, the phase III SWOG S0819 trial showed no overall benefit of adding cetuximab (Erbitux) to carboplatin/paclitaxel both with and without bevacizumab (Avastin) in patients with previously untreated stage IV non–small cell lung cancer (NSCLC). A survival benefit of cetuximab was observed in the subgroup of patients with epidermal growth factor receptor (EGFR) fluorescence in situ hybridization (FISH)-positive squamous cell carcinoma.

Study Details

In the open-label trial, 1,313 patients from 277 sites in the United States and Mexico were randomized between August 2009 and May 2014 to a control group (n = 657) receiving carboplatin (AUC = 6 every 21 days) and paclitaxel (200 mg/m² every 21 days) with (n = 277) or without (n = 380) bevacizumab (15 mg/kg every 21 days) or the cetuximab group (n = 656) receiving cetuximab (250 mg/m² weekly after loading dose) plus carboplatin/paclitaxel with (n = 283) or without (n = 373) bevacizumab. Patients were placed in the no-bevacizumab stratum if they did not receive bevacizumab, with reasons including being unsuitable for bevacizumab or patient or physician decision not to treat with bevacizumab. Randomization was stratified by bevacizumab treatment, smoking status, and M substage.

The coprimary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population in the intent-to-treat analysis. EGFRFISH was assessable in 976 patients; of them, 400 (41%) were EGFRFISH-positive (all others were considered not positive), including 199 in the cetuximab group and 201 in the control group.

Progression-Free and Overall Survival

The median follow-up for survivors was 35.2 months. Median progression-free survival among EGFR FISH-positive patients was 5.4 months in the cetuximab group vs 4.8 months in the control group (hazard ratio [HR] = 0.92, P = .40). Among all patients, median overall survival was 10.9 vs 9.2 months (HR = 0.93, P = .22). In a prespecified analysis of EGFR FISH-positive patients with squamous cell histology, median overall survival was 11.8 months in the cetuximab group vs 6.1 months in the control group (HR = 0.58, P = .0071), with a nonsignificant improvement in median progression-free survival (4.5 vs 2.8 months, HR = 0.68, P = .055).

No differences between groups were observed for overall survival (HR = 1.04, P = .77) or progression-free survival (HR = 1.02, P = .88) among patients who were not EGFR FISH-positive (negative or with squamous cell histology). No differences were observed in overall or progression-free survival among patients with nonsquamous histology who were EGFR FISH-positive (HR = 0.88, P = .34; HR = .99, P = .96) or not EGFR FISH-positive (HR = 1.00, P = .97; HR = 1.03, P = .69). Bevacizumab was not associated with overall or progression-free survival in the entire population or according to EGFRFISH status.

Adverse Events

The most common grade 3 or 4 adverse events among all patients were decreased neutrophil count (37% in cetuximab group vs 25% in control group), decreased leukocyte count (16% vs 20%), fatigue (13% vs 20%), and acne/rash (8% vs < 1%). Death due to adverse events and any unexpected treatment-related grade 4 adverse event occurred in 9% vs 5% of patients. Death related to treatment occurred in 6% vs 2%.

The investigators concluded: “Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation.”

The study was funded by the National Cancer Institute and Eli Lilly and Company.

Roy S. Herbst, MD, of Yale Cancer Center, Yale School of Medicine, is the corresponding author of The Lancet Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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