Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma

The study population includes patients 18 years of age or older with advanced HCC, Barcelona Clinic Liver Cancer stage B not eligible for locoregional therapy or stage C, and Child-Pugh A classification liver disease. Patients must not have received any prior systemic therapy for unresectable HCC.

Patients in all treatment arms may continue receiving their originally assigned treatment, at the Investigator's discretion, until progression

Patients in all arms with confirmed PD who, in the Investigator's opinion, continue to receive benefit from their assigned treatment and meet the criteria for treatment in the setting of PD may continue to receive their assigned treatment.

If a patient discontinues study drug(s) due to disease progression, the patient will enter survival follow-up. Patients who have discontinued treatment due to toxicity or symptomatic deterioration or who have commenced subsequent anticancer therapy, will have tumor assessments until confirmed PD and will be followed for survival

• Durvalumab (Drug), also known as MEDI4736: Durvalumab IV (intravenous infusion).
• Tremelimumab (Regimen 1) (Drug): Tremelimumab IV (intravenous infusion).
• Tremelimumab (Regimen 2) (Drug): Tremelimumab IV (intravenous infusion).
• Sorafenib (Drug): Sorafenib, as per standard of care
• Durvalumab (Regimen 1) (Drug): Durvalumab IV (intravenous infusion).
• Durvalumab (Regimen 2) (Drug): Durvalumab IV (intravenous infusion).

Primary outcomes

• Overall Survival (OS) - Treme 300 mg x1 Dose + Durva 1500 mg vs Sora 400 mg [From the date of randomization until death due to any cause, assessed up to the data cut-off date (27Aug2021, to a maximum of approximately 46 months).]: OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This primary outcome measure presents OS analysis of Treme 300mg x1 dose + Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).

Secondary outcomes

• Overall Survival (OS) - Durva 1500 mg vs Sora 400 mg [From the date of randomization until death due to any cause, assessed up to the data cut-off date (27Aug2021, to a maximum of approximately 46 months).]: OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This secondary outcome measure presents OS analysis of Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).
• Overall Survival (OS) at 18, 24, and 36 Months After Randomization [At 18, 24, and 36 months post-randomization. Assessed at the final analysis DCO (27Aug2021).]: Percentage of participants who were alive at fixed time points (18, 24, and 36 months) after randomization. The estimated percentage of survival along with the 95% confidence interval were calculated using Kaplan-Meier technique on the full analysis set.
• Progression Free Survival (PFS) [Tumor scans performed at baseline, every 8 weeks for the first 48 weeks following randomization, and every 12 weeks thereafter until RECIST 1.1-defined progression. Assessed up to DCO (27Aug2021, to a maximum of approximately 46 months)]: PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 \[RECIST 1.1\] using Investigator assessments) was defined as the time from the date of randomization until the date of objective disease progression or death by any cause in the absence of progression, regardless of whether the patient withdrew from study treatment or received another anticancer therapy prior to progression. Progression (i.e., PD) was defined as a at least 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir.
• Time To Progression (TTP) [From the date of randomization until objective tumor progression, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).]: TTP was defined as the time from randomization until objective tumor progression in the absence of death. If participants died without tumor progression, they were censored at the time of death.
• Objective Response Rate (ORR) [From the date of randomization until objective tumor progression, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).]: ORR (per RECIST 1.1 as assessed by the Investigator) was defined as the number (%) of participants with at least 1 confirmed visit response of CR or PR until progression, or the last evaluable assessment in the absence of progression. Participants who go off treatment without progression, receive a subsequent therapy, and then respond will not be included as responders in the ORR. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters.
• Disease Control Rate (DCR) [From the date of randomization until objective tumor progression or date of death, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).]: Number (%) of participants with a Best Objective Response (BoR) of CR, PR, or SD. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters. Stable disease (ie., SD) was defined as neither sufficient decrease in sum of diameters to qualify for PR nor sufficient increase to qualify for progression.
• Duration of Objective Response (DoR) [From the date of first documented response until the first date of documented progression or death, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).]: Time from the date of first documented confirmed response (complete or partial response) until the first date of documented progression or death in the absence of disease progression. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters.
• Overall Survival (OS) by PD-L1 [From the date of randomization until death due to any cause, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).]: Overall survival by baseline PD-L1 expression levels (positive vs. negative). PD-L1 expression level is based on the Tumor and Immune Cell Positivity (TIP) score method as: PD-L1 Positive (TIP ≥ 1%) or PD-L1 Negative (TIP < 1%).
• EORTC QLQ-C30 Time to Global Health Status/QoL Deterioration [At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.]: European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQ-C30), which consists of 30 questions combined to produce a global health status/QoL scale. Higher scores indicate better health. A clinically meaningful deterioration is defined as a decrease in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
• EORTC QLQ-HCC18 Time to Symptom (Abdominal Pain) Deterioration [At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.]: EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
• EORTC QLQ-HCC18 Time to Symptom (Shoulder Pain) Deterioration [At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.]: EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
• EORTC QLQ-HCC18 Time to Symptom (Abdominal Swelling) Deterioration [At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months.]: EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
• Presence of ADA for Durvalumab [Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of durvalumab. Assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).]: Number of participants with Anti-Drug Antibody (ADA) response to Durvalumab. ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA. Results are reported as number of participants with ADA responses to Durvalumab for each indicated category.
• Presence of ADA for Tremelimumab [Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of tremelimumab. Assessed up to approximately 46 months after the first randomization.]: Number of participants with Anti-Drug Antibody (ADA) response to Tremelimumab. ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA. Results are reported as number of participants with ADA responses to Tremelimumab for each indicated category.
• Summary of Durvalumab Concentration Over Time [To evaluate the PK of Durvalumab, samples were collected pre-dose at week 4 and week 12 and post-dose at week 12. Assessed at the final analysis DCO (27Aug2021).]: Blood sample were collected at pre-specified timepoints and Durvalumab concentrations in serum (ug/mL) were reported over time.
• Summary of Tremelimumab Concentration Over Time [To evaluate the PK of Tremelimumab, samples were collected at week 0 (post-dose), week 4, and week 12. Assessed at the final analysis DCO (27Aug2021).]: Blood sample were collected at pre-specified timepoints and Tremelimumab concentrations in serum (ug/mL) were reported over time.

Sex: All, ages: 18 Years to 100 Years

Inclusion criteria

* HCC based on histopathological confirmation
* No prior systemic therapy for HCC
* Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C
* Child-Pugh Score class A
* ECOG performance status of 0 or 1 at enrollment

Exclusion criteria

* Hepatic encephalopathy within past 12 months or requirement for medication to prevent or control encephalopathy
* Clinically meaningful ascites
* Main portal vein tumor thrombosis
* Active or prior documented GI bleeding (eg, esophageal varices or ulcer bleeding) within 12 months
* HBV and HVC co-infection, or HBV and Hep D co-infection

Participant flow

Outcome results

• Overall Survival (OS) - Treme 300 mg x1 Dose + Durva 1500 mg vs Sora 400 mg (Primary), Median, months: Durva 1500 mg 16.56 (14.06 to 19.12); Treme 300 mg x1 Dose + Durva 1500 mg 16.43 (14.16 to 19.58); Treme 75 mg x4 Doses + Durva 1500 mg 16.36 (12.39 to 19.65); Sora 400 mg 13.77 (12.25 to 16.13) (p 0.0035)
• Overall Survival (OS) - Durva 1500 mg vs Sora 400 mg (Secondary), Median, months: Durva 1500 mg 16.56 (14.06 to 19.12); Treme 300 mg x1 Dose + Durva 1500 mg 16.43 (14.16 to 19.58); Treme 75 mg x4 Doses + Durva 1500 mg 16.36 (12.39 to 19.65); Sora 400 mg 13.77 (12.25 to 16.13)
• Overall Survival (OS) at 18, 24, and 36 Months After Randomization (Secondary), Number, percentage of survival: Durva 1500 mg 47.4 (42.4 to 52.3); Treme 300 mg x1 Dose + Durva 1500 mg 48.7 (43.6 to 53.5); Treme 75 mg x4 Doses + Durva 1500 mg 46.4 (38.4 to 54.1); Sora 400 mg 41.5 (36.5 to 46.4)
• Progression Free Survival (PFS) (Secondary), Median, months: Durva 1500 mg 3.65 (3.19 to 3.75); Treme 300 mg x1 Dose + Durva 1500 mg 3.78 (3.68 to 5.32); Treme 75 mg x4 Doses + Durva 1500 mg 3.65 (2.79 to 4.86); Sora 400 mg 4.07 (3.75 to 5.49)
• Time To Progression (TTP) (Secondary), Median, months: Durva 1500 mg 3.75 (3.68 to 5.42); Treme 300 mg x1 Dose + Durva 1500 mg 5.42 (3.81 to 5.62); Treme 75 mg x4 Doses + Durva 1500 mg 3.75 (3.55 to 5.59); Sora 400 mg 5.55 (5.13 to 5.75)
• Objective Response Rate (ORR) (Secondary), Count of participants, Participants: Durva 1500 mg 66; Treme 300 mg x1 Dose + Durva 1500 mg 79; Treme 75 mg x4 Doses + Durva 1500 mg 26; Sora 400 mg 20
• Disease Control Rate (DCR) (Secondary), Count of participants, Participants: Durva 1500 mg 213; Treme 300 mg x1 Dose + Durva 1500 mg 236; Treme 75 mg x4 Doses + Durva 1500 mg 89; Sora 400 mg 236
• Duration of Objective Response (DoR) (Secondary), Median, months: Durva 1500 mg 16.82 (7.43 to NA); Treme 300 mg x1 Dose + Durva 1500 mg 22.34 (8.54 to NA); Treme 75 mg x4 Doses + Durva 1500 mg 14.75 (7.46 to 14.75); Sora 400 mg 18.43 (6.51 to 25.99)
• Overall Survival (OS) by PD-L1 (Secondary), Median, months: Durva 1500 mg 17.22 (12.29 to 24.38); Treme 300 mg x1 Dose + Durva 1500 mg 17.00 (13.11 to 22.31); Treme 75 mg x4 Doses + Durva 1500 mg 24.21 (14.55 to 27.24); Sora 400 mg 15.93 (10.68 to 21.72)
• EORTC QLQ-C30 Time to Global Health Status/QoL Deterioration (Secondary), Median, months: Durva 1500 mg 7.4 (5.68 to 9.33); Treme 300 mg x1 Dose + Durva 1500 mg 7.5 (5.82 to 10.84); Treme 75 mg x4 Doses + Durva 1500 mg 7.3 (5.65 to 9.33); Sora 400 mg 5.7 (4.80 to 7.39)
• EORTC QLQ-HCC18 Time to Symptom (Abdominal Pain) Deterioration (Secondary), Median, months: Durva 1500 mg 14.1 (9.46 to 24.41); Treme 300 mg x1 Dose + Durva 1500 mg 16.8 (11.17 to NA); Treme 75 mg x4 Doses + Durva 1500 mg 14.7 (8.97 to 36.04); Sora 400 mg 8.9 (7.23 to 11.14)
• EORTC QLQ-HCC18 Time to Symptom (Shoulder Pain) Deterioration (Secondary), Median, months: Durva 1500 mg 16.0 (9.03 to 22.31); Treme 300 mg x1 Dose + Durva 1500 mg 12.6 (9.23 to 19.58); Treme 75 mg x4 Doses + Durva 1500 mg 13.8 (6.47 to 19.19); Sora 400 mg 9.4 (7.46 to 13.37)
• EORTC QLQ-HCC18 Time to Symptom (Abdominal Swelling) Deterioration (Secondary), Median, months: Durva 1500 mg 16.7 (9.46 to 24.8); Treme 300 mg x1 Dose + Durva 1500 mg 20.9 (12.88 to 36.01); Treme 75 mg x4 Doses + Durva 1500 mg 11.3 (5.78 to 19.19); Sora 400 mg 11.1 (9.26 to 13.73)
• Presence of ADA for Durvalumab (Secondary), Count of participants, Participants: Durva 1500 mg 8; Treme 300 mg x1 Dose + Durva 1500 mg 9; Treme 75 mg x4 Doses + Durva 1500 mg 5; Sora 400 mg
• Presence of ADA for Tremelimumab (Secondary), Count of participants, Participants: Durva 1500 mg ; Treme 300 mg x1 Dose + Durva 1500 mg 20; Treme 75 mg x4 Doses + Durva 1500 mg 23; Sora 400 mg
• Summary of Durvalumab Concentration Over Time (Secondary), Geometric mean, ug/mL: Durva 1500 mg 74.7 +/- 86.7; Treme 300 mg x1 Dose + Durva 1500 mg 59.9 +/- 101.6; Treme 75 mg x4 Doses + Durva 1500 mg 65.1 +/- 68.4; Sora 400 mg
• Summary of Tremelimumab Concentration Over Time (Secondary), Geometric mean, ug/mL: Durva 1500 mg ; Treme 300 mg x1 Dose + Durva 1500 mg 78.0 +/- 117.2; Treme 75 mg x4 Doses + Durva 1500 mg ; Sora 400 mg

Adverse events

Time frame: All treatment-emergent adverse events (TEAEs) were collected up to the final analysis DCO (27Aug2021, to a maximum of approximately 46 months).

Serious adverse events by term

230 more terms not shown.

Other adverse events by term

60 more sites not listed.

• Results publication: Rimassa L, Chan SL, Sangro B, Lau G, Kudo M, Reig M, Breder V, Ryu MH, Ostapenko Y, Sukeepaisarnjaroen W, Varela M, Tougeron D, Crysler OV, Bouattour M, Dao TV, Tam VC, Faccio A, Furuse J, Jeng LB, Kang YK, Kelley RK, Kurland JF, Balaji K, Abou-Alfa GK. Plain language summary of five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma (liver cancer). Future Oncol. 2026 May;22(12):1359-1372. doi: 10.1080/14796694.2026.2665323. Epub 2026 May 10. PMID 42108643
• Results publication: Chan SL, Kudo M, Sangro B, Kelley RK, Kim JH, Pham B, Hong JY, Waldschmidt DT, Marino D, Joycelyn Lee JX, Gerolami R, Burgoyne AM, Li Q, Nakamura H, Sun P, Baur B, Rimassa L. Early Safety Results from the Phase 3b SIERRA Study of Durvalumab and Tremelimumab as First-Line Treatment for Participants with Unresectable Hepatocellular Carcinoma and a Poor Prognosis. Liver Cancer. 2025 Dec 18. doi: 10.1159/000549955. Online ahead of print. PMID 41585428
• Results publication: Rimassa L, Chan SL, Sangro B, Lau G, Kudo M, Reig M, Breder V, Ryu MH, Ostapenko Y, Sukeepaisarnjaroen W, Varela M, Tougeron D, Crysler OV, Bouattour M, Van Dao T, Tam VC, Faccio A, Furuse J, Jeng LB, Kang YK, Kelley RK, Paskow MJ, Ran D, Xynos I, Kurland JF, Negro A, Abou-Alfa GK. Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC. J Hepatol. 2025 Oct;83(4):899-908. doi: 10.1016/j.jhep.2025.03.033. Epub 2025 Apr 11. PMID 40222621
• Results publication: Lau G, Abou-Alfa GK, Cheng AL, Sukeepaisarnjaroen W, Van Dao T, Kang YK, Thungappa SC, Kudo M, Sangro B, Kelley RK, Furuse J, Park JW, Sunpaweravong P, Fasolo A, Yau T, Kawaoka T, Azevedo S, Reig M, Assenat E, Yarchoan M, He AR, Makowsky M, Gupta C, Negro A, Chan SL. Outcomes in the Asian subgroup of the phase III randomised HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. J Hepatol. 2025 Feb;82(2):258-267. doi: 10.1016/j.jhep.2024.07.017. Epub 2024 Jul 31. PMID 39089633
• Results publication: Sangro B, Galle PR, Kelley RK, Charoentum C, De Toni EN, Ostapenko Y, Heo J, Cheng AL, Wilson Woods A, Gupta C, Abraham J, McCoy CL, Patel N, Negro A, Vogel A, Abou-Alfa GK. Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2024 Aug 10;42(23):2790-2799. doi: 10.1200/JCO.23.01462. Epub 2024 May 28. PMID 38805668
• Results publication: Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgue A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. doi: 10.1056/EVIDoa2100070. Epub 2022 Jun 6. PMID 38319892
• Results publication: Addendum 1: Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma. J Immunother Cancer. 2023 Sep;11(9):e002794add1. doi: 10.1136/jitc-2021-002794add1. No abstract available. PMID 37678916
• Results publication: Patel TH, Brewer JR, Fan J, Cheng J, Shen YL, Xiang Y, Zhao H, Lemery SJ, Pazdur R, Kluetz PG, Fashoyin-Aje LA. FDA Approval Summary: Tremelimumab in Combination with Durvalumab for the Treatment of Patients with Unresectable Hepatocellular Carcinoma. Clin Cancer Res. 2024 Jan 17;30(2):269-273. doi: 10.1158/1078-0432.CCR-23-2124. PMID 37676259

• Study Protocol (PDF, 2024-06-17)
• Statistical Analysis Plan (PDF, 2021-07-30)

NIH grants: 2016