<p> Supplemental Digital Content 2 Table S1: Specific adverse event rates (95% CI; 95% PI) by first-line therapy. Adverse event Gefitinib Erlotinib Afatinib Chemotherapy Diarrhea 0.46 (95% CI 0.4-0.52; 95% PI 0.35-0.57) 0.4 (95% CI 0.21-0.64; 95% PI 0.12-0.77) 0.95 (95% CI 0.92-0.97)b 0.17 (95% CI 0.1-0.27; 95% PI 0.04-0.51) Grade ≥ 3 0.03 (95% CI 0.02-0.04; 95% PI 0.02-0.05) 0.03 (95% CI 0.01-0.07; 95% PI 0.01-0.07) 0.09 (95% CI 0.04-0.18; 95% PI 0.03-0.25) 0.01 (95% CI 0-0.01; 95% PI 0-0.03) Rash or acne 0.73 (95% CI 0.66-0.79; 95% PI 0.58-0.84) 0.77 (95% CI 0.7-0.82; 95% PI 0.7-0.82) 0.89 (95% CI 0.84-0.92)b 0.13 (95% CI 0.08-0.19; 95% PI 0.04-0.33) Grade ≥ 3 0.06 (95% CI 0.02-0.18; 95% PI 0.01-0.44) 0.06 (95% CI 0.02-0.19; 95% PI 0.01-0.31) 0.15 (95% CI 0.12-0.19; 95% PI 0.12-0.19) 0.01 (95% CI 0.01-0.02; 95% PI 0.01-0.02) Stomatitus or mucositis 0.2 (95% CI 0.12-0.33; 95% PI 0.06-0.51) 0.13 (95% CI 0.08-0.22)b 0.72 (95% CI 0.66-0.77)b 0.1 (95% CI 0.04-0.23; 95% PI 0.01-0.57) Grade ≥ 3 0 (95% CI 0-0.02; 95% PI 0-0.04) 0.01 (95% CI 0-0.07)b 0.07 (95% CI 0.05-0.1; 95% PI 0.05-0.1) 0 (95% CI 0-0.01; 95% PI 0-0.01) Paronychia 0.17 (95% CI 0.09-0.29; 95% PI 0.05-0.43) 0.04 (95% CI 0.01-0.1)b 0.57 (95% CI 0.5-0.63)b 0 (95% CI 0-0.01; 95% PI 0-0.04) Grade ≥ 3 0.01 (95% CI 0-0.03; 95% PI 0-0.05) 0 (95% CI 0-0.04)b 0.11 (95% CI 0.08-0.16)b 0 (95% CI 0-0)a ALT elevation 0.5 (95% CI 0.23-0.76; 95% PI 0.12-0.88) 0.37 (95% CI 0.28-0.48)b 0.29 (95% CI 0.19-0.42; 95% PI 0.12-0.53) Grade ≥ 3 0.13 (95% CI 0.04-0.36; 95% PI 0.02-0.57) 0.04 (95% CI 0.01-0.1)b 0.01 (95% CI 0-0.03; 95% PI 0-0.03) AST elevation 0.5 (95% CI 0.23-0.76; 95% PI 0.12-0.88) 0.16 (95% CI 0.11-0.21; 95% PI 0.11-0.21) Grade ≥ 3 0.13 (95% CI 0.09-0.18; 95% PI 0.09-0.18) 0.02 (95% CI 0.01-0.04; 95% PI 0.01-0.04) Dry skin 0.42 (95% CI 0.26-0.59; 95% PI 0.16-0.73) 0.29 (95% CI 0.24-0.35)b 0.02 (95% CI 0.02-0.04; 95% PI 0.02-0.04) Grade ≥ 3 0 (95% CI 0-0)a 0 (95% CI 0-0.02)b 0 (95% CI 0-0)a Pruritus 0.33 (95% CI 0.15-0.56; 95% PI 0.08-0.72) 0.19 (95% CI 0.14-0.24)b 0.07 (95% CI 0.02-0.2; 95% PI 0.01-0.43) Grade ≥ 3 0.01 (95% CI 0-0.01; 95% PI 0-0.01) 0 (95% CI 0-0.02)b 0 (95% CI 0-0.01; 95% PI 0-0.01) Anorexia or appetite loss 0.26 (95% CI 0.14-0.41; 95% PI 0.08-0.58) 0.31 (95% CI 0.22-0.41)b 0.21 (95% CI 0.16-0.26)b 0.58 (95% CI 0.37-0.76; 95% PI 0.15-0.91) Grade ≥ 3 0.05 (95% CI 0.02-0.13; 95% PI 0.01-0.31) 0 (95% CI 0-0.04)b 0.03 (95% CI 0.01-0.06)b 0.06 (95% CI 0.02-0.22; 95% PI 0-0.67) Anemia 0.24 (95% CI 0.16-0.35; 95% PI 0.12-0.44) 0.08 (95% CI 0.04-0.15; 95% PI 0.04-0.17) 0.03 (95% CI 0.01-0.06)b 0.62 (95% CI 0.44-0.78; 95% PI 0.19-0.92) Grade ≥ 3 0.02 (95% CI 0.01-0.03; 95% PI 0.01-0.03) 0.01 (95% CI 0-0.04; 95% PI 0-0.04) 0 (95% CI 0-0.02)b 0.09 (95% CI 0.07-0.13; 95% PI 0.04-0.19) Asthenic conditions or 0.22 (95% CI 0.13-0.34; 95% PI 0.07-0.51) 0.21 (95% CI 0.03-0.73; 95% PI 0-0.93) 0.17 (95% CI 0.13-0.23)b 0.53 (95% CI 0.36-0.7; 95% PI 0.14-0.89) fatigue Grade ≥ 3 0.02 (95% CI 0.01-0.07; 95% PI 0-0.24) 0.01 (95% CI 0-0.14; 95% PI 0-0.39) 0.01 (95% CI 0-0.04)b 0.05 (95% CI 0.02-0.16; 95% PI 0-0.62) Nausea 0.19 (95% CI 0.15-0.23; 95% PI 0.14-0.25) 0.18 (95% CI 0.13-0.23)b 0.76 (95% CI 0.52-0.91; 95% PI 0.23-0.97) Grade ≥ 3 0 (95% CI 0-0.01; 95% PI 0-0.01) 0.01 (95% CI 0-0.03)b 0.02 (95% CI 0.01-0.03; 95% PI 0.01-0.03) Infection 0.03 (95% CI 0.01-0.07)b 0.17 (95% CI 0.1-0.26)b 0.07 (95% CI 0.04-0.12; 95% PI 0.04-0.12) Grade ≥ 3 0.02 (95% CI 0-0.06)b 0.01 (95% CI 0-0.07)b 0.02 (95% CI 0.01-0.06; 95% PI 0-0.08) Vomiting 0.12 (95% CI 0.08-0.19; 95% PI 0.05-0.25) 0.17 (95% CI 0.13-0.22)b 0.41 (95% CI 0.2-0.65; 95% PI 0.07-0.86) Grade ≥ 3 0 (95% CI 0-0.01; 95% PI 0-0.01) 0.03 (95% CI 0.01-0.06)b 0.04 (95% CI 0.02-0.09; 95% PI 0.01-0.24) Alopecia 0.1 (95% CI 0.08-0.12; 95% PI 0.08-0.12) 0.14 (95% CI 0.08-0.23)b 0.57 (95% CI 0.36-0.76; 95% PI 0.15-0.91) Grade ≥ 3 0 (95% CI 0-0)a 0 (95% CI 0-0.04)b 0 (95% CI 0-0.21; 95% PI 0-0.98) Constipation 0.13 (95% CI 0.09-0.18; 95% PI 0.07-0.24) 0 (95% CI 0-0.04)b 0.03 (95% CI 0.01-0.06)b 0.3 (95% CI 0.19-0.45; 95% PI 0.08-0.68) Grade ≥ 3 0 (95% CI 0-0)a 0 (95% CI 0-0.04)b 0 (95% CI 0-0.02)b 0 (95% CI 0-0.01; 95% PI 0-0.01) Epistaxis 0.13 (95% CI 0.09-0.18)b 0.01 (95% CI 0-0.05)b Grade ≥ 3 0 (95% CI 0-0.02)b 0.01 (95% CI 0-0.05)b Cheilitis 0.12 (95% CI 0.09-0.17)b 0.01 (95% CI 0-0.05)b Grade ≥ 3 0 (95% CI 0-0.02)b 0 (95% CI 0-0.03)b Leukopenia 0.12 (95% CI 0.09-0.16; 95% PI 0.09-0.16) 0.02 (95% CI 0.01-0.04)b 0.61 (95% CI 0.25-0.88; 95% PI 0.05-0.98) Grade ≥ 3 0.01 (95% CI 0.01-0.02; 95% PI 0.01-0.02) 0 (95% CI 0-0.02)b 0.2 (95% CI 0.11-0.34; 95% PI 0.04-0.61) Arthralgia 0.06 (95% CI 0.04-0.08; 95% PI 0.04-0.08) 0.11 (95% CI 0.06-0.19)b 0.2 (95% CI 0.07-0.46; 95% PI 0.02-0.73) Grade ≥ 3 0 (95% CI 0-0.01; 95% PI 0-0.01) 0.01 (95% CI 0-0.06)b 0.02 (95% CI 0.01-0.06; 95% PI 0-0.14) Neurotoxic effects 0.06 (95% CI 0.03-0.11; 95% PI 0.01-0.21) 0.1 (95% CI 0.05-0.18)b 0.41 (95% CI 0.24-0.61; 95% PI 0.09-0.83) Grade ≥ 3 0 (95% CI 0-0.01; 95% PI 0-0.01) 0.01 (95% CI 0-0.06)b 0.04 (95% CI 0.02-0.06; 95% PI 0.02-0.07) Bilirubin elevation 0.09 (95% CI 0.05-0.15)b 0.16 (95% CI 0.1-0.24)b Grade ≥ 3 0 (95% CI 0-0.03)b 0.01 (95% CI 0-0.05)b Thrombocytopenia 0.08 (95% CI 0.06-0.12; 95% PI 0.05-0.14) 0.02 (95% CI 0.01-0.06; 95% PI 0.01-0.06) 0.33 (95% CI 0.21-0.48; 95% PI 0.1-0.68) Grade ≥ 3 0.01 (95% CI 0-0.02; 95% PI 0-0.02) 0 (95% CI 0-0.02)a 0.07 (95% CI 0.02-0.19; 95% PI 0-0.58) Neutropenia 0.08 (95% CI 0.06-0.11; 95% PI 0.06-0.11) 0.01 (95% CI 0-0.15; 95% PI 0-0.4) 0.01 (95% CI 0-0.03)b 0.67 (95% CI 0.46-0.82; 95% PI 0.19-0.95) Grade ≥ 3 0.02 (95% CI 0.01-0.04; 95% PI 0.01-0.06) 0 (95% CI 0-0.02)a 0 (95% CI 0-0.02)b 0.45 (95% CI 0.28-0.64; 95% PI 0.08-0.89) Myalgia 0.08 (95% CI 0.06-0.1)b 0.32 (95% CI 0.28-0.35)b Grade ≥ 3 0 (95% CI 0-0.01)b 0.02 (95% CI 0.01-0.03)b Potassium elevation 0.06 (95% CI 0.03-0.12)b 0.1 (95% CI 0.06-0.17)b Grade ≥ 3 0 (95% CI 0-0.03)b 0 (95% CI 0-0.03)b Sodium elevation 0.04 (95% CI 0.02-0.1)b 0.15 (95% CI 0.1-0.23)b Grade ≥ 3 0 (95% CI 0-0.03)b 0.02 (95% CI 0-0.06)b Creatinine elevation 0.01 (95% CI 0.01-0.04; 95% PI 0.01-0.04) 0.2 (95% CI 0.09-0.37; 95% PI 0.06-0.52) Grade ≥ 3 0 (95% CI 0-0.01)a 0 (95% CI 0-0.01)a Any grade ≥ 3 0.32 (95% CI 0.26-0.37; 95% PI 0.23-0.41) 0.29 (95% CI 0.13-0.53; 95% PI 0.08-0.68) 0.42 (95% CI 0.34-0.51; 95% PI 0.29-0.57) 0.63 (95% CI 0.58-0.68; 95% PI 0.51-0.74) AE leading to 0.07 (95% CI 0.05-0.09)b 0.05 (95% CI 0.01-0.22; 95% PI 0-0.44) 0.07 (95% CI 0.05-0.09; 95% PI 0.05-0.09) 0.16 (95% CI 0.09-0.28; 95% PI 0.04-0.5) discontinuation of drug Dose modification due to 0.16 (95% CI 0.13-0.19)b 0.12 (95% CI 0.05-0.27; 95% PI 0.03-0.41) 0.38 (95% CI 0.28-0.49; 95% PI 0.21-0.58) toxic effects AE leading to death 0.03 (95% CI 0.01-0.05; 95% PI 0.01-0.06) 0.01 (95% CI 0-0.04; 95% PI 0-0.04) 0.02 (95% CI 0.01-0.04)b 0.01 (95% CI 0-0.02; 95% PI 0-0.06) SAE 0.05 (95% CI 0.01-0.29; 95% PI 0-0.6) 0.21 (95% CI 0.1-0.38; 95% PI 0.06-0.51) 0.09 (95% CI 0.02-0.33; 95% PI 0-0.76) SAE leading to 0.05 (95% CI 0.01-0.24; 95% PI 0-0.51) 0.01 (95% CI 0-0.37; 95% PI 0-0.86) hospitalization Interstitial lung disease 0.03 (95% CI 0.02-0.04; 95% PI 0.02-0.04) 0.01 (95% CI 0-0.04; 95% PI 0-0.04) 0 (95% CI 0-0.01; 95% PI 0-0.03) Interstitial lung disease 0.01 (95% CI 0-0.02; 95% PI 0-0.02) 0 (95% CI 0-0.04)b 0.01 (95% CI 0-0.04)b 0 (95% CI 0-0.01; 95% PI 0-0.01) leading to death a Meta-estimate for adverse event rate where no events were observed calculated assuming no study effect. b Meta-estimate represents results of a single study.</p>