Clinical trialPhase 3Liver cancer

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

N Engl J Med · 2020501 patients (336 atezolizumab + bevacizumab, 165 sorafenib)

Finn RS, Qin S, Ikeda M, et al. N Engl J Med. 2020. 382:1894-1905

A newer report of this study has been published: Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma (2022)

Study type: Clinical trial
Study name: IMbrave150
Phase: Phase 3
Design: Randomised, open-label, global trial; 2:1 randomisation
Sample size: 501 patients (336 atezolizumab + bevacizumab, 165 sorafenib)
Source: N Engl J Med · 2020
Trial registration: NCT03434379

In plain words

This large study showed for the first time that combining an immunotherapy drug (atezolizumab) with a drug that blocks the growth of the tumour's blood vessels (bevacizumab) helps people with advanced liver cancer live significantly longer than sorafenib tablets, the standard treatment at the time. Both drugs are given as an infusion into a vein once every three weeks. Because bevacizumab carries a risk of bleeding, an endoscopy is usually done before treatment starts to look for swollen veins in the oesophagus (varices), and blood pressure must be checked regularly.

Key results

HR 0.58

Hazard ratio for death (primary analysis)

95% CI 0.42–0.79; P<0.001; data cutoff 29 August 2019

67.2% vs 54.6%

12-month overall survival

95% CI 61.3–73.1 vs 45.2–64.0

6.8 vs 4.3 months

Median progression-free survival

HR 0.59 (95% CI 0.47–0.76); P<0.001

28% vs 12%

Objective response rate (RECIST 1.1, independent review)

Complete response 7% vs 0; per mRECIST: 33% vs 13%; FDA label

19.2 vs 13.4 months

Median overall survival (updated analysis)

HR 0.66 (95% CI 0.52–0.85); median follow-up 15.6 months; Cheng AL et al., J Hepatol 2022 (PMID 34902530)

6.9 vs 4.3 months

Median progression-free survival (updated analysis)

HR 0.65 (95% CI 0.53–0.81); Cheng AL et al., J Hepatol 2022

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 + bevacizumab

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 (control group)

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: ClinicalTrials.gov NCT03434379 (Interventions section: atezolizumab 1200 mg and bevacizumab 15 mg/kg IV on day 1 every 21 days; sorafenib 400 mg twice daily, days 1 to 21); FDA label for Tecentriq (DailyMed, IMbrave150 study section); abstract of the updated analysis Cheng AL, J Hepatol 2022 (PMID 34902530)

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

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 endpoints: objective response rate, safety and patient-reported outcomes.

Safety and side effects

Grade 3 or 4 adverse events occurred in 56.5% of 329 patients in the atezolizumab + bevacizumab group and 55.1% of 156 patients in the sorafenib group. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab + bevacizumab group; other severe events were infrequent.

According to the FDA label (atezolizumab + bevacizumab group): serious adverse events 38% (gastrointestinal haemorrhage 7%, infection 6%); fatal adverse events 4.6% (most common: gastrointestinal and oesophageal variceal haemorrhage 1.2% and infection 1.2%); grade 3 to 4 proteinuria 3%; atezolizumab discontinuation due to adverse events 9% and interruption 41%.

In the updated analysis, treatment-related grade 3 or 4 adverse events occurred in 43% versus 46%, and treatment-related fatal events in 6 patients (2%) versus 1 patient (less than 1%).

Clinical significance and place in guidelines

Based on this study, the FDA approved atezolizumab + bevacizumab in 2020 for first-line treatment of unresectable or metastatic HCC, and the EMA has also approved it. The AASLD 2023 guidance names this combination (alongside durvalumab + tremelimumab) as a preferred first-line option in Child-Pugh A patients (Level 2, Strong) and recommends upper endoscopy to assess varices before starting it.

Limitations

Open-label design (no placebo); short follow-up at the primary analysis (median about 8.6 months), so the median overall survival of the intervention group was reported only in the updated, descriptive (post hoc) analysis; only patients with preserved liver function (Child-Pugh A) were enrolled and treatment of varices was required, which limits generalisability to patients with more advanced cirrhosis or a high bleeding risk.

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.