• In the Phase III (n = 1,093) SQUIRE trial of necitumumab/cis/gemcitabine (gem) versus cis/gem as first-line treatment for Stage IV squamous NSCLC, a significant improvement in OS was observed on the necitumumab arm (11.5 versus 9.9 months), although the rate of Grade ≥3 adverse events (hypomagnesemia, venous thromboembolic events, rash) was also higher.
• The Phase III (n = 633) INSPIRE trial comparing necitumumab/cis/pem to cis/pem as first-line treatment for Stage IV nonsquamous NSCLC demonstrated no improvement in OS with the addition of necitumumab with an increase in Grade ≥3 adverse events.

The integration of EGFR antibodies has a checkered history in NSCLC research. A prior study of cetuximab (FLEX) demonstrated a modest improvement in OS, but that agent was not subsequently approved for use. More recently, 2 large Phase III trials evaluated the addition of another EGFR antibody, necitumumab, to up-front induction chemotherapy for metastatic disease. In the INSPIRE trial in nonsquamous disease this agent was added to cis/pem with no benefit, but the similarly designed SQUIRE trial, which used the same chemotherapy backbone in squamous NSCLC, did demonstrate a modest but statistically significant benefit in OS but not response rate. EGFR expression did not correlate with benefit. Necitumumab is currently under FDA review, and even if approved, it is not clear to what extent this therapy will be incorporated into clinical practice.