•Necitumumab plus gemcitabine and cisplatin significantly improved overall survival.•Improved progression-free survival and objective response rate were also observed.•Quality of life was not negatively impacted by the addition of necitumumab.•Necitumumab plus gemcitabine and cisplatin was well tolerated by patients in Japan. This open-label, multicenter, phase 1b/2 study assessed necitumumab plus gemcitabine and cisplatin (GC + N) in patients with previously untreated squamous non-small cell lung cancer in Japan. The phase 1b part determined the gemcitabine dose for the phase 2 part, in which patients were randomized 1:1 to GC + N or gemcitabine and cisplatin (GC) (gemcitabine 1250 mg/m2 on days 1 and 8; cisplatin 75 mg/m2 on day 1 of maximum four 3-week cycles; nectimumab 800 mg on days 1 and 8 of a 3-week cycle continued until progressive disease or unacceptable toxicity). The primary endpoint of the phase 2 part was overall survival. In the phase 2 part, 181 patients received GC + N (N = 90) or GC (N = 91). Overall survival was significantly improved with GC + N versus GC (median, 14.9 months vs 10.8 months; hazard ratio HR = 0.66, 95% CI: 0.47 – 0.93, p = 0.0161). Improvements were also observed in progression-free survival (median, 4.2 months vs 4.0 months; HR = 0.56; p = 0.0004) and objective response rate (51% vs 21%; p < 0.0001). Survival was also significantly prolonged with GC + N versus GC for patients with epidermal growth factor receptor-positive tumors. Grade ≥3 treatment-emergent adverse events at ≥5% higher incidence with GC + N than GC were neutrophil count decreased (42% vs 35%), febrile neutropenia (12% vs 3%), decreased appetite (11% vs 4%), and dermatitis acneiform (6% vs 0%). GC + N is well tolerated and has significant and clinically meaningful treatment benefit in the first-line treatment of patients with squamous non-small cell lung cancer in Japan. Clinicaltrials.gov identifier: NCT01763788.