Addition of Necitumumab to First-Line Gemcitabine-Cisplatin Improves Overall Survival in Stage IV Squamous NSCLC
In the phase III SQUIRE trial reported in The Lancet Oncology, Thatcher et al found that the addition of the second-generation epidermal growth factor receptor (EGFR) antibody necitumumab to first-line gemcitabine-cisplatin improved overall survival among patients with stage IV squamous non–small cell lung cancer (NSCLC).
Study Details
In this open-label trial, 1,093 patients from 26 countries were randomly assigned between January 2010 and February 2012 to receive gemcitabine-cisplatin with (n = 545) or without (n = 548) necitumumab. Necitumumab 800 mg was given intravenously on days 1 and 8 of 3-week cycles and continued after the end of chemotherapy until disease progression or intolerable toxicity. Gemcitabine 1,250 mg/m² was given on days 1 and 8, and cisplatin 75 mg/m² was given on day 1 of 3-week cycles. Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status and geographic region. The primary endpoint was overall survival in an intent-to-treat analysis.
For the necitumumab and control groups, the median age was 62 years in both; 83% and 84% of patients were male; 84% and 83% were white; the geographic region was North America, Europe, or Australia for 87% in both South America, South Africa, or India for 6% in both, and Eastern Asia for 8% and 7%; Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 30% and 33%, 1 in 61% and 58%, and 2 in 9% in both; and 55% in both had metastatic disease involving more than two organ systems.
Increased Overall Survival
The median number of gemcitabine-cisplatin cycles was six in the necitumumab group and five in the control group. Median follow-up was 25.2 months in the necitumumab group and 24.8 months in the control group. Median overall survival was 11.5 months (95% confidence interval = 10.4–12.6 months) in the necitumumab group vs 9.9 months (95% CI = 8.9–11.1) in the control group (stratified hazard ratio [HR] = 0.84, P = .01).
Subgroup analyses showed benefit of necitumumab across most subgroups. EGFR protein expression level was available for 982 patients. The benefit of necitumumab appeared to be greater among 374 patients with high expression (H-score ≥ 200; HR = 0.75, 95% CI = 0.60–0.94) than among 608 with lower expression (HR = 0.90, 95% CI = 0.75–1.07). Subsequent systemic therapy was received by 47% vs 45% of patients.
Median progression-free survival was 5.7 months (95% CI = 5.6–6.0 months) vs 5.5 months (95% CI = 4.8–5.6 months; stratified HR = 0.85, P = .02). Objective response was observed in 31% vs 29% of patients, and disease control rates were 82% vs 77% (P = .043).
Adverse Events
Grade ≥ 3 adverse events were more common in the necitumumab group (72% vs 62%); those that were more common in the necitumumab group included hypomagnesemia (9% vs 1%) and rash (4% vs < 1%). Serious adverse events occurred in 48% vs 38%. Adverse events led to delay or modification of at least one study drug in 60% vs 58% and to discontinuation of at least one study drug in 31% vs 25%; neutropenia and thrombocytopenia were the most common causes of treatment discontinuation. Death considered related to treatment occurred in 3% vs 2% of patients.
The investigators concluded: “Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous NSCLC and represents a new first-line treatment option for this disease.”
Nick Thatcher, FRCP, of The Christie Hospital NHS Trust, Manchester, United Kingdom, is the corresponding author of The Lancet Oncology article.
The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit www.thelancet.com.
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