Clinical trialPhase 3Liver cancer

Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma

Annals of Oncology · 20241171 patients (393 in the STRIDE group, 389 in the durvalumab group and 389 in the sorafenib group)

Sangro B, Chan S, Kelley R, Lau G, Kudo M, Sukeepaisarnjaroen W, et al. Annals of Oncology. 2024. 35:448-457

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: Phase 3 randomised trial; four-year overall survival update (data cut-off: 23 January 2023)
Sample size: 1171 patients (393 in the STRIDE group, 389 in the durvalumab group and 389 in the sorafenib group)
Source: Annals of Oncology · 2024
Trial registration: NCT03298451

In plain words

In this study, patients with advanced liver cancer that could not be operated on and who had not yet had any drug treatment for the whole body were treated with a combination of two immunotherapy drugs (tremelimumab and durvalumab, the STRIDE regimen) or with the drug sorafenib. After about four years of follow-up, more of the patients who had received STRIDE were still alive: 25.2% of them were alive after 48 months, versus 15.1% in the sorafenib group. No new serious side effects were seen during the long follow-up.

Key results

49.12 months / 48.46 months / 47.31 months

Median follow-up (STRIDE / durvalumab / sorafenib)

95% CI 46.95–50.17 / 46.82–49.81 / 45.08–49.15 months

0.78

Hazard ratio for overall survival (STRIDE vs sorafenib)

95% CI 0.67–0.92

30.7% vs 19.8%

36-month overall survival rate (STRIDE vs sorafenib)

25.2% vs 15.1%

48-month overall survival rate (STRIDE vs sorafenib)

57.3% (59 of 103)

Long-term survivors in the STRIDE group without subsequent anticancer therapy

Total long-term survivors in the STRIDE group: 103

Non-inferiority for overall survival was maintained

Durvalumab vs sorafenib

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)

393 patients. 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)

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

3Sorafenib (control group)

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

Source of the regimen details: This paper is a follow-up report and gives no doses; the regimen is that of the original HIMALAYA trial: abstract of the original paper (NEJM Evid 2022) and 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

In this update, overall survival (OS) and serious adverse events were assessed. Baseline characteristics and subsequent treatments in long-term survivors (36 months or more after randomisation) were also analysed.

Safety and side effects

In the STRIDE group, no new serious treatment-related adverse events occurred compared with the primary analysis (17.5%; 68 of 388). No late safety signal was identified in the durvalumab group either.

Clinical significance and place in guidelines

This update shows that the overall survival advantage of STRIDE over sorafenib was sustained at four-year follow-up, and no new late safety signal was reported. Durvalumab alone also maintained non-inferiority to sorafenib. The status of approvals and guideline recommendations should be checked in current official sources; the abstract gives no information on them.

Limitations

The abstract does not state the limitations of the study. The analysis of long-term survivors (36 months or more) is descriptive, and further details on methodology and doses are in the full text of the paper.

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.