Observational registry of sorafenib use in clinical practice across. Child-Pugh subgroups: The GIDEON study

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1 Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study Jorge A. Marrero, Masatoshi Kudo, Alan P. Venook, Sheng-Long Ye, Jean-Pierre Bronowicki, Xiao-Ping Chen, Lucy Dagher, Junji Furuse, Jean-Francois H. Geschwind, Laura Ladrón de Guevara, Christos Papandreou, Tadatoshi Takayama, Arun J. Sanyal, Seung Kew Yoon, Keiko Nakajima, Robert Lehr, Stephanie Heldner, Riccardo Lencioni Table of contents Supplementary Table 1. Components of Child-Pugh score not assessed leading to patients being non-evaluable for Child-Pugh score Supplementary Table 2. Sorafenib administration by baseline bilirubin levels Supplementary Table 3. Disease characteristics by treatment duration beyond 28 weeks Supplementary Table 4. Sorafenib administration by BCLC Child-Pugh crossclassification Supplementary Table 5. Rate of most common adverse events across Child-Pugh subgroups Supplementary Table 6. Adverse events leading to permanent discontinuation in 2% of patients by Child-Pugh score Supplementary Table 7. Incidence of adverse events leading to permanent discontinuation in 2% of Child-Pugh B patients by treatment duration Supplementary Table 8. Overall safety profile of sorafenib by baseline bilirubin level

2 Supplementary Table 9. Cox regression analysis using single independent variables on overall survival Supplementary Fig. 1. Median overall survival by BCLC Child-Pugh crossclassification Supplementary Fig. 2. Median overall survival by individual components of Child- Pugh score: (A) albumin level; (B) ascites; (C) bilirubin level; (D) encephalopathy; (E) international normalized ratio

3 Supplementary Table 1. Components of Child-Pugh score not assessed leading to patients being non-evaluable for Child-Pugh score. Item of Child- Pugh score not reported a, n (%) Asia- Pacific (n = 928) Japan (n = 508) Europe (n = 1113) USA (n = 563) Latin America (n = 90) Total (N = 3202) International normalized ratio/prothrombin time 124 (13) 15 (3) 97 (9) 122 (22) 9 (10) 367 (11) Albumin 42 (5) 6 (1) 103 (9) 61 (11) 9 (10) 221 (7) Encephalopathy 37 (4) 1 (<1) 22 (2) 71 (13) (4) Bilirubin 34 (4) 4 (<1) 33 (3) 54 (10) 1 (1) 126 (4) Ascites 37 (4) 1 (<1) 11 (<1) 62 (11) (3) a Patients may have more than one missing item. 3

4 Supplementary Table 2. Sorafenib administration by baseline bilirubin levels. Bilirubin at baseline (mg/dl) a <2.0 (n = 2584) (n = 313) >3.0 (n = 177) Initial dose, n (%) 800 mg 1838 (71) 217 (69) 116 (66) 400 mg 651 (25) 84 (27) 45 (25) Median daily dose b, mg Dose reduction, n (%) 984 (38) 89 (28) 45 (25) Dose increase, n (%) 522 (20) 46 (15) 23 (13) Median treatment c duration, weeks a Recorded at study entry, which is defined as start of therapy and is indicated by the initial visit; b based on patients with available data (n = 2857); c based on patients with available data (n = 3130). 4

5 Supplementary Table 3. Disease characteristics by treatment duration beyond 28 weeks. n (%) Bilirubin (mg/dl) 28 weeks (n = 2259) >28 weeks (n = 943) < (79) 810 (86) (11) 62 (7) > (7) 25 (3) Albumin (g/l) > (50) 599 (64) (35) 227 (24) < (9) 42 (5) International normalized ratio (seconds) < (84) 791 (84) (3) 34 (4) > (1) 10 (1) Encephalopathy Absent 2114 (93) 891 (94) Moderate 42 (2) 20 (2) Severe 3 (<1) 0 Ascites Absent 1641 (73) 786 (83) Slight 379 (17) 100 (11) Moderate 162 (7) 21 (2) 5

6 n (%) BCLC Child-Pugh cross-classification a BCLC A / CP A (n = 158) BCLC B / CP A (n = 435) BCLC C / CP A (n = 1124) BCLC D / CP A (n = 60) BCLC A / CP B (n = 37) BCLC B / CP B (n = 136) BCLC C / CP B (n = 373) BCLC D / CP B (n = 30) AEs (all grades) Supplementary Table 4. Sorafenib administration by BCLC Child-Pugh crossclassification. Drugrelated AEs (all grades) Serious AEs b Drugrelated serious AEs All grade 3 or 4 AEs Drugrelated grade 3 or 4 AEs 126 (80) 372 (86) 949 (84) 47 (78) 29 (78) 116 (85) 338 (91) 26 (87) 105 (66) 319 (73) 765 (68) 33 (55) 24 (65) 86 (63) 241 (65) 17 (57) 39 (25) 135 (31) 441 (39) 23 (38) 19 (51) 84 (62) 224 (60) 16 (53) 10 (6) 44 (10) 105 (9) 4 (7) 6 (16) 23 (17) 53 (14) 4 (13) 60 (38) 161 (37) 340 (30) 16 (27) 15 (41) 49 (36) 106 (28) 7 (23) 48 (30) 131 (30) 260 (23) 16 (27) 9 (24) 33 (24) 81 (22) 4 (13) Deaths c 17 (11) 50 (11) 231 (21) 17 (28) 6 (16) 43 (32) 146 (39) 11 (37) a Recorded at study entry, which is defined as start of therapy and is indicated by the initial visit; b any AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; c treatment-emergent deaths occurring up to 30 days after last sorafenib dose. 6

7 Supplementary Table 5. Rate of most common adverse events across Child- Pugh subgroups. Events per patient-year Child-Pugh A (n = 1968) Child-Pugh B (n = 666) Child-Pugh C (n = 74) Any adverse event Diarrhea Hand-foot skin reaction Fatigue Anorexia Abdomen pain Liver dysfunction a Rash/desquamation Nausea a Liver dysfunction as an adverse event was based on physicians selection on case report forms. 7

8 Supplementary Table 6. Adverse events leading to permanent discontinuation in 2% of patients by Child-Pugh score. n (%) Child-Pugh score a A (<7) (n = 1968) B (7 9) b (n = 666) C (>9) (n = 74) AE Drugrelated AE AE Drugrelated AE AE Drugrelated AE AEs leading to permanent discontinuation (any) 568 (29) 339 (17) 267 (40) 141 (21) 32 (43) 11 (15) Diarrhea 51 (3) 46 (2) 26 (4) 25 (4) 2 (3) 2 (3) Hand-foot skin reaction 68 (4) 67 (3) 13 (2) 13 (2) 2 (3) 2 (3) Fatigue 63 (3) 46 (2) 31 (5) 31 (5) 1 (1) 1 (1) Abdominal pain 24 (1) 15 (<1) 12 (2) 12 (2) 2 (3) 1 (1) Liver dysfunction b 65 (3) 15 (<1) 42 (6) 42 (6) 5 (7) 0 a Recorded at study entry, which is defined as start of therapy and is indicated by the initial visit; b liver dysfunction as an adverse event was based on physicians selection on case report forms. 8

9 Supplementary Table 7. Incidence of adverse events leading to permanent discontinuation in 2% of Child-Pugh B patients by treatment duration. n (%) 0 4 weeks (n = 136) 4 24 weeks (n = 336) >24 28 weeks (n = 29) >28 weeks (n = 136) Liver dysfunction a 19 (14) 18 (5) 0 5 (4) Fatigue 12 (9) 17 (5) 1 (3) 3 (2) Diarrhea 10 (7) 13 (4) 2 (7) 1 (<1) Hyperbilirubinemia 9 (7) 7 (2) 0 1 (<1) Encephalopathy 6 (4) 5 (1) 2 (7) 5 (4) Nausea 6 (4) 6 (2) 0 0 Vomiting 5 (4) 6 (2) 0 1 (<1) Anorexia 5 (4) 5 (1) 0 0 Abdomen pain 5 (4) 6 (2) 0 1 (<1) Rash/desquamation 4 (3) 4 (1) 0 0 Ascites 4 (3) 5 (1) 0 0 Hand-foot skin reaction 3 (2) 9 (3) 0 1 (<1) Fever 3 (2) 1 (<1) 0 0 Hypertension 3 (2) a Liver dysfunction as an adverse event was based on physicians selection on case report forms. 9

10 Supplementary Table 8. Overall safety profile of sorafenib by baseline bilirubin level. n (%) Bilirubin at baseline (mg/dl) a <2.0 (n = 2584) (n = 313) >3.0 (n = 177) AEs (all grades) 2192 (85) 262 (84) 168 (95) Drug-related AEs (all grades) 1758 (68) 186 (59) 91 (51) Serious AEs b 1022 (40) 172 (55) 135 (76) Drug-related serious AEs 241 (9) 28 (9) 20 (11) All grade 3 or 4 AEs 842 (32) 85 (27) 47 (27) Drug-related grade 3 or 4 AEs 635 (25) 66 (21) 30 (17) AEs leading to permanent discontinuation (any) Drug-related AEs leading to permanent discontinuation (any) 786 (30) 102 (33) 81 (46) 453 (18) 51 (16) 29 (16) Deaths c 525 (20) 104 (33) 95 (54) a Recorded at study entry, which is defined as start of therapy and is indicated by the initial visit; b any AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; c treatment-emergent deaths occurring up to 30 days after last sorafenib dose. 10

11 Supplementary Table 9. Cox regression analysis using single independent variables on overall survival. Variable N Hazard ratio 95% confidence interval Bilirubin Albumin International normalized ratio Ascites Encephalopathy

12 Supplementary Fig. 1. Median overall survival by BCLC Child-Pugh crossclassification. NR, not reached. 12

13 Supplementary Fig. 2. Median overall survival by individual components of Child-Pugh score: (A) albumin level; (B) ascites; (C) bilirubin level; (D) encephalopathy; (E) international normalized ratio. Moderate encephalopathy refers to stage I or II; severe encephalopathy refers to stage III or IV. Patients with radiologically or clinically assessed ascites were included. INR, international normalized ratio. 13