[T]he addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease.
—Nick Thatcher, PhD, FRCP, and colleagues
In the phase III SQUIRE trial reported in The Lancet Oncology, Nick Thatcher, PhD, FRCP, of The Christie Hospital NHS Trust, Manchester, UK, and colleagues 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).1
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 intravenously) was given 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.
The necitumumab and control groups were generally balanced for age (median, 62 years in both; 19% and 20% 65–69 years, 20% and 18% ≥ 70 years), sex (83% and 84%), ECOG performance status (0 for 30% and 33%, 1 for 61% and 58%, 2 for 9% in both), race/ethnicity (84% and 83% white, 8% Asian in both), geographic region (North America, Europe, or Australia for 87% in both, South America, South Africa, or India for 6% in both, Eastern Asia for 8% and 7%), smoking history (92% and 90% current smokers), metastatic disease involving more than two organ systems (55% in both), metastatic disease sites (eg, lung in 83% in both, lymph nodes in 79% and 82%, bone in 22% and 24%), and previous therapies (surgery in 21% and 19%, radiotherapy in 8% in both, adjuvant/neoadjuvant systemic therapy in 4% and 3%).
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 [CI] = 10.4–12.6 months) in the necitumumab group vs 9.9 months (95% CI = 8.9–11.1 months) in the control group (stratified hazard ratio [HR] = 0.84, P = .01). Subgroup analyses showed a benefit of necitumumab in most examined subgroups, with hazard ratios being significant in patients aged 65 to 69 years, men, white patients, and current smokers.
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 patients with lower expression (HR = 0.90, 95% CI = 0.75–1.07).
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), with a benefit of necitumumab being observed in nearly all subgroups. The benefit of necitumumab did not appear to be greater among patients with high EGFR protein expression (HR = 0.88, 95% CI = 0.70–1.11) than among those with low expression (HR = 0.83, 95% CI = 0.69–0.99). Objective response was observed in 31% vs 29% of patients, and disease control rates were 82% vs 77% (P = .043).
Poststudy systemic therapy was received by 47% of the necitumumab group and 45% of the control group, with the most common being docetaxel (31% and 23%) and erlotinib (10% and 14%).
Grade ≥ 3 adverse events were more common in the necitumumab group (72% vs 62%). Among adverse events of interest of grade ≥ 3, the most common were neutropenia (24% vs 28%), anemia (10% vs 10%), thrombocytopenia (10% vs 10%), hypomagnesemia (9% vs 1%), and rash (7% vs < 1%). Venous thromboembolism occurred in 9% vs 5% (grade ≥ 3 in 5% vs 3%). Fatal arterial or venous thromboembolic events occurred in < 1% of both groups.
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% (due to neutropenia, thrombocytopenia, anemia, or leukopenia in 40% and 42%) and to discontinuation of at least one study drug in 31% vs 25% (most commonly due to neutropenia and thrombocytopenia). 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 non-small-cell lung cancer and represents a new first-line treatment option for this disease.” ■
Disclosure: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit www.thelancet.com.
1. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol 16:763-774, 2015.