Background: In a previous global phase III trial (LUX-Head & Neck 1), second-line (2L) afatinib significantly improved PFS vs methotrexate (MTX) in pts with R/M HNSCC. Here, we compared efficacy/safety of 2L afatinib vs MTX in Asian pts with R/M HNSCC. Methods: Pts progressing on/after platinum therapy were randomized (2:1) to 40 mg/day afatinib (feeding tube or oral) or 40 mg/m²/week iv MTX. Primary endpoint was PFS by independent review. Secondary endpoints were OS, ORR, and patient-reported outcomes. Results: 340 pts were randomized (afatinib 228, MTX 112). Median (range) duration of treatment (Tx) was 3.0 ( < 0.1–35.9) and 1.4 ( < 0.1–8.8) mos, respectively. Afatinib significantly decreased the risk of progression or death by 37% compared with MTX (HR 0.63; 95% CI: 0.48, 0.82 p = 0.0005, median PFS, 2.9 vs 2.6 mos; landmark analysis at 12 and 24 wks, 58 vs 41%, 21 vs 9%). There was no significant difference in OS (HR 0.88; 95% CI: 0.68, 1.13; median 6.9 vs 6.4 mos). ORR was 28% with afatinib and 13% with MTX (OR 2.8; 95% CI: 1.5, 5.2, p = 0.016). More pts had clinically relevant improvements in global health status/quality of life (GHS/QoL; 40 vs 23%, p < 0.01), swallowing (34 vs 18%, p = 0.01) and pain (34 vs 25%, p = 0.22) with afatinib vs MTX. Post-baseline change in GHS/QoL score was more favorable with afatinib (p < 0.001). Treatment-related adverse events (TRAEs; all/grade ≥3) were reported in 89/16% and 67/23% pts with afatinib and MTX. The most common grade ≥3 TRAEs were rash/acne (4%), diarrhea (4%), and stomatitis (3%) with afatinib, and anemia, leukopenia, and fatigue (all 5%) with MTX. Fatal AEs were reported in 23 and 11% pts with afatinib and MTX. Two ( hypoglycemia, pneumonitis/lung infiltration) and 4 pts had fatal AEs considered related to Tx with afatinib and MTX. 11% and 17% pts discontinued Tx due to TRAEs. Conclusions: LUX-Head & Neck 3 achieved its primary endpoint. Two randomized phase III trials have now demonstrated clinical benefit with 2L afatinib vs MTX. Safety data were consistent with the known tolerability profiles of afatinib and MTX. Clinical trial information: NCT01856478