The most frequent grade 3 or 4 drug-related adverse events were rash or acne ( 31 [ 10 % ] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group ) , diarrhoea ( 30 [ 9 % ] vs three [ 2 % ] ) , stomatitis ( 20 [ 6 % ] vs 13 [ 8 % ] ) , fatigue ( 18 [ 6 % ] vs five [ 3 % ] ) , and neutropenia ( 1 [ < 1 % ] vs 11 [ 7 % ] ) ; serious adverse events occurred in 44 ( 14 % ) of afatinib-treated patients and 18 ( 11 % ) of methotrexate-treated patients .