Clinical trialPhase 3Liver cancer

Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma

Journal of Hepatology · 2022501 patients (intention-to-treat population)

Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Journal of Hepatology. 2022. 76:862-873

Study type: Clinical trial
Study name: IMbrave150
Phase: Phase 3
Design: Open-label randomised trial with 2:1 randomisation; this report is an updated post hoc analysis of efficacy and safety.
Sample size: 501 patients (intention-to-treat population)
Source: Journal of Hepatology · 2022
Trial registration: NCT03434379

In plain words

This study compared a combination of two drugs, atezolizumab and bevacizumab, with the oral drug sorafenib in people with advanced liver cancer that could not be removed by surgery and who had not yet had any drug treatment for it. After longer follow-up, people who received atezolizumab and bevacizumab lived on average about 5.8 months longer than those in the sorafenib group (19.2 months versus 13.4 months). Serious side effects were similar in the two groups and matched the results of the first analysis. Treatment decisions should always be made with your own doctor, based on each patient's situation.

Key results

15.6 months (range 0–28.6)

Median follow-up

Data cutoff 31 August 2020; median follow-up at the primary analysis was 8.6 months

19.2 months (95% CI 17.0–23.7) vs 13.4 months (95% CI 11.4–16.9)

Median overall survival (OS)

HR 0.66; 95% CI 0.52–0.85; descriptive P < 0.001

6.9 months (95% CI 5.7–8.6) vs 4.3 months (95% CI 4.0–5.6)

Median progression-free survival (PFS)

HR 0.65; 95% CI 0.53–0.81; descriptive P < 0.001

143 (43%) of 329 vs 72 (46%) of 156

Treatment-related grade 3/4 adverse events

Atezolizumab + bevacizumab vs sorafenib

6 (2%) vs 1 (less than 1%)

Treatment-related grade 5 adverse events

Drugs in this study:Bevacizumab (Avastin)Sorafenib (Nexavar)Atezolizumab (Tecentriq)

Dose and schedule cards

Atezolizumab + bevacizumab (IMbrave150)

Unresectable or metastatic HCC, no prior systemic therapy; in the trial: Child-Pugh A and ECOG 0–1Cycle length: Every 21 daysOn the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Unresectable or metastatic HCC, no prior systemic therapy; in the trial: Child-Pugh A and ECOG 0–1

Drug	Dose	Route	Schedule
Atezolizumab	1200 mg (or 840 mg every 2 weeks or 1680 mg every 4 weeks)	IV; first infusion over 60 min, subsequent infusions over 30 min if tolerated	Day 1, before bevacizumab
Bevacizumab	15 mg/kg	IV	Day 1, after atezolizumab

Cycle length: Every 21 days
Duration: Until progression or intolerable toxicity; if one of the two drugs is discontinued, the other may be continued alone

IMbrave150 exclusion criteria: untreated or incompletely treated varices with a high risk of bleeding, variceal bleeding within the past 6 months, Child-Pugh B or C, moderate to severe ascites, history of hepatic encephalopathy, and autoimmune disease. Stop bevacizumab at least 28 days before elective surgery and do not start it until 28 days after major surgery and until the wound has healed.

Bevacizumab monitoring: blood pressure every 2 to 3 weeks and periodic urine dipstick testing for proteinuria.

Modifications: dose reduction is not recommended for either drug; atezolizumab is withheld for grade 3 immune-related adverse events and permanently discontinued for grade 4 (for hepatitis with tumour involvement of the liver, separate ALT/AST thresholds are given in the label). Bevacizumab is withheld for proteinuria of 2 g or more per 24 hours until it falls below 2 g, and permanently discontinued for nephrotic syndrome, grade 3 or 4 haemorrhage, gastrointestinal perforation or hypertensive crisis.

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

Atezolizumab + bevacizumab (IMbrave150)

Unresectable or metastatic hepatocellular carcinoma without prior systemic therapyOn the page “Atezolizumab (Tecentriq)” · Combination regimens (FDA label)

Unresectable or metastatic hepatocellular carcinoma without prior systemic therapy

Drug	Dose	Route	Schedule
Atezolizumab	840 mg every 2 weeks, or 1200 mg every 3 weeks, or 1680 mg every 4 weeks	IV, before bevacizumab	Day 1
Bevacizumab	15 mg/kg	IV	Every 3 weeks

Cycle length: Every 21 days (with the 1200 mg dose)
Duration: Until progression or unacceptable toxicity

In IMbrave150, patients were assessed for varices within 6 months before treatment, and untreated or incompletely treated varices with bleeding or at high risk of bleeding were an exclusion criterion; variceal bleeding was the most common cause of death from an adverse event (1.2%).

On the page “Atezolizumab (Tecentriq)” · Combination regimens (FDA label)

Atezo/Bev

Advanced liver cancer, first lineCycle length: Every 21 daysOn the page “Atezolizumab with bevacizumab in liver cancer”

Advanced liver cancer, first line

Drug	Dose	Route	Schedule
Atezolizumab	1200 mg	IV	Day 1
Bevacizumab	15 mg/kg	IV	Day 1

Cycle length: Every 21 days
Duration: Until progression or toxicity

As in IMbrave150.

Dose source:.

On the page “Atezolizumab with bevacizumab in liver cancer”

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

1Atezolizumab plus bevacizumab — 336 patients

Atezolizumab 1200 mg IV infusion followed on the same day by bevacizumab 15 mg/kg IV, on day 1 of each 21-day cycle, until unacceptable toxicity or loss of clinical benefit. If one of the two drugs was discontinued (e.g. because of an adverse event), the other could be continued alone (FDA label).

2Sorafenib — 165 patients

Sorafenib 400 mg orally twice daily, days 1 to 21 of each 21-day cycle, until unacceptable toxicity or loss of clinical benefit.

Source of the regimen details: Abstract of the paper (doses); this paper is a follow-up report and the regimen is that of the original IMbrave150 trial: ClinicalTrials.gov NCT03434379 (Interventions section) and the FDA label for Tecentriq (DailyMed, IMbrave150 study section)

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 unresectable locally advanced and/or metastatic HCC who had received no prior systemic therapy, with ECOG 0 or 1 and Child-Pugh A liver function. According to the FDA label: assessment of varices within 6 months before treatment was required, and patients with variceal bleeding within the past 6 months, untreated or incompletely treated varices with bleeding, or a high risk of bleeding were excluded; Child-Pugh B or C cirrhosis, moderate or severe ascites, history of hepatic encephalopathy, history of autoimmune disease and untreated or corticosteroid-dependent brain metastases were also exclusion criteria. 82% of patients had BCLC stage C disease and about 75% had macrovascular invasion and/or extrahepatic spread.

Endpoints

Primary (co-primary) endpoints: overall survival (OS) and progression-free survival (PFS) per RECIST 1.1 by independent assessment, in the intention-to-treat population. Secondary efficacy endpoints: objective response rate and exploratory subgroup analyses.

Safety and side effects

Treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 patients in the atezolizumab + bevacizumab group and 72 (46%) of 156 patients in the sorafenib group. Treatment-related grade 5 events were reported in 6 patients (2%) and 1 patient (less than 1%), respectively. The authors judged the safety profile to be consistent with the primary analysis.

Clinical significance and place in guidelines

This updated analysis shows that the superiority of atezolizumab plus bevacizumab over sorafenib in overall survival and progression-free survival is maintained with longer follow-up and that the safety profile is unchanged. The authors consider this regimen the standard first-line treatment for advanced hepatocellular carcinoma. The exact status of drug approvals and guideline recommendations should be checked separately.

Limitations

This report is an updated post hoc analysis and its P values are descriptive. The study is open-label. Subgroup analyses are exploratory. Treatment-related grade 5 events were numerically more frequent in the atezolizumab + bevacizumab group (6 versus 1 patient).

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.