NO EFFECT OF NECITUMUMAB IN NSCLC

In the phase III INSPIRE trial reported in The Lancet Oncology, Paz-Ares et al found that the addition of the anti-EGFR IgG1 monoclonal antibody necitumumab to first-line pemetrexed (Alimta)-cisplatin did not improve overall survival in patients with previously untreated stage IV nonsquamous non–small cell lung cancer (NSCLC). Enrollment was stopped due to excess fatal and nonfatal thromboembolic events in the necitumumab group.

Study Details

In this open-label trial, 633 patients from 103 sites in 20 countries were randomly assigned between November 2009 and February 2011 to receive cisplatin at 75 mg/m² and pemetrexed at 500 mg/m² on day 1 of 3-week cycles for a maximum of six cycles with (n = 315) or without (n = 318) necitumumab at 800 mg on days 1 and 8 of each cycle. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxicity. The primary endpoint was overall survival in the intention-to-treat population.

Enrollment was stopped in February 2011 based on the observation of excess fatal and nonfatal thromboembolic events and overall number of deaths from all causes in the experimental group. Analysis indicated that most fatal thromboembolic events occurred within the first two cycles of therapy, with necitumumab thus being discontinued in patients who had not completed two cycles.

No Survival Benefit

Median duration of follow-up was 24.5 months in the necitumumab group and 25.6 months in the control group. Median overall survival was 11.3 months (95% confidence interval [CI] = 9.5–13.4 months) vs 11.5 months (95% CI = 10.1–13.1 months; hazard ratio [HR] = 1.01, P = .96). There was no difference between groups in median progression-free survival (5.6 vs 5.6 months; HR = 0.96, P = .66) or objective response rate (31% vs 32%; stable disease in 42% in both). Analysis by EGFR expression level showed no differences between treatments in overall or progression-free survival among patients with high EGFR H score or low EGFR H score.

Subsequent treatment was generally balanced between groups, with docetaxel and erlotinib being the most frequently used agents in both.

Toxicity

Grade ≥ 3 adverse events occurred in 72% of the necitumumab group vs 59% of the control group. Death considered related to study drug occurred in 5% vs 3%. Grade 3 or 4 rash (15% vs < 1%), hypomagnesemia (8% vs 2%), and venous thromboembolic events (8% vs 4%) were more common in the necitumumab group. Serious adverse events occurred in 51% vs 41% of the necitumumab vs control groups, respectively.

The investigators concluded: “Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.”

Luis Paz-Ares, MD, of Hospital Universitario Doce de Octubre, Seville, is the corresponding author for The Lancet Oncology article.

The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit www.thelancet.com.