Combination of Atezolizumab and Bevacizumab Shows Early Efficacy in Unresectable HCC

Atezolizumab in combination with bevacizumab induced objective responses in patients with unresectable hepatocellular carcinoma, according to results presented at the 2019 ESMO Congress from 2 small clinical trials. 

Michael Lee, MD

Atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) induced objective responses in patients with unresectable hepatocellular carcinoma (HCC), according to results presented at the 2019 ESMO Congress from 2 small clinical trials.

Clinically meaningful responses were seen in more than one-third of patients in an uncontrolled evaluation of the combination, three-fourths of which were ongoing with a median follow-up exceeding a year. A randomized trial showed that the combination reduced the risk of disease progression or death by 45% versus atezolizumab monotherapy.

“In both arms, the combination of atezolizumab and bevacizumab was generally well tolerated, and toxicities were manageable,” said Michael Lee, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill. “The combination of atezolizumab and bevacizumab may become a promising treatment option for patients with unresectable hepatocellular carcinoma. The combination is being evaluated in the phase III IMbrave150 study.”

Invited discussant Arndt Vogel, MD, of the University of Hannover in Germany, said the two small trials demonstrated “impressive” activity with the combination in a population of patients with advanced disease. Collectively, the studies provided a clear signal to proceed to phase III evaluation, but he noted several questions that require answers.

“What is not yet clear is whether the effects are synergistic or additive,” said Vogel. “Can bevacizumab really turn cold tumors into hot tumors? Who needs to be treated with the doublet with respect to the risk-benefit balance?”

VEGF receptor tyrosine kinase inhibitors represent the global first-line standard for system treatment of unresectable or metastatic HCC. The drugs offer a modest survival benefit and come at a cost of considerable toxicity, said Lee.

Bevacizumab has demonstrated modest single-agent activity in HCC, he continued. PD-1/L1 immune checkpoint inhibitors have demonstrated activity but have yet to show superiority in randomized studies of advanced HCC.

The rationale for combining an angiogenesis inhibitor and a PD-L1 inhibitor includes evidence that many HCC tumors exhibit hypervascularity and over express VEGF and PD-L1.

“VEGF inhibition may help reverse VEGF-mediated immunosuppression and enhance anticancer immunity,” said Lee. “Dual blockade of PD-L1 and VEGF has shown clinical benefit in other tumor types.”

Investigators in the United States, Japan, South Korea, and Taiwan conducted two studies of the atezolizumab-bevacizumab combination in patients with unresectable/metastatic HCC. The first trial involved 104 patients with no prior systemic therapy. All of the patients received atezolizumab at 1200 mg every 3 weeks plus bevacizumab at 15 mg/kg every 3 weeks. In the second study, investigators randomized 119 patients with untreated HCC to the same combination or to single-agent atezolizumab.

The first study had primary endpoints of safety and objective response by independent review. In the randomized study, PFS by independent review and safety were the primary endpoints.

In the single-arm trial, the patients had a median age of 62, men accounted for 81% of the study population, 57% of the patients were from Asia (excluding Japan), the HCC origin was hepatitis B (HBV) in 49%, hepatitis C (HCV) in 30%, and nonviral in 21%. More than half of the patients had undergone transarterial chemoembolectomy (TACE), and 19% had been treated with radiotherapy.

The results showed that 37 (36%) patients had confirmed responses, including a complete response rate of 12%. An additional 37 patients had stable disease, resulting in a disease control rate of 71%.

Lee said 28 of 37 responses were ongoing after a median follow-up of 12.4 months. Median duration of response had yet to be reached, and response duration ranged from 1.6 to 31 months. Responses persisted 9 months or longer in 20 (54%) cases and 12 months or longer in 11 (30%).

The study population in the single-arm trial had a median PFS of 7.3 months, 54% remained alive and free of progression at 6 months and 35% had not progressed at 12 months. The median overall survival (OS) was 17.1 months, 6-month OS was 82%, and 12-month OS was 63%.

In the randomized study, the patient population had a median age of 60 to 63 years, men accounted for about 85% of the patients, and 65% of the patients were from Asia. The distribution of disease etiology (viral vs nonviral) was similar to the first trial, as was prior treatment with TACE and/or radiotherapy.

After a median follow-up of 6.6 months, 35 (58%) PFS events had occurred in the combination arm as compared with 39 (66%) among patients randomized to single-agent atezolizumab. The difference translated into a hazard ratio of 0.55 in favor of the combination (P = .0108). The combination arm had a median PFS of 5.6 months versus 3.4 months for the atezolizumab control group.

Lee reported that 12 (20%) patients had confirmed responses with the combination and 10 (17%) with atezolizumab alone. An additional 28 (47%) in the combination arm had stable disease compared with 19 (32%) in the control group, resulting in DCR of 67% with the combination and 49% with atezolizumab alone.

The patients randomized to the combination had a median treatment duration of about 5 months with each of the two drugs, as compared with 1.6 months in the patients who received single-agent atezolizumab. Treatment-related adverse events (TRAEs, all grades) occurred in 68% and 41% of the two arms, respectively.

Grade 3/4 adverse events occurred in 37% of the combination group and 14% of the atezolizumab group. The events were considered treatment related in 20% and 5% of patients, respectively. Serious adverse events occurred in 25% of the combination group and 10% of the atezolizumab group and were considered treatment related in 12% and 3% of cases, respectively. Lee said 2% to 3% of patients in each treatment arm discontinued because of adverse events.

The most common adverse events in the combination arm were proteinuria (23%, 5% grade 3/4), fatigue (20%), rash (20%), diarrhea, hypertension, and abdominal pain (15% each). The most common grade 3/4 adverse events were proteinuria and hypertension (5% each). Among patients treated with single-agent atezolizumab, common adverse events consisted of decreased appetite (15%), diarrhea (12%), fatigue (10%), and rash (10%). Grade 3/4 adverse events consisted of a single case of hypertension.


Lee M, Ryoo B-Y, Hsu C-H, et al. Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA39.