On May 29, 2020, atezolizumab in combination with bevacizumab was approved for treatment of patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.^1-3

Supporting Efficacy Data

Approval was based on findings in the international, open-label, phase III IMbrave150 trial (Clinical Trials.gov identifier NCT03434379).^2-4 In the trial, 501 patients with locally advanced unresectable or metastatic disease who had not received prior systemic therapy were randomly assigned 2:1 to receive atezolizumab at 1,200 mg followed by bevacizumab at 15 mg/kg on the same day every 3 weeks (n = 329) or sorafenib at 400 mg twice daily (n = 156), continuing treatment until disease progression or unacceptable toxicity. Patients could discontinue atezolizumab or bevacizumab (eg, for adverse reactions) and continue on single-agent therapy until disease progression or unacceptable toxicity.

Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. They were required to be evaluated for varices within 6 months prior to treatment and were excluded if they had variceal bleeding within the previous 6 months, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients were excluded from the trial if they had Child-Pugh B or C cirrhosis, moderate or severe ascites, a history of hepatic encephalopathy, a history of autoimmune disease, had received a live attenuated vaccine within 4 weeks prior to randomization, had received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive agents within 2 weeks prior to randomization, or had untreated or corticosteroid-dependent brain metastases.

Median patient age was 65 years (range = 26–88 years); 83% were male, 57% were Asian, 35% were white, and 40% were from Asia (excluding Japan). Approximately 75% presented with macrovascular invasion or extrahepatic spread, 37% had baseline alpha-fetoprotein ≥ 400 ng/mL, and ECOG performance status was 0 in 62% and 1 in 38%. Overall, risk factors for hepatocellular carcinoma were hepatitis B in 48%, hepatitis C in 22%, and nonviral in 31%. Barcelona Clinic Liver Cancer stage was C in 82%, B in 16%, and A in 3%.

The main efficacy outcome measures were overall survival and independent review facility–assessed progression-free survival using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Additional efficacy outcome measures were independent review facility–assessed overall response rate on RECIST version 1.1 and modified RECIST (mRECIST).

Median overall survival was not reached in patients receiving atezolizumab/bevacizumab and was 13.2 months (95% confidence interval [CI]= 10.4 months to not estimable) for those receiving sorafenib (hazard ratio [HR] = 0.58, 95% CI = 0.42–0.79, P = .0006). Median progression-free survival was 6.8 months (95% CI = 5.8–8.3 months) vs 4.3 months (95% CI = 4.0–5.6 months; HR = 0.59, 95% CI = 0.47–0.76, P < .0001). Objective response rates on RECIST version 1.1 were 28% vs 12% (P < .0001), including complete response in 7.0% vs 0%, with median response durations of not estimable (range = 1.3+ to 13.4+ months) vs 6.3 months (range = 1.4+ to 9.1+ months). Response rates on mRECIST were 33% vs 13% (P < .0001), with median response durations of not estimable vs 6.3 months.

How It Is Used

For the current indication, the recommended dosages for the combination are atezolizumab at 1,200 mg via infusion over 60 minutes, followed by bevacizumab at 15 mg/kg via infusion over 90 minutes on the same day, administered every 3 weeks until disease progression or unacceptable toxicity. If bevacizumab is discontinued for toxicity, the recommended dosage of atezolizumab is 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks until disease progression or unacceptable toxicity.

If the first infusion of atezolizumab is tolerated, subsequent infusions can be given over 30 minutes. If the first infusion of bevacizumab is tolerated, the second infusion can be given over 60 minutes; if this is tolerated, subsequent infusions can be given over 30 minutes.

No dose reductions for atezolizumab are recommended. Infusion should be slowed or interrupted for grade 1 or 2 infusion reactions and permanently discontinued for grade 3 or 4 reactions.

No dose reductions of bevacizumab are recommended. Infusion should be discontinued for severe infusion-related reactions, interrupted for clinically significant reactions, and resumed at a decreased rate after resolution of symptoms; and decreased in rate for mild, clinically insignificant reactions.

Atezolizumab prescribing information provides instructions for atezolizumab dosage modification, advising withholding and discontinuation of treatment for adverse reactions including pneumonitis; hepatitis in patients with cancers other than hepatocellular carcinoma; hepatitis in patients with hepatocellular carcinoma; colitis or diarrhea endocrinopathies, including but not limited to hypophysitis, adrenal insufficiency, hyperthyroidism, and type 1 diabetes; other immune-mediated adverse reactions involving a major organ; infections; infusion-related reactions; persistent grade 2 or 3 adverse reactions (excluding endocrinopathies); inability to taper corticosteroid treatment; and recurrent grade 3 or 4 adverse reactions.

Bevacizumab should be withheld for at least 28 days prior to elective surgery and should not be administered until at least 28 days following surgery and full wound healing. Prescribing information provides instructions for dosage modification, including withholding and discontinuation of treatment for adverse reactions including gastrointestinal perforations and fistulae, wound healing complications, hemorrhage, thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, renal injury and proteinuria, infusion-related reactions, and congestive heart failure.

Safety Profile

In IMbrave150, median durations of exposure were 7.4 months (range = 0–16 months) for atezolizumab and 6.9 months (range = 0–16 months) for bevacizumab.

The most common adverse events of any grade (at least 15% of patients) with atezolizumab/bevacizumab were hypertension (30% vs 24% in sorafenib group), fatigue/asthenia (26% vs 32%), proteinuria (20% vs 7%), pruritus (19% vs 10%), diarrhea (19% vs 49%), decreased appetite (18% vs 24%), and pyrexia (18% vs 10%). The most common grade 3 or 4 adverse events included hypertension (15% vs 12%) and proteinuria (3% vs < 1%). The most common grade 3 or 4 laboratory abnormalities were increases in aspartate transaminase (16% vs 16%), decreased lymphocytes (13% vs 11%), decreased sodium (13% vs 9%), and increased glucose (9% vs 5%).

Serious adverse events occurred in 38% of patients receiving atezolizumab/bevacizumab, the most common being hemorrhage (7%), infections (6%), and pyrexia (2.1%).

Adverse events led to interruption of atezolizumab therapy in 41% of patients (the most common causes being liver function laboratory abnormalities in 8% and infections in 6%) and to interruption of bevacizumab administration in 46% (the most common causes being proteinuria, infections, and hypertension in 6% each). Adverse events led to discontinuation of atezolizumab therapy in 9% of patients, the most common causes being hemorrhage (1.2%), increased transaminases or bilirubin (1.2%), infusion-related reaction/cytokine-release syndrome (0.9%), and autoimmune hepatitis (0.6%). Bevacizumab was discontinued due to adverse events in 15%, the most common causes being hemorrhage (4.9%) and increased transaminases or bilirubin (0.9%). Immune-related adverse events requiring systemic corticosteroid therapy occurred in 12% of patients. Adverse events led to death in 4.6% of patients, the most common causes being gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).

Atezolizumab has warnings/precautions for immune-related pneumonitis, immune-related hepatitis, immune-related colitis, immune-related endocrinopathies (including hypophysitis, thyroid disorders, adrenal insufficiency, and type 1 diabetes), infections, infusion-related reactions, and embryofetal toxicity. Patients should be monitored for changes in liver function and changes in thyroid function. Patients should be advised not to breastfeed while receiving atezolizumab.

Bevacizumab has warnings/precautions for gastrointestinal perforations and fistula; surgery and wound complications; hemorrhage, including severe and fatal hemorrhage; arterial thromboembolic events; venous thromboembolic events; hypertension; posterior reversible encephalopathy syndrome; renal injury and proteinuria; infusion-related reactions; embryofetal toxicity; ovarian failure; and congestive heart failure. Blood pressure and urine protein should be monitored. Patients should be advised not to breastfeed while receiving bevacizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma. Accessed June 8, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Tencentriq (atezolizumab) injection. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761034s025lbl.pdf. Accesses June 8, 2020.

3. U.S. Food and Drug Administration: Highlights of prescribing information for Avastin (bevacizumab) injection. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125085s332lbl.pdf. Accessed June 8, 2020.

4. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.