The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction ( 22 [ 16 % ] of 136 patients in the regorafenib group vs none in the placebo group ) , hypertension ( 15 [ 11 % ] vs two [ 3 % ] of 68 patients in the placebo group ) , hyperbilirubinaemia ( nine [ 7 % ] vs one [ 1 % ] ) , hypophosphataemia ( nine [ 7 % ] vs none ) , alanine aminotransferase concentration increases ( nine [ 7 % ] vs none ) , aspartate aminotransferase concentration increases ( eight [ 6 % ] vs none ) , lipase concentration increases ( six [ 4 % ] vs one [ 1 % ] ) , and maculopapular rash ( six [ 4 % ] vs none ) .