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1 Supplementary Online Content Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. doi: /jama emethods. Hepatitis etable 1. Guidelines for Treatment and Monitoring Based on Results of Hepatitis B Screening at Baseline etable 2. Time to Definitive Deterioration of EORTC QLQ-C30 Scores in the Full Analysis Set etable 3. Clinically Notable Adverse Events of Any Cause in the Safety Population This supplementary material has been provided by the authors to give readers additional information about their work.

2 emethods. Hepatitis Hepatitis Screening at Baseline At baseline, all patients were screened for the presence of hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B surface antibody (HBsAb), and hepatitis C virus (HCV) RNA. All screening was performed at a central laboratory. Antiviral prophylaxis was provided to at-risk patients as outlined in etable 1. Definitions of HBV Reactivation and HCV Flare In patients who were HBV-DNA-positive or HBsAg-positive at baseline, HBV reactivation was defined as an increase of 1 log in HBV-DNA relative to baseline or new appearance of measurable HBV-DNA. In patients who were HBV-DNA-, HBsAg-, and HBsAB-positive with no history of HBV vaccination, or HBcAb-positive, reactivation was defined as the new appearance of measurable HBV- DNA. New appearance of measurable HBV-DNA was defined as an HBV-DNA level greater than the lower limit of quantification (ie, 29 U/mL). For patients with detectable HCV-RNA at baseline, HCV flare was defined as >2 log IU/mL increase in HCV-RNA and ALT elevation >5 ULN or 3 baseline level, whichever was higher. Among patients with known HCV history with no detectable HCV-RNA at baseline, HCV flare was defined as new appearance of detectable HCV-RNA and ALT elevation >5 ULN or 3 baseline level, whichever was higher. All assessments were performed at a central laboratory.

3 etable 1. Guidelines for Treatment and Monitoring Based on Results of Hepatitis B Screening at Baseline Test Result Result Result Result Result HBV-DNA Positive Negative Negative Negative HBsAg Positive Negative Negative Negative HBsAb HBcAb Recommendation Prophylactic antiviral treatment initiated 1-2 weeks before the first dose of study drug and continued during treatment and for 4 weeks after treatment discontinuation HBV DNA monitored every 6 weeks from visit 2 onward Positive and no prior HBV vaccination Positive No prophylactic antiviral therapy HBV DNA monitored every 3 weeks from visit 2 onward Negative or positive with prior HBV vaccination Negative No specific action taken DNA, deoxyribonucleic acid; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B serum antibody; HBsAg, hepatitis B serum antigen; HBV, hepatitis B virus.

4 etable 2. Time to Definitive Deterioration of EORTC QLQ-C30 Scores in the Full Analysis Set Everolimus + Best (N=362) Placebo + Best (N=184) Definitive deterioration in the global QoL score by 5% compared with baseline Hazard Ratio (95% CI) P Value Median time to event, months (95% CI) 2.9 ( ) 3.5 ( ) 1.09 ( ).4712 Definitive deterioration in the physical functioning score by 5% compared with baseline Median time to event, months (95% CI) 2.7 ( ) 3.5 ( ) 1.37 ( ).0101 CI, confidence interval; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer 30-item Quality of Life Questionnaire; QoL, quality of life.

5 etable 3. Clinically Notable Adverse Events of Any Cause in the Safety Population Grouping Everolimus + Best (N=361) Placebo + Best (N=182) Any clinically notable adverse event 317 (87.8) 108 (59.3) Stomatitis/related events 166 (46.0) 11 (6.0) Infections and infestations 155 (42.9) 34 (18.7) Hemorrhages 113 (31.3) 31 (17.0) Rash and similar events 93 (25.8) 19 (10.4) Cytopenia 86 (23.8) 7 (3.8) Hepatic impairment 67 (18.6) 36 (19.8) Renal events 37 (10.2) 9 (4.9) Hyperglycemia/new onset of diabetes mellitus 32 (8.9) 13 (7.1) Preexisting infection 25 (6.9) 8 (4.4) Noninfectious pneumonitis 24 (6.6) 3 (1.6) Thromboembolic events 13 (3.6) 10 (5.5) Muscle waste/muscle loss 8 (2.2) 0 Hypersensitivity reactions (anaphylactic reaction) 7 (1.9) 1 (0.5) Intestinal obstruction/ileus 6 (1.7) 3 (1.6) Cholelithiasis 2 (0.6) 0 Pancreatitis 1 (0.3) 0 Clinically notable adverse events (AEs) consist of groupings of AEs for which there is a specific clinical interest as a result of their observation in earlier studies of everolimus or those AEs that are similar in nature.