Clinical trialPhase 3Liver cancer

Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma

NEJM Evid · 20221171 patients (393 STRIDE, 389 durvalumab, 389 sorafenib)

Abou-Alfa GK, Lau G, Kudo M, et al. NEJM Evid. 2022. 1:EVIDoa2100070

A newer report of this study has been published: Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC (2025)

Study type: Clinical trial
Study name: HIMALAYA
Phase: Phase 3
Design: Randomised, open-label, global, three-arm trial (1:1:1)
Sample size: 1171 patients (393 STRIDE, 389 durvalumab, 389 sorafenib)
Source: NEJM Evid · 2022
Trial registration: NCT03298451

In plain words

This study tested a double immunotherapy combination called STRIDE: the drug tremelimumab is given only once at the start of treatment, and durvalumab continues every 4 weeks. Compared with sorafenib tablets, this combination lengthened the lives of patients with advanced liver cancer, and after 4 years about a quarter of patients in the STRIDE group were still alive (versus about 15% with sorafenib). Because this regimen does not include bevacizumab, it is considered a suitable option for some patients at risk of bleeding.

Key results

16.43 (STRIDE) vs 13.77 months (sorafenib)

Median overall survival

HR 0.78 (96.02% CI 0.65–0.93); P=0.0035

30.7% / 24.7% / 20.2%

36-month overall survival

STRIDE, durvalumab and sorafenib, respectively

16.56 vs 13.77 months; non-inferior

Durvalumab monotherapy vs sorafenib

HR 0.86 (95.67% CI 0.73–1.03)

25.2% vs 15.1%

48-month overall survival (4-year follow-up)

STRIDE vs sorafenib; HR 0.78 (95% CI 0.67–0.92); 36-month survival in this analysis 30.7% vs 19.8%; Sangro B et al., Ann Oncol 2024 (PMID 38382875)

Drugs in this study:Sorafenib (Nexavar)Durvalumab (Imfinzi)

Dose and schedule cards

Durvalumab + tremelimumab (STRIDE regimen, HIMALAYA)

Unresectable HCC, no prior systemic therapy (BCLC C, or BCLC B unsuitable for locoregional therapy)Cycle length: Every 28 daysOn the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Unresectable HCC, no prior systemic therapy (BCLC C, or BCLC B unsuitable for locoregional therapy)

Drug	Dose	Route	Schedule
Cycle 1, day 1 (once only)
Tremelimumab	300 mg (body weight less than 30 kg: 4 mg/kg)	IV, 60-min infusion	Single dose; before durvalumab on the same day
From cycle 1
Durvalumab	1500 mg (body weight less than 30 kg: 20 mg/kg)	IV, 60-min infusion	Day 1, every 4 weeks

Cycle length: Every 28 days
Duration: Durvalumab until progression or intolerable toxicity

No antiangiogenic agent; in HIMALAYA, endoscopy before enrollment was not mandatory, but patients with a history of variceal bleeding or at high risk of it required appropriate endoscopic treatment.

Durvalumab monotherapy (1500 mg IV every 4 weeks) was non-inferior to sorafenib in the same trial.

On the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

STRIDE

Advanced liver cancer, first line, Child-Pugh ACycle length: Every 4 weeksOn the page “Durvalumab and tremelimumab in liver cancer (STRIDE)”

Advanced liver cancer, first line, Child-Pugh A

Drug	Dose	Route	Schedule
First dose
Tremelimumab	300 mg	IV	Day 1 (once)
Durvalumab	1500 mg	IV	Day 1, then every 4 weeks

Cycle length: Every 4 weeks
Duration: Until progression

As in HIMALAYA.

Dose source:.

On the page “Durvalumab and tremelimumab in liver cancer (STRIDE)”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1STRIDE (tremelimumab + durvalumab)

Tremelimumab 300 mg IV infusion, a single dose only on day 1 of cycle 1, with durvalumab 1500 mg IV on the same day (tremelimumab before durvalumab); then durvalumab 1500 mg IV every 4 weeks until disease progression or unacceptable toxicity (continuation beyond progression was allowed in clinically stable patients with clinical benefit).

According to the FDA label: for body weight below 30 kg, tremelimumab 4 mg/kg once + durvalumab 20 mg/kg, then durvalumab 20 mg/kg every 4 weeks; tremelimumab is infused over 60 minutes.

2Durvalumab monotherapy

Durvalumab 1500 mg IV infusion every 4 weeks until disease progression or unacceptable toxicity.

3Sorafenib (control group)

Sorafenib 400 mg orally twice daily until disease progression or unacceptable toxicity.

Source of the regimen details: Abstract of the paper (NEJM Evid 2022); FDA labels for Imjudo and Imfinzi (openFDA/DailyMed, dosing and HIMALAYA study sections); ClinicalTrials.gov NCT03298451 (eligibility criteria)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with histologically confirmed unresectable HCC and no prior systemic therapy, BCLC stage C or B (not eligible for locoregional therapy), with Child-Pugh A and ECOG 0 or 1 (ClinicalTrials.gov). Exclusion criteria: hepatic encephalopathy in the past 12 months, clinically significant ascites (according to the FDA label: ascites requiring non-pharmacological intervention in the past 6 months), tumour thrombosis of the main portal vein trunk, active or prior gastrointestinal bleeding in the past 12 months, HBV and HCV or HBV and HDV co-infection, and active or prior autoimmune disease. According to the FDA label, endoscopy before enrolment was not mandatory, but adequate endoscopic treatment was required in patients with a history of variceal bleeding or at high risk of it.

Endpoints

Primary endpoint: overall survival with STRIDE versus sorafenib.

Key secondary endpoint: non-inferiority of overall survival with durvalumab monotherapy versus sorafenib (non-inferiority margin 1.08); also progression-free survival, response and safety.

Safety and side effects

Grade 3 or 4 treatment-emergent adverse events occurred in 50.5% of patients in the STRIDE group, 37.1% in the durvalumab group and 52.4% in the sorafenib group.

According to the FDA label (STRIDE, 388 patients): serious adverse events 41% (haemorrhage 6%, diarrhoea 4%); fatal adverse events 8% (including intracranial haemorrhage, cardiac arrest, pneumonitis, hepatic failure and immune-mediated hepatitis, 0.5% each); permanent discontinuation because of an adverse event 14% and treatment interruption or delay 35%.

At 4-year follow-up, no new serious treatment-related adverse events with STRIDE were seen compared with the primary analysis (17.5%; 68 of 388), and no late safety signal was identified.

Clinical significance and place in guidelines

In 2022 the FDA approved tremelimumab + durvalumab (STRIDE) for unresectable HCC, and the EMA has also approved it. The AASLD 2023 guideline considers this regimen, alongside atezolizumab + bevacizumab, a preferred first-line option in Child-Pugh A patients (Level 2, Strong) and lists it as an alternative for patients with recent gastrointestinal bleeding or untreated high-risk varices.

Limitations

Open-label design; no significant difference in progression-free survival between the groups; exclusion of patients with recent gastrointestinal bleeding, significant ascites or encephalopathy, which limits generalisation of the results to patients with less stable liver function; the comparator was sorafenib, and there has been no direct comparison with atezolizumab + bevacizumab.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.