No Benefit From Adding Cetuximab to Pemetrexed in Recurrent/Progressive NSCLC After Platinum-Based Therapy


Key Points

  • Cetuximab/pemetrexed did not improve progression-free survival or overall survival compared with pemetrexed alone.
  • No differences in outcomes were observed according to histology or EGFR status.

In a phase III trial reported in The Lancet Oncology, Edward S. Kim, MD, of Levine Cancer Institute, Carolinas HealthCare System, and colleagues investigated whether the addition of cetuximab (Erbitux) to pemetrexed (Alimta) improved progression-free survival in patients with recurrent or progressive non–small cell lung cancer (NSCLC) after platinum-based therapy. There was no significant difference in progression-free survival for cetuximab/pemetrexed vs pemetrexed alone.

Study Details

In this open-label trial, patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the United States who had progressive disease during or after one previous platinum-based regimen were initially randomly assigned to receive pemetrexed (500 mg/m²) or docetaxel (75 mg/m²) each with or without cetuximab (400 mg/m² first dose and 250 mg/m² weekly thereafter). However, during the trial, data became available indicating that pemetrexed had efficacy comparable to docetaxel in second-line treatment and was associated with a better adverse effect profile, resulting in a shift in the standard of care.

The trial was thus amended, with investigators choosing whether patients would receive pemetrexed or docetaxel on a case-by-case basis. Since then, additional data have indicated that pemetrexed is superior to docetaxel in patients with nonsquamous histology. The primary outcome measure of the study was changed to a comparison of progression-free survival with cetuximab/pemetrexed vs pemetrexed alone.

Although EGFR expression was not required for study entry, tumor tissue was analyzed for EGFR expression by immunohistochemistry, and histoscore assessment was performed by central pathologists and correlated with clinical outcome using a predefined cutoff for low (< 200) and high (≥ 200).

Of 938 patients allocated to treatment, 301 patients received cetuximab/pemetrexed and 304 pemetrexed alone and 167 received cetuximab/docetaxel and 166 docetaxel alone. The cetuximab/pemetrexed and pemetrexed groups were balanced for age (median, 64 and 65 years), ethnicity (89% and 87% white), country (88% and 89% from the United States), Karnofsky performance status (80–100 in 84% in both), EGFR status (1+ to 3+ in 66% and 65%), nonsquamous histology (75% and 77%), distant metastases (68% and 64%), time from last platinum dose to progression/recurrence (≤ 90 days in 55% and 54%), and previous paclitaxel therapy (74% in both).

Efficacy Outcomes

Median progression-free survival was 2.9 months in the cetuximab/pemetrexed group vs 2.8 months in the pemetrexed group (hazard ratio [HR] = 1.03, P = .76). There were no differences in progression-free survival in the two groups according to nonsquamous (HR = 0.95, 95% confidence interval [CI] = 0.79–1.15) or squamous histology (HR = 1.27, 95% CI = 0.90–1.79) or EGFR-positive (HR = 1.02, 95% CI = 0.83–1.24) or undetectable status (HR = 1.14, 95% CI = 0.63–2.05).

Median overall survival was 6.9 vs 7.8 months (HR = 1.01, P = .86); there were no significant differences in median overall survival according to nonsquamous (HR = 0.94, 95% CI = 0.77–1.14) or squamous histology (HR = 1.26, 95% CI = 0.90–1.78) or EGFR-positive (HR = 1.08, 95% CI =0.88–1.33) or undetectable status (HR 1.07, 95% CI 0.59-1.94). The objective response rates were 7% vs 4% (odds ratio = 1.59, P = .20), with no complete responses observed.

Adverse Events

The most common grade 3 or 4 adverse events with cetuximab/pemetrexed were fatigue (11% vs 8% with pemetrexed), acneiform rash (11% vs 0%), dyspnea (10% vs 12%), and decreased neutrophil count (10% vs 9%), and the most common with pemetrexed alone were dyspnea, decreased neutrophil count, and fatigue. Serious adverse events occurred in 41% vs 29% of patients (P = .0054). Treatment was discontinued due to adverse events in 13% vs 7%. Death due to adverse events occurred in 3.1% vs 1.7%.

The investigators concluded: “Our findings show that adding cetuximab to pemetrexed does not improve efficacy or safety outcomes in this unselected population of patients receiving second-line therapy for advanced NSCLC. There is no predictive association between EGFR status, as assessed by immunohistochemistry staining or histoscore, and survival for cetuximab. Further work is needed to better define biomarkers that can identify patients who could most benefit from anti-EGFR antibody treatment in lung cancer.”

The study was funded by Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.

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®.